Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Ovarian High-Grade Serous Carcinoma. Core disease mechanisms, molecular an...

This report is retrieval-only and is generated directly from Asta results.

• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Unveiling drug resistance pathways in high-grade serous ovarian cancer(HGSOC): recent advances and future perspectives

• Authors: Ruiting Fu, Ruiyue Hu, Wenting Li, X. Lv, Hanwei Zhao et al.
• Year: 2025
• Venue: Frontiers in Immunology
• URL: https://www.semanticscholar.org/paper/2f295e8c7119ec53d42252f9fd6519f2938abfa0
• DOI: 10.3389/fimmu.2025.1556377
• PMID: 40370464
• PMCID: 12075240
• Citations: 5
• Summary: The research indicates that HGSOC drug resistance constitutes a complex process characterized by multifactorial interactions, involving aberrant cell signaling pathways, dynamic alterations in the tumor microenvironment, and specific expressions of molecular markers.
• Evidence snippets:
• Snippet 1 (score: 0.609) > High-Grade Serous Ovarian Carcinoma (HGSOC) represents the most prevalent and lethal subtype of ovarian cancer, with approximately 225,000 new cases reported globally each year and a five-year survival rate of merely 49.1%. The clinical management of HGSOC encounters substantial challenges, primarily attributable to its intricate drug resistance mechanisms, which involve multiple biological processes, including tumor cell heterogeneity, microenvironment remodeling, gene mutations, and drug efflux. This study systematically reviews the most recent advancements in HGSOC drug resistance research, concentrating on the molecular biological foundations of resistance mechanisms, innovative detection strategies, and potential therapeutic approaches. The research indicates that HGSOC drug resistance constitutes a complex process characterized by multifactorial interactions, involving aberrant cell signaling pathways, dynamic alterations in the tumor microenvironment, and specific expressions of molecular markers. In this review, we systematically analyzed and investigated the intricate biological behaviors associated with HGSOC drug resistance, which not only enhances the understanding of disease progression but also provides essential theoretical foundations for the development of more precise and effective targeted therapies. This review firstly illustrated the detailed drug resistance cellular and molecular mechanisms underlying HGSOC chemotherapy, which can pave the way for future studies in HGSOC drug resistance practices.

[2] An evolving story of the metastatic voyage of ovarian cancer cells: cellular and molecular orchestration of the adipose-rich metastatic microenvironment

• Authors: T. Motohara, K. Masuda, M. Morotti, Yiyan Zheng, Salma El-Sahhar et al.
• Year: 2018
• Venue: Oncogene
• URL: https://www.semanticscholar.org/paper/94e8742c8e77f59c6a2648bfdf0d8a9c9c928d7b
• DOI: 10.1038/s41388-018-0637-x
• PMID: 30568223
• PMCID: 6755962
• Citations: 192
• Influential citations: 4
• Summary: The biological mechanisms that regulate the highly orchestrated crosstalk between ovarian cancer cells and various cancer-associated stromal cells in the metastatic tumor microenvironment with regard to the omentum are reviewed to provide further insights into the development of novel therapeutic approaches for patients with advanced ovarian cancer.
• Evidence snippets:
• Snippet 1 (score: 0.592) > cell carcinoma, and mucinous carcinoma [10]. These cancer types are inherently diverse diseases that are characterized by differences in precursor lesions, molecular mechanisms of carcinogenesis, patterns of progression and metastasis, responses to chemotherapy, and clinical outcomes [11][12][13][14]. In the early twenty-first century, a series of morphological and molecular genetic studies led researchers to propose a dualistic model of ovarian carcinogenesis that divided ovarian cancer into two groups: type I and type II [15,16]. High-grade serous carcinoma, which is a prototypical type II tumor, is the most common and extremely aggressive subtype and contributes primarily to the poor prognosis of ovarian cancer patients [5,17,18]. Because of the high metastatic potential of high-grade serous carcinoma, a large proportion of patients are diagnosed at an advanced stage with multiple intraperitoneal disseminated tumors. Furthermore, a marked predilection for the adipose-rich omentum as the site of metastasis can be observed [4,5]. Considering that most ovarian cancer-related deaths are directly attributable to the development of metastatic disease, an in-depth understanding of the cellular and molecular aspects of ovarian cancer metastasis is crucial to overcome this life-threatening disease [19][20][21]. > Over a century ago, the English surgeon Stephen Paget proposed the "seed and soil" hypothesis, which stated that the pattern of metastasis is not random and that the development of cancer metastasis depends on the crosstalk between particular cancer cells "the seeds" and a specific organ microenvironment "the soil" [22,23]. Since then, extensive efforts have been made to evaluate the reciprocal interactions between cancer cells and tumor microenvironments, which are heterogeneously composed of different cell types, including fibroblasts, endothelial cells, adipocytes, various bone marrow-derived cells, such as myeloidderived suppressor cells, mesenchymal stem cells (MSCs), and macrophages [24,25]. Researchers have shown that a host of strom

[3] ARID1A restrains EMT and stemness of ovarian cancer cells through the Hippo pathway

• Authors: Shouying Xu, Chongying Zhu, Qiang Xu, Zihao An, Shu Xu et al.
• Year: 2024
• Venue: International Journal of Oncology
• URL: https://www.semanticscholar.org/paper/8ce03dc5d9407a55746931638d38d135aa767197
• DOI: 10.3892/ijo.2024.5664
• PMID: 38873993
• PMCID: 11251745
• Citations: 17
• Summary: The role of ARID1A through the Hippo/TAZ pathway in modulating EMT and stemness of ovarian cancer cells is uncovered, providing with evidence that TAZ inhibitors could effectively prevent initiation and metastasis of ovarian cancer cases where ARID1A is lost or mutated.
• Evidence snippets:
• Snippet 1 (score: 0.590) > Ovarian cancer, one of the most lethal gynecological malignancies, affects 240,000 women worldwide annually, with a five-year survival rate <45% (1).Ovarian cancers can be classified into different types based on clinical behavior, histopathology, and molecular and genetic analyses.These include type I (low-grade serous carcinomas, low-grade endometrioid carcinomas, clear cell carcinomas and sero-mucinous carcinomas) and type II (high-grade serous carcinomas, high-grade endometrioid carcinomas and undifferentiated carcinomas) tumors, with epithelial ovarian malignancies accounting for the majority (2).Previous epidemiological studies and meta-analyses have identified several risk factors for ovarian cancer, including family genetic history (for example, mutations in BRCA1 and BRCA2 genes), contraceptive use, short lactation duration, a body mass index ≥30 kg/m 2 , and other gynecological diseases such as vaginitis and polycystic ovary syndrome (1,3). > Curative and survival trends in ovarian cancer have not significantly improved owing to the challenges of early diagnosis, including the lack of clear screening tools, and indistinct signs and symptoms.Moreover, high metastasis and recurrence rates and drug resistance to chemotherapy are also important reasons for the poor prognosis of patients with ovarian cancer (4).Therefore, it is important to identify potential ovarian cancer targets and clarify their roles and molecular mechanisms in the malignant biological behavior of ovarian cancer. > Cancer stem cells (CSCs), a subpopulation within tumors, possess self-renewal and differentiation capacities akin to those of stem cells, thus sustaining tumor growth and the regeneration of an heterogeneous tumor mass (5,6).Accumulating evidence indicates that CSCs exist in numerous types of tumors, including leukemia, breast, rectal and ovarian cancer.A previous study revealed that CSCs have become the significant drivers of chemoresistance in ovarian cancer (7).

[4] Development of a Mouse Model of Menopausal Ovarian Cancer

• Authors: Elizabeth R. Smith, Ying Wang, Xiang-Xi Xu
• Year: 2014
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/b8d0aec8a47b56483fafde2755c4b682e871d817
• DOI: 10.3389/fonc.2014.00036
• PMID: 24616881
• PMCID: 3935315
• Citations: 15
• Summary: Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention and may provide clues to these questions currently perplexing ovarian cancer biology.
• Evidence snippets:
• Snippet 1 (score: 0.584) > Most ovarian cancers are epithelial-derived, and of the four major histological subtypes, serous ovarian cancer accounts for approximately 70% of the tumors (1)(2)(3)(4). Serous ovarian carcinomas usually present as high-grade, with limited therapy options (5)(6)(7). Standard treatment regimens involve surgery to remove all visible disease, followed by a combination of taxane and platinumbased chemotherapy. Most patients who respond to first line chemotherapy will eventually relapse and die from drug-resistant disease. Despite intensive research and improvements in surgery and chemotherapy, the 5-year survival rate for ovarian cancer patients has languished around 30% for the past 30 years (5)(6)(7). This dismal survival rate attests to the urgency for a clear, more accurate understanding of basic ovarian cancer biology and etiology. > In the last several decades, great effort has been devoted to understanding ovarian cancer and the research has yielded significant knowledge and information about the biology and genetics of the disease (1)(2)(3)(4). BRCA1 and BRCA2 mutations are associated with hereditary breast and ovarian cancers (1)(2)(3)(4), which account for only a small fraction (estimated to be around 5-10%) of ovarian cancer cases. Recently, the Cancer Genome Atlas Project has provided a molecular profile of serous cancers (8): the tumor suppressor Tp53 is frequently mutated, but no other somatic mutation is consistently or frequently found. Nevertheless, Tp53 deletion alone is insufficient to induce epithelial tumors in mouse models (9)(10)(11)(12)(13)(14). Thus, the molecular mechanism of ovarian serous cancer is not completely understood. In all the many types of ovarian tumor mouse models published so far, none reflects both the genetic (p53 mutation) and serous histology of human cancer. > Another key question in ovarian cancer biology related to reproductive etiology remains unanswered (1)(2)(3)(4).

[5] P53, MAPK, topoisomerase II alpha and Ki67 immunohistochemical expression and KRAS/BRAF mutation in ovarian serous carcinomas

• Authors: Dinka Šundov, Ana Čarić, I. Mrklić, Dijana Gugić, V. Čapkun et al.
• Year: 2013
• Venue: Diagnostic Pathology
• URL: https://www.semanticscholar.org/paper/d534500e1f8f64d5bf9a0e42913932b7c2972319
• DOI: 10.1186/1746-1596-8-21
• PMID: 23388101
• PMCID: 3570323
• Citations: 25
• Influential citations: 1
• Summary: Investigating the immunohistochemical expression of p53, MAPK, topoisomerase II alpha (topoII alpha) and Ki67 in ovarian serous carcinomas along with mutational analysis for KRAS and BRAF found that activation of MAPK pathway is not ultimately related either to KRAS or BRAF mutation.
• Evidence snippets:
• Snippet 1 (score: 0.580) > In the Western hemisphere ovarian carcinomas still remain the most frequent cause of death due to gynecological cancer [1]. Efforts in early detection and new insights in therapeutic approaches demonstrated no clear benefit. In a sense, we are forced to go "back to basics". > Historically, the principal means of classifying ovarian carcinomas has been histological assessment of cell type. This approach is reflected in the current World Health Organization's ovarian carcinoma classification [2]. Meanwhile, morphological studies upgraded by molecular genetic studies have enabled new insights into the pathogenesis of ovarian cancer with possible consequences on future cancer screening and platinum-based treatments. It has become apparent that the different subtypes of ovarian carcinoma represent distinct disease entities. > The discovery of biological differences between lowgrade and high-grade serous carcinomas has provided a basis for Baltimore group led by Robert J. Kurman to propose a new dualistic model of ovarian carcinogenesis that recognized "type I" and "type II" pathways, with serous type ovarian carcinoma as a prototype [1,3]. According to proposed model, ovarian serous carcinomas (OSCs) which evolve along type I pathway are relatively indolent low-grade neoplasms that arise in a stepwise fashion from well-characterized precursor lesions and usually present as large FIGO stage I neoplasms. They often harbor somatic mutations of genes encoding protein kinases, including KRAS and BRAF, the upstream regulators of mitogen-activated protein kinase (MAPK) [4]. According to Siedman et al. [5] low-grade serous carcinomas are significantly less common than high-grade and represent approximately 10% of serous carcinomas. > In contrast, OSCs which evolve along type II pathway are aggressive high-grade neoplasms, with a larger volume of tumor occurring outside the ovaries. More than 75% of high-grade carcinomas harbor TP53 mutations. Recent data suggest that these neoplasms arise from intraepithelial carcinomas, the majority of which have been detected in the tubal fimbriae [1,6]. > The loss of wild type p53 as a

[6] Oncoproteomic Analysis Reveals Co-Upregulation of RELA and STAT5 in Carboplatin Resistant Ovarian Carcinoma

• Authors: N. Jinawath, Chanont Vasoontara, A. Jinawath, X. Fang, Kejia Zhao et al.
• Year: 2010
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/dae9078957e236eeb04f8d559f7fbf1422874713
• DOI: 10.1371/journal.pone.0011198
• PMID: 20585448
• PMCID: 2887843
• Citations: 89
• Influential citations: 2
• Summary: It is shown that NF-κB and STAT5 inhibitor could sensitize carboplatin-resistant cells and suggest that such inhibitors can be used to benefit patients with carboplati-resistant recurrent ovarian cancer.
• Evidence snippets:
• Snippet 1 (score: 0.580) > Ovarian cancer is the most lethal gynecological malignancy in the United States with an estimated 21,550 new cases and 14,600 deaths in 2009 [1].Among all histological types of ovarian epithelial carcinoma, high-grade serous carcinoma is the most common and aggressive type, and is referred to generally as ''ovarian cancer''.High-grade serous carcinoma is highly malignant with a 5-year survival rate of less than 30%.The majority of patients are diagnosed late after tumor cells have disseminated within the peritoneal cavity when surgical and medical intervention is far less effective.Patients with advanced stage disease are treated with cytoreduction surgery followed by carboplatin-based chemotherapy.Despite initial responsiveness to combined carboplatin and paclitaxel chemotherapy, most patients develop chemoresistant tumors and ultimately succumb to the recurrent disease [2].Thus, elucidating the pathogenesis of chemoresistance is fundamental to the development of new therapeutics to overcome drug resistance in ovarian cancer patients. > To elucidate the molecular mechanisms of drug resistance investigators have employed several genome-wide techniques, including transcriptome analysis, to identify genes and their associated pathways in developing chemoresistance.As a result, a number of new drug resistant-associated genes have been identified.For example, we have reported that the expression levels of Nac1, Rsf-1 (HBXAP), fatty acid synthase and annexin A11 were significantly higher in recurrent, high-grade ovarian serous carcinoma specimens after chemotherapy and, more importantly, expression of these genes played a causal role in conferring drug resistance in vitro [3], [4], [5], [6], [7], [8].In addition to genomic approaches, comparison of the proteomes between primary and recurrent post-chemotherapeutic carcinomas could represent another effective approach to identifying proteins involved in developing drug resistance.

[7] Comparative analysis between high-grade serous ovarian cancer and healthy ovarian tissues using single-cell RNA sequencing

• Authors: Xiao Zhang, Shihao Hong, Cheng-Jian Yu, Xiaobo Shen, Fangying Sun et al.
• Year: 2023
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/e605d4ce14944a8e0f032024eb351973519d1861
• DOI: 10.3389/fonc.2023.1148628
• PMID: 37124501
• PMCID: 10140397
• Citations: 8
• Influential citations: 1
• Summary: Differences in function, gene expression and cell interaction patterns between ovarian cancer and healthy ovarian cell populations are revealed and provide key insights on further research into the treatment of ovarian cancer.
• Evidence snippets:
• Snippet 1 (score: 0.580) > Ovarian cancer is one of the most common gynecologic malignancies in the world, with dismal prognosis (1). High-grade serous ovarian cancer (HGSOC) is the most aggressive type of ovarian cancer (2). High-grade ovarian serous cancer is associated with poor survival rates compared with early-stage and high-grade cancers, with the 5-year survival rate being only 27% (3). Advanced high-grade serous ovarian cancers tend to invade adjacent organs, metastasizing to the peritoneum and lymph nodes (4). So far, studies of high-grade serous ovarian cancer and the discovery of long-term effective treatment strategies for this disease are limited. Therefore, there is need for in depth research into the regulation mechanisms of genes associated with progression of high-grade ovarian cancer. Data from high throughput sequencing technologies indicate that many human genes are transcribed into RNAs, but only a small part of RNAs is finally translated into proteins (5,6). Genome information flows through various molecular layers, including epigenome, transcriptome, proteome, and metabolome, to produce characteristic traits (7). As a result, we have gained a deeper understanding of the molecular complexity of ovarian cancer, especially the complexity of the genome. RNA-seq is a technique used to analyze RNA expression in whole tissues. However, this approach does not highlight contributions from different cell types (8). Single-cell RNA sequencing (scRNA-Seq) technologies provide essential opportunities to study cellular heterogeneity on the gene level (9). > Single-cell sequencing technology involves separation of groups of cells within tissues and body fluid into single cells, and analyzing their genetic materials using high-throughput sequencing techniques to reveal cellular heterogeneity among different tissues and cell types (10,11). Each single cell found within high-grade serous ovarian cancer has unique microenvironment, transcriptomic and epigenomic characteristics (12). Although cells contain the same genes, differences in mechanisms of transcriptional modulation drives stochastic gene expression.

[8] A Systems Biology Comparison of Ovarian Cancers Implicates Putative Somatic Driver Mutations through Protein-Protein Interaction Models

• Authors: Mary Yang, L. Elnitski
• Year: 2016
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/3ef71867c8dd9a4323dfd8a62dd6bc4985c077c4
• DOI: 10.1371/journal.pone.0163353
• PMID: 27788148
• PMCID: 5082879
• Citations: 11
• Summary: Novel network-based molecular signatures identified here may be used to identify new targets for intervention and to improve the treatment of invasive ovarian cancer as well as early diagnosis.
• Evidence snippets:
• Snippet 1 (score: 0.580) > Ovarian carcinomas can be aggressive with a high mortality rate (e.g., high-grade serous ovarian carcinomas, or HGSOCs), or indolent with much better long-term outcomes (e.g., low-malignant-potential, or LMP, serous ovarian carcinomas). By comparing LMP and HGSOC tumors, we can gain insight into the mechanisms underlying malignant progression in ovarian cancer. However, previous studies of the two subtypes have been focused on gene expression analysis. Here, we applied a systems biology approach, integrating gene expression profiles derived from two independent data sets containing both LMP and HGSOC tumors with protein-protein interaction data. Genes and related networks implicated by both data sets involved both known and novel disease mechanisms and highlighted the different roles of BRCA1 and CREBBP in the two tumor types. In addition, the incorporation of somatic mutation data revealed that amplification of PAK4 is associated with poor survival in patients with HGSOC. Thus, perturbations in protein interaction networks demonstrate differential trafficking of network information between malignant and benign ovarian cancers. The novel network-based molecular signatures identified here may be used to identify new targets for intervention and to improve the treatment of invasive ovarian cancer as well as early diagnosis.

[9] Survival-Related Profile, Pathways, and Transcription Factors in Ovarian Cancer

• Authors: A. Crijns, R. Fehrmann, S. de Jong, F. Gerbens, G. Meersma et al.
• Year: 2009
• Venue: PLoS Medicine
• URL: https://www.semanticscholar.org/paper/ce1a2f2e044b0a45ce38580027860a218cd49818
• DOI: 10.1371/journal.pmed.1000024
• PMID: 19192944
• PMCID: 2634794
• Citations: 190
• Influential citations: 11
• Summary: The aims of this study were to develop a gene expression profile associated with overall survival in advanced stage serous ovarian cancer, to assess the association of pathways and transcription factors with Overall survival, and to validate the identified profile and pathways/transcription factors in an independent set of ovarian cancers.
• Evidence snippets:
• Snippet 1 (score: 0.573) > Ovarian carcinoma is the leading cause of death from gynecologic malignancies in the Western world [1]. Debulking surgery followed by platinum-based chemotherapy is considered standard of care for patients with advanced stage ovarian cancer, but despite an initial response rate of 65%-80% to first-line chemotherapy, most patients will relapse with drug-resistant disease [2]. Consequently, the 5-y survival rate of patients with advanced-stage disease is only about 5%-30% [3]. > To date, a variety of studies have employed gene expression profiling to classify ovarian carcinomas in clinically relevant subtypes [4][5][6][7][8][9]. These studies provided valuable first clues to molecular changes in serous ovarian cancer that might be exploited in new treatment strategies. However, most studies were of relatively limited size and the number of overlapping genes in the identified profiles was minimal. Although identification of gene expression profiles associated with clinically relevant subtypes in ovarian cancer is important, knowledge is now rapidly emerging on how genes interact in pathways, networks and complexes; this new information allows us to unravel the cellular pathways determining the biological behavior of ovarian cancer, and these pathways might be successfully targeted with drugs. > The aim of our study was to (1) develop a gene expression profile associated with overall survival in advanced-stage serous ovarian cancer, (2) assess the association of pathways and transcription factors with overall survival, and (3) validate our profile and identified pathways/transcription factors in a fully independent, publicly available dataset of serous ovarian cancers.

[10] MET/HGF Signaling Pathway in Ovarian Carcinoma: Clinical Implications and Future Direction

• Authors: P. Mhawech-Fauceglia, M. Afkhami, T. Pejovic
• Year: 2012
• Venue: Pathology Research International
• URL: https://www.semanticscholar.org/paper/75951006487bc5277321b2000ffb75523ab45d9a
• DOI: 10.1155/2012/960327
• PMID: 23320251
• PMCID: 3540829
• Citations: 25
• Summary: The HGF/MET pathway plays a role in the initiation and progression of ovarian cancer through the most distinctive biologic program known as “invasive growth" which is accomplished through a coordinated activation of cell motility, invasiveness, degradation of extracellular matrix, survival, and proliferation.
• Evidence snippets:
• Snippet 1 (score: 0.572) > A few years after its introduction, the authors confirmed its reproducibility and urged its use to facilitate the clinical trials and protocols [14,15]. > Even though the origin of epithelial ovarian cancer is still a subject of debate, three anatomical sites, fallopian tube, mesothelial cells covering the peritoneum, and surface ovarian epithelium, have been suggested to be the potential sites of origin for ovarian serous adenocarcinomas [16,17]. In the last decade, a remarkable advance in understanding the genetic fingerprint of ovarian cancer has been revealed. Two major pathways has been proposed. the first is for low grade serous carcinoma that followed a progression model, which has been defined as a progression from serous borderline tumor (low malignant potential/LMP) to low grade carcinoma, similar to the well-accepted model of adenomacarcinoma progression of the colon. Low grade serous carcinomas present in younger women and they occur at early stage disease. Although, they have indolent disease course, they are relatively resistant to standard carboplatin and taxol chemotherapy. The second pathway is the de novo model consisting of high grade serous carcinomas which present in older women and typically detected as very advanced stage disease. Although they are sensitive to the standard chemotherapy, they are very aggressive disease with a high mortality rate. The genetic pathway in low grade serous carcinoma involves BARF, KRAS, and ERBB2 mutations and microsatellite instability (MSI). However, the genetic abnormalities seen in de novo high grade serous carcinoma are much more complex as it involves numerous genetic abnormalities. But the most frequent and constant genetic change in high grade serous carcinoma is p53 mutations occurring in 50-80% of cases [18]. c-MET protooncogene (Gene ID: 4233) is located at 7q31 locus of chromosome 7 [19,20]. It is a membrane receptor that is essential for embryonic development and wound healing.

[11] cAMP-Dependent Signaling and Ovarian Cancer

• Authors: A. Kilanowska, A. Ziółkowska, Piotr Stasiak, M. Gibas-Dorna
• Year: 2022
• Venue: Cells
• URL: https://www.semanticscholar.org/paper/f85e87f856f753f7a93996ca93c4afb784dd50a5
• DOI: 10.3390/cells11233835
• PMID: 36497095
• PMCID: 9738761
• Citations: 41
• Summary: It is indicated that targeting particular stages of cAMP-dependent processes might provide promising therapeutic opportunities for the effective management of patients with ovarian cancer.
• Evidence snippets:
• Snippet 1 (score: 0.572) > Further research confirmed however that high-grade serous ovarian carcinomas originate in the fallopian tube [7][8][9]. The tissue of origin became the basis for traditional cancer classification determining a histological type of a tumor. That is why ovarian cancer is characterized by such a high heterogeneity [10] and different level of tumorigenic differentiation associated with precursor changes, pathogenesis, mode of spread, sensitivity to chemotherapy, and further prognosis [11,12]. > In 2020, the 5th edition of the World Health Organization Classification of Tumors established a coherent cancer classification, including female genital tumors, in which five main histotypes of ovarian cancer were distinguished: high-grade serous cancer (HGSC), low-grade serous cancer (LGSC), mucous cancer (MC), endometrioid carcinoma (EC) and clear cell carcinoma (CCC). This classification is based on the recognition of specific phenotypes and is the basis for distinguishing ovarian cancer subclasses, i.e., molecular subtypes. For each of them, the source of origin was described and immunohistochemical markers (WT1/p53/napsin A/PR) were recognized allowing for reliable identification of a specific histotype with high accuracy [13]. Cancer development is influenced by many factors including genomic mutations and epigenetic changes which are the features that enable the identification of subtypes [13]. The research focused on mutations as epigenetic changes may provide detailed information relevant to early diagnosis and treatment response [14]. > For these reasons, the elucidation of the mechanisms driving ovarian cancer development and growth is particularly important to establish effective targeted treatment [15]. Signal transduction pathways (STPs) control and participate in many cellular processes, including cell division and differentiation, migration, and metabolism. Hypo-or hyperactivation of certain STPs may be associated with uncontrolled tumor growth and metastatic spread. Therefore, it is believed that STPs may serve as good targets for an effective treatment strategies.

[12] Crosstalk of Immune Cells and Platelets in an Ovarian Cancer Microenvironment and Their Prognostic Significance

• Authors: K. Pankowska, G. E. Będkowska, Joanna Chociej-Stypułkowska, M. Rusak, M. Dabrowska et al.
• Year: 2023
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/f3fc773ac60724b3826db9a9279ad645640148c7
• DOI: 10.3390/ijms24119279
• PMID: 37298230
• PMCID: 10253437
• Citations: 26
• Summary: The role and contribution of immune cells and platelets in TME are discussed and their potential prognostic significance to help in the early detection of OC and to predict disease outcome is discussed.
• Evidence snippets:
• Snippet 1 (score: 0.559) > Here, two lines of ovarian carcinogenesis development with the degree of histological and molecular differentiation were identified and taken into consideration. > Serous (low-grade serous ovarian carcinoma (LGSOC)), clear cell, and endometrial cancers are examples of well-differentiated tumors that fall under type I and are characterized by slow development and minimal spreading potential. Serous (high-grade serous ovarian carcinomas (HGSOC)), endometrial, and sarcomas are examples of type II low-differentiated carcinomas that exhibit rapid growth and a strong metastatic potential. Over 95% of cases of HGSOC are correlated with genetic mutations in the tumor suppressor protein p53, which account for the late stage (FIGO III/IV) diagnosis of the disease when the cancer has advanced to the peritoneum [7]. Additionally, almost 85% of hereditary OC cases and more than one-fifth of all occurrences of OC are linked to mutation in genes such as BRCA1 and BRCA2 [8,9]. > Combination therapy, which consists of surgery and platinum-based chemotherapy, is the recommended approach for treating OC. However, the effectiveness of this treatment varies depending on the histological nature of the tumor. Recent clinical trials suggest that drugs targeting signaling pathways, such as the PI3K-and RAS-signaling pathways, may be a new and promising option for treating OC [10]. Despite this, recurrence is seen in the majority of women within 18 months [10,11]. > To gain a better understanding of OC development and progression, it is vital to recognize the functioning of the ovarian tumor microenvironment, particularly the activity and characteristics of immune cells. Various soluble factors (cytokines, chemokines, and proteins) and direct cell-to-cell interactions comprise the active network required for the development of local immunosuppression, allowing cancer cells to survive, grow, and develop metastatic qualities.

[13] Advances and challenges in the origin and evolution of ovarian cancer organoids

• Authors: Mengpei Zhang, Rutie Yin, Kemin Li
• Year: 2024
• Venue: Frontiers in Oncology
• URL: https://www.semanticscholar.org/paper/50e928bed57f6ebf0248010db66bcdf02d876525
• DOI: 10.3389/fonc.2024.1429141
• PMID: 39220646
• PMCID: 11362079
• Citations: 9
• Influential citations: 3
• Summary: The emerging role of ovarian cancer organoids, meticulously cultivated cellular clusters within three-dimensional models, is summarized, as a groundbreaking paradigm in research.
• Evidence snippets:
• Snippet 1 (score: 0.555) > The ovarian surface is distinctively composed of a single layer of flat or cuboidal epithelial cells, supported beneath by a thin layer of dense connective tissue referred to as the tunica albuginea. The ovarian parenchyma is further divided into an outer cortex and a central medulla. The genesis of ovarian cancer is multifaceted, stemming from various cell types within the ovary. Ovarian carcinoma is distinguished by its intricate heterogeneity, manifesting at molecular, cellular, and anatomical levels. This multifaceted heterogeneity profoundly influences the responsiveness to surgical interventions and/or systemic therapeutic strategies, concurrently fostering both intrinsic and acquired drug resistance mechanisms. Epithelial ovarian cancer, which comprises the majority of cases, encompasses various histological subtypes that have been grouped into two broad categories based on histopathological, molecular, and genetic criteria. Type I tumors, which include low-grade serous carcinoma (LGSOC), mucinous, endometrioid, clear cell, and transitional carcinomas, are known for their indolent growth and comparatively favorable prognosis. In contrast, Type II tumors, notably high-grade serous ovarian carcinoma (HGSOC), undifferentiated carcinoma, and carcinosarcoma, exhibit a more aggressive clinical course (8). HGSOC, accounting for approximately 70% of OC cases, is particularly devastating, with a 5-year survival rate of merely 30% (1). Historically, epithelial ovarian cancer was postulated to originate from the ovarian surface epithelium. However, with the evolution of research, particularly in molecular biology and genetics, scientists have postulated a hypothesis suggesting that high-grade serous carcinoma might originate from the epithelium of the fallopian tube (9). The standard treatment for HGSOC is surgical cytoreduction, sequentially followed by platinum-based chemotherapy. However, 70% of patients relapse within 2 years, and most recurrent cases develop chemoresistance, becoming unresponsive to standard therapies (10).

[14] Impact of BRCA Gene Testing on Ovarian Cancer Management

• Authors: Nyoman B Mahendra, William Alexander Setiawan
• Year: 2022
• Venue: European Journal of Medical and Health Sciences
• URL: https://www.semanticscholar.org/paper/ee0a578f4d0540d65ce9d56633319498e42bdc93
• DOI: 10.24018/ejmed.2022.4.5.1483
• Summary: This review focuses on BRCA mutations and their relationship to the development of ovarian cancer, as well as future therapeutic targets.
• Evidence snippets:
• Snippet 1 (score: 0.554) > Ovarian cancer has the highest mortality rate of any gynecologic cancer in the United States. Ovarian cancer was predicted to take the lives of about 14,240 people in 2016. Despite medical advancements, the 5-year survival rate for newly diagnosed patients has only increased to 46% in the last 20 years. Both the high prevalence of advanced disease at diagnosis and the dearth of novel therapeutic options are major contributors to the stagnation. Most cases of ovarian cancer are diagnosed as epithelial ovarian cancer (EOC), which can be further classified by cell type, grade, and anatomic site. In roughly 70% of cases of EOC, the cancer is of the high-grade serous variety [1]. Traditionally, ovarian cancer has been treated with a combination of cytoreductive surgery and subsequent chemotherapy. Patients who undergo an optimal or complete surgical cytoreduction have been shown to fare better in studies examining this hypothesis, and this benefit has been consistently observed when surgery is performed immediately after diagnosis. Platinum and taxanebased therapy form the backbone of ovarian cancer chemotherapy. Improvements in administration methods, such as intraperitoneal chemotherapy, have slowed the disease's progression and extended patients' lives [2]. While advances have been made in recent years thanks to new targeted therapies (such as bevacizumab), future progress will require a deeper understanding of the genetic basis of the disease to identify new targets. > Particularly aggressive forms of ovarian carcinoma, such as high-grade serous ovarian cancer (HGSOC), are extremely mutagenic. In 2011, The Cancer Genome Atlas (TCGA) conducted a comprehensive analysis of ovarian carcinoma and discovered numerous genes to be significantly mutated; most notably p53, which was mutated in nearly 96% of HGSOC. The BRCA1/2 genes were also found to play a role in many HGSOC, independent of germline status, through this investigation. In addition, pathway analysis revealed that mutations in a single gene involved in homologous recombination function were present in nearly half of all tumors analyzed.

[15] Genomics and molecular mechanisms of high grade serous ovarian cancer: the 12th Biennial Rivkin Center Ovarian Cancer Research Symposium

• Authors: Erinn B. Rankin
• Year: 2019
• Venue: International Journal of Gynecological Cancer
• URL: https://www.semanticscholar.org/paper/aaf938e8f450bb3d5f5f469c83e863779f2be368
• DOI: 10.1136/ijgc-2019-000490
• PMID: 31462542
• Citations: 3
• Summary: Improved understanding of the mechanisms of poly ADP ribose polymerase inhibitor resistance may lead to new therapeutic strategies to enhance outcomes in women with high grade serous ovarian cancer.
• Evidence snippets:
• Snippet 1 (score: 0.552) > Objective The aim of this study was to review current research efforts in genomics and molecular mechanisms of high grade serous ovarian cancer, presented at the 12th Biennial Rivkin Center Ovarian Cancer Research Symposium, held at the University of Washington. Methods The 12th Biennial Rivkin Center Ovarian Cancer Research Symposium brought together leaders in the field to discuss recent advances in ovarian cancer research and therapy. Results The genomics and molecular mechanisms of ovarian cancer session featured invited speaker presentations by Dr Alan D’ Andrea on ‘Deoxyribonucleic acid (DNA) repair in ovarian cancer’ and Dr Kathleen Cho on ‘Modeling the genomics of high grade serous carcinoma in the mouse’. Eight additional oral presentations and 46 poster presentations were selected from the submitted abstracts that highlighted current research efforts in p53, DNA repair, genomic instability and modeling disease in mice, and organoids in high grade serous ovarian cancer. Conclusions New technologies utilizing clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (CAS9) approaches in mice, organoids, and cell based screens continue to advance our knowledge of key molecular drivers of ovarian cancer initiation, progression, and drug resistance. Improved understanding of the mechanisms of poly ADP ribose polymerase inhibitor resistance may lead to new therapeutic strategies to enhance outcomes in women with high grade serous ovarian cancer.

[16] Molecular Clustering Based on ERα and EIG121 Predicts Survival in High-Grade Serous Carcinoma of the Ovary/Peritoneum

• Authors: M. Schlumbrecht, S. Xie, G. Shipley, D. Urbauer, R. Broaddus
• Year: 2010
• Venue: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
• URL: https://www.semanticscholar.org/paper/a317302af405ed1b70f06a317d7f3c53d05e7e71
• DOI: 10.1038/modpathol.2010.211
• PMID: 21102415
• PMCID: 3058634
• Citations: 46
• Influential citations: 3
• Summary: High expression of ERα and the estrogen-induced gene EIG121 predicts shorter overall survival in patients with high-grade serous ovarian carcinoma, and such a biomarker panel may potentially be used to guide management with estrogen antagonists in this patient population.
• Evidence snippets:
• Snippet 1 (score: 0.551) > survival would be seen in women whose ovarian tumors expressed high levels of ERα and estrogen-induced genes. However, this was not observed. High expression of ERα and estrogen-induced genes was not only associated with worse overall survival, but it was a negative prognostic factor independent of other patient-dependent covariates such as age, race, and BMI. Such a finding suggests that the molecular mechanisms underlying ovarian tumorigenesis may in fact be quite different in high-grade serous ovarian cancer compared to hormone sensitive tumors at other disease sites, or perhaps even different ovarian histologies. It is known that exposure to unopposed estrogen is associated with an increased risk of developing ovarian carcinoma (28). However, more detailed epidemiological studies have shown that a specific type of ovarian carcinoma, the less common histotype endometrioid adenocarcinoma, is most closely linked to estrogen exposure, while high-grade serous carcinoma is not linked to estrogen exposure (29). Therefore, the findings reported for our current study may be specific for ovarian high-grade serous carcinoma and not applicable to endometrioid-type ovarian tumors. > There is some experimental data that estrogen and/or genes induced by estrogen may actually promote adverse biological properties of ovarian cancer cells. Murdoch and Van Kirk (30) showed that ovarian cancer cells treated with estrogen had a significantly decreased ability to undergo apoptosis. In addition, after causing cellular stress by treatment with cisplatin, ovarian cancer cells exposed to estrogen had significantly increased DNA repair activity (30). The authors suggested that estrogen antagonized the apoptotic pathway triggered by chemotherapy-induced DNA damage. While the pathways by which estrogen achieved these changes were not specifically elucidated, these findings are significant because platinum drugs are one of two primary agents used for the treatment of ovarian carcinoma, including high grade serous carcinoma. > Estrogen's role in stimulating ovarian cancer progression may also lie in the activation of non-genomic signaling mechanisms. Park et al (31) found that when estrogen-sensitive ovarian cancer cell lines

[17] Molecular Characterization of an Intact p53 Pathway Subtype in High-Grade Serous Ovarian Cancer

• Authors: Takahide Hayano, Y. Yokota, K. Hosomichi, H. Nakaoka, K. Yoshihara et al.
• Year: 2014
• Venue: PLoS ONE
• URL: https://www.semanticscholar.org/paper/05a3979d059165783efc45c78e143e0b3d8316df
• DOI: 10.1371/journal.pone.0114491
• PMID: 25460179
• PMCID: 4252108
• Citations: 19
• Summary: A novel subtype of patients with HGSOC is demonstrated by an intact p53 pathway, with limited genomic alterations and specific gene expression profiles, which indicates the involvement of specific biological processes that are relevant to genomic stability and cancer etiology.
• Evidence snippets:
• Snippet 1 (score: 0.550) > The age adjusted rates of ovarian and other uterine adnexa cancers in 2002 were 10.6 per 100,000, and 5.2 per 100,000 person-years in USA and Japan, respectively [1]. Epithelial ovarian cancer is a heterogenous entity comprising multiple histological types such as high-grade serous, low-grade serous, clear cell, endometrioid, and mucinous cancers [2,3]. Ovarian cancers are divided into Type I and Type II tumors [2,4]; Type I tumors include low-grade serous, low-grade endometrioid, clear-cell, and mucinous carcinomas. These tumors poorly respond to platinum-based therapy, harbor a high frequency of mutations in genes that encode components of the RAS signaling pathway, and are relatively stable in genomic structure. Type II tumors include high-grade serous and high-grade endometrioid carcinomas and are highly aggressive. A large-scale study of highgrade serous ovarian cancer (HGSOC) by The Cancer Genome Atlas (TCGA) group characterized HGSOC as TP53-mutation enriched (96%) with aberrations of genome-wide somatic gene copy numbers. This study identified commonly altered pathways such as RB1, PI3K/RAS, NOTCH, homologous recombination, and FOXM1 pathways [5]. The mutation status of TP53 is associated with stages, gene expression patterns, and the survival of patients with serous ovarian cancer [6]. > We attempted to establish a risk classification system for serous ovarian cancer using gene expression profiles acquired using microarray data [7,8]. We identified 88 genes related to progression-free survival in 110 Japanese patients with advanced-stage serous ovarian cancer [7], as well as 126 genes related to overall survival in 260 Japanese patients with advanced-stage HGSOC [8]. To provide a better understanding of the molecular mechanisms involved in the pathogenesis of these cancers and to develop a risk classification system, we conducted profiling of the somatic mutations present in these tumors.

[18] Association of Anti-EGFR Antibody and MEK Inhibitor in Gynecological Cancer Harboring RAS Mutation: A Case Series

• Authors: J. Niogret, V. Derangère, C. Richard, L. Nuttin, F. Ghiringhelli et al.
• Year: 2022
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/ee95226dddcc95b19bfd41976f7bfb681f1cb3f6
• DOI: 10.3390/ijms23063343
• PMID: 35328764
• PMCID: 8948991
• Citations: 3
• Summary: The MEK inhibitor is effective in the advanced stages of low-grade serous carcinoma harboring RAS mutation with acceptable tolerance, and the anti-EGFR antibody does not provide any additional benefit.
• Evidence snippets:
• Snippet 1 (score: 0.546) > Ovarian carcinoma is the leading cause of death from gynecologic malignancies in developed countries [1]. Low-grade serous ovarian carcinoma represents a minority of ovarian serous carcinoma-about 10% of all serous ovarian carcinoma [2]. Women with low-grade serous ovarian carcinoma are diagnosed at a younger age and have a longer overall survival than women with high-grade serous ovarian carcinoma. Furthermore, low-grade serous ovarian carcinoma is less aggressive than high-grade serous ovarian carcinoma. Although women with low-grade serous ovarian carcinoma usually have an indolent clinical history, they have multiple recurrences and may die of this disease [3]. > Although the overall prognosis is better in women with low-grade than that in highgrade serous ovarian carcinoma, women with low-grade serous ovarian carcinoma have lower response rates to conventional ovarian carcinoma treatments. Since low-grade serous ovarian carcinomas are less responsive to conventional chemotherapy than high-grade serous ovarian carcinomas, it appears necessary to find other treatments, such as targeted therapies [2]. Effective and high-quality evidence-based treatment options for advancedstage, low-grade serous ovarian carcinoma are lacking. > The classic mitogen-activated protein kinase (MAPK) cascade, also called the RAS/RAF/ MEK/ERK pathway, is one of the major biologic pathways frequently altered in human carcinoma [4], mainly by constitutive activation of RAS and RAF proteins [5]. BRAF, KRAS, and NRAS mutations occurred in approximately 33%, 35%, and 20%, respectively, of all low-grade serous ovarian carcinoma [6,7]. BRAF and KRAS mutations occurred in approximately 2% and 19%, respectively, of advanced-stage low-grade serous ovarian carcinoma [8].

[19] In Silico Approach to Molecular Profiling of the Transition from Ovarian Epithelial Cells to Low-Grade Serous Ovarian Tumors for Targeted Therapeutic Insights

• Authors: A. Leblebici, Ceren Sancar, Bahar Tercan, Zerrin Işık, M. Arayıcı et al.
• Year: 2024
• Venue: Current Issues in Molecular Biology
• URL: https://www.semanticscholar.org/paper/ab0805346868b1a5910ce2b80806267bdb04de81
• DOI: 10.3390/cimb46030117
• PMID: 38534733
• PMCID: 10968906
• Citations: 2
• Summary: The main goal of the current study is to elucidate the differentially coexpressed genes, their potential mechanisms, and possible drug targets in low-grade invasive serous ovarian carcinoma (LGSC) in terms of the biologic continuity of normal, borderline, and malignant LGSC in order to generate in silico inferences.
• Evidence snippets:
• Snippet 1 (score: 0.546) > Ovarian cancer is a very heterogeneous disease. The most common type is epithelial ovarian cancer, and high-grade (HG) serous tumors are the most common histology [20]. Recent data suggest that HG serous tumors mostly. originate from fallopian tube epithelium (STIC lesions) with p53 abnormality. Other rare histological subtypes, such as clear-cell and endometrioid tumors, arise from endometriotic cysts associated with endometriosis, and MOC from transitional cell nests at the tubal-mesothelial junction [21,22]. Just one histological type, low-grade (LG) serous tumors, are accepted to have a clearer progression model from benign serous cystadenoma to borderline serous tumor and then low-grade carcinoma [23,24]. Since the behavior and the prognosis of each histology differ from each other, adjuvant treatment of each case has been managed individually and translational medicine evolves the treatment modalities from "one fits for all" to targeted therapies according to molecular alterations. In this unique study, we investigated the differentially expressed genes and performed gene-coexpression network and drug-gene interaction analyses to identify the potential targeted therapies in the biologic continuum of normal ovarian epithelial cells, borderline serous ovarian tumor cells, and, finally, low-grade serous ovarian epithelial cells. > Most of the studies regarding LG serous tumors demonstrated that K-RAS and B-RAF proto-oncogene mutations are frequent, and RAS mutations were found to be associated with the recurrence of LG serous tumors [25][26][27]. Since standard chemotherapy regimens are not as effective in LG tumors as they are in HG tumors, recent studies have focused on targeted therapies related to aforementioned mutations and also hormonal therapies.

[20] Reclassifying ovarian cancer: origins, subtypes and resistance to therapy

• Authors: D. Bowtell
• Year: 2012
• Venue: Hereditary Cancer in Clinical Practice
• URL: https://www.semanticscholar.org/paper/1935ebc8a97acdd67cf97d0914373768ccffbf60
• DOI: 10.1186/1897-4287-10-S2-A35
• PMCID: 3327254
• Summary: The presentation focuses on the increasing understanding of the molecular differences between and within different ovarian cancer histotypes, and efforts to understand the drivers of molecular subtypes of high-grade serous cancers.
• Evidence snippets:
• Snippet 1 (score: 0.544) > Recent pathological and molecular studies have forced a very significant re-evaluation of the conventional classification of EOC. Microarray and other molecular experiments demonstrate that EOC is a series of molecularly distinct diseases that individually bear more resemblance to certain non-ovarian cancers than they do to each other. Ovarian cancer really represents a spectrum of distinct diseases that share an anatomical location. The presentation focuses on the increasing understanding of the molecular differences between and within different ovarian cancer histotypes. Particular attention is given to high-grade ovarian serous cancers, which account for about two thirds of ovarian cancer deaths, and ovarian clear cell cancers, a tumour type with generally poor response to platinum-based therapy. > Using both gene expression (GE) and DNA copy number (CN) analyses, we have defined novel molecular subtypes of high-grade serous cancers [1]. The molecular subtypes are robustly represented in multiple datasets and are associated with distinct clinical outcomes, and therefore appear to be biologically meaningful. Our efforts to understand the drivers of molecular subtypes of high-grade serous will be discussed [2,3]. A clear cell cohort was analysed using GE and CN analyses, demonstrating deregulation of receptor tyrosine kinases and cytokine pathways [4]. In particular, deregulation of IL6/STAT3/HIF pathway and its targeting in a clinical setting will be described. > Platinum remains the mainstay of treatment for high-grade serous cancers, however, about 20% of patients fail initial treatment and of those that respond, the majority relapse within 2 years and progressively develop resistance to treatment. We have identified mechanisms of primary treatment failure [5,6] and are currently analysing paired primary and relapse samples to determine mechanisms of acquired treatment failure as part of the ICGC project. Studies in treatment resistance will be discussed.

Notes

• This provider combines search_papers_by_relevance with snippet_search.
• No synthesis or second-stage model call is performed.

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

• Disease Name: Ovarian High-Grade Serous Carcinoma
• MONDO ID: (if available)
• Category:

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Ovarian High-Grade Serous Carcinoma. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

• What are the primary pathophysiological mechanisms?
• What molecular pathways are dysregulated?
• What cellular processes are affected?

2. Key Molecular Players

• Genes/Proteins: Which genes are causally involved or implicated?
• Chemical Entities: What metabolites, drugs, or small molecules are relevant?
• Cell Types: Which cell types are primarily affected?
• Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

• What biological processes (GO terms) are disrupted?
• Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

• Where in the cell do key processes occur?
• Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

• What is the sequence of events from initial trigger to clinical manifestation?
• Are there distinct stages or phases?

6. Phenotypic Manifestations

• What are the key clinical phenotypes?
• How do they relate to the underlying mechanisms?

Citation Requirements

• Cite primary literature (PMID preferred) for all mechanistic claims
• Prioritize recent reviews and landmark papers
• Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Comprehensive Research Report: Pathophysiology of Ovarian High‑Grade Serous Carcinoma (HGSC/HGSOC)

Target disease

• Disease name: Ovarian high-grade serous carcinoma (HGSC; often clinically grouped as “tubo‑ovarian” HGSC)
• Category: Epithelial ovarian cancer, Type II tumor (high genomic instability) (arcieri2024howbrcaand pages 1-2)
• MONDO ID: Not resolved in the current tool context. Closely related ontology entities captured in OpenTargets include ovarian serous adenocarcinoma (EFO_0002917) and ovarian serous carcinoma (EFO_1001516) (tool output referenced in context; not assigned a citeable context ID).

Key recent sources prioritized (2023–2024)

• Wang et al., Jan 2024, J Clin Invest (Review): https://doi.org/10.1172/jci174013 (wang2024biologydriventherapyadvances pages 1-2)
• Arcieri et al., Mar 2024, Frontiers in Oncology (Review): https://doi.org/10.3389/fonc.2024.1335196 (arcieri2024howbrcaand pages 1-2)
• Sveen et al., Jan 2024, JCI Insight (Primary, multisite WES): https://doi.org/10.1172/jci.insight.170423 (sveen2024evolutionarymodeand pages 1-2)
• Yoon et al., Aug 2024, Am J Surg Pathol (Primary, genomic catastrophe): https://doi.org/10.1097/PAS.0000000000002229 (yoon2024genomiccatastrophe(chromothripsis pages 1-3)
• Flesken‑Nikitin et al., Oct 2024, Nat Commun (Primary, cell-state origin): https://doi.org/10.1038/s41467-024-52984-1 (fleskennikitin2024preciliatedtubalepithelial pages 1-2)
• Talbot et al., Feb 2023, Cancer Gene Therapy (Review, copy-number targets): https://doi.org/10.1038/s41417-023-00589-z (talbot2023amplifiedtherapeutictargets pages 1-2)
• Micek et al., Feb 2023, APL Bioengineering (Primary, spheroid ECM): https://doi.org/10.1063/5.0132254 (micek2023modelofcollective pages 1-2)
• Sivakumar et al., Jan 2023, Clinical and Translational Medicine (Primary, spheroid dispersion): https://doi.org/10.1002/ctm2.1176 (sivakumar2023basalcelladhesion pages 1-3)
• Carey et al., Dec 2024, Journal of Ovarian Research (Primary, subtype–immune microenvironment): https://doi.org/10.1186/s13048-024-01556-4 (carey2024subtypespecificanalysisof pages 1-2)
• Balan et al., May 2024, Frontiers in Oncology (Review, single-cell/TME heterogeneity): https://doi.org/10.3389/fonc.2024.1388663 (balan2024unlockingovariancancer pages 1-2)

1) Key concepts and definitions (current understanding)

1.1 Definition and clinical identity

High-grade serous ovarian cancer (HGSOC/HGSC) is the dominant lethal epithelial ovarian cancer entity, accounting for ~70% of ovarian cancer cases and nearly ~80% of deaths (US 2023 projections embedded in review context) (wang2024biologydriventherapyadvances pages 1-2). It is frequently diagnosed at advanced stage and characterized by peritoneal dissemination (sveen2024evolutionarymodeand pages 1-2).

1.2 Cell of origin and precursor lesions: fallopian tube paradigm

The prevailing model is that many HGSCs originate in the distal fallopian tube (fimbria) from serous tubal intraepithelial carcinoma (STIC) precursors, rather than ovarian surface epithelium (OSE) (wang2024biologydriventherapyadvances pages 1-2).

Direct quote (definition-level): - “The concept that HGSOC originates in the secretory cells of the FTE is now at the forefront of the field.” (wang2024biologydriventherapyadvances pages 1-2)

A related evolutionary synthesis places distal fallopian tube origin at ~80% of cases (sveen2024evolutionarymodeand pages 1-2).

1.3 Hallmark genomic architecture: copy-number driven cancer

HGSC is a canonical chromosomal instability / copy-number alteration cancer with near-universal TP53 mutation and widespread gains/losses, rather than being dominated by recurrent point mutations (talbot2023amplifiedtherapeutictargets pages 1-2).

Direct quote: - “High-grade serous ovarian carcinoma is a unique cancer characterised by universal TP53 mutations and widespread copy number alterations.” (talbot2023amplifiedtherapeutictargets pages 1-2)

2) Core pathophysiology (molecular & cellular mechanisms)

2.1 Early initiating events: TP53 mutation and tubal epithelial transformation

A central near-universal early event is somatic TP53 mutation in tubal epithelium.

Direct quote: - “Somatic mutation of TP53 is thought to be the first mutagenic event in the fimbria…” (wang2024biologydriventherapyadvances pages 1-2)

Wang et al. also explicitly state TP53 alterations are “identified in more than 95% of cases of HGSOC” (wang2024biologydriventherapyadvances pages 1-2). TP53-mutant foci occur in histologically normal fimbrial epithelium (p53 signatures) and are associated with DNA damage markers (γ‑H2AX) (wang2024biologydriventherapyadvances pages 1-2).

2.2 DNA repair dysregulation: homologous recombination deficiency (HRD)

A major mechanistic axis is defective homologous recombination repair. - HRD affects ~50% of HGSC and drives genomic instability; this is the mechanistic basis of PARP inhibitor synthetic lethality (arcieri2024howbrcaand pages 1-2, sveen2024evolutionarymodeand pages 1-2).

Direct quote (review-level statement): - “About 50% of High Grade Serous Ovarian Cancer exhibit a high degree of genomic instability due to mutation of genes involved in Homologous Recombination (HRD)…” (arcieri2024howbrcaand pages 1-2)

2.3 Chromosomal instability (CIN), catastrophic genome events, and tumor geography

HGSC frequently exhibits structural genomic alterations, including catastrophic events.

Yoon et al. quantified catastrophic genomic events (CGE) (chromothripsis-like patterns and/or polyploidy): - CGE 15/26 (57.7%) - Chromothripsis-like patterns 13/26 (50.0%) - Polyploidy 6/26 (23.1%) (yoon2024genomiccatastrophe(chromothripsis pages 1-3)

These CGEs correlate with ovarian parenchymal involvement (9/9 with ovarian involvement vs 6/17 without; p=0.0024) (yoon2024genomiccatastrophe(chromothripsis pages 1-3), supporting biologically distinct growth/dissemination trajectories.

Yoon et al. further summarize phylogenetic timing models: ~6.5 years from STIC development to HGSC initiation, then metastasis over ~2 years (yoon2024genomiccatastrophe(chromothripsis pages 1-3).

2.4 Dissemination as an evolutionary process (multisite WES)

Sveen et al. reconstructed trajectories across 23 patients, sampling a median of 5 sites (total 108 samples) (sveen2024evolutionarymodeand pages 1-2). They describe: - Low median TMB: 1.1 nonsilent mutations/Mb (sveen2024evolutionarymodeand pages 1-2) - Three dissemination modes (monoclonal vs polyclonal; linear vs branched) (sveen2024evolutionarymodeand pages 1-2) - Disseminated clones often arise late, especially in DNA repair–deficient tumors (sveen2024evolutionarymodeand pages 1-2)

This aligns with an “early genomic destabilization, late dissemination burst” model that is clinically consistent with diagnosis at disseminated stage.

2.5 Metastatic units: spheroids in ascites and peritoneal implantation

HGSC frequently spreads transcoelomically via ascites, where tumor cells exist as single cells and multicellular spheroids (micek2023modelofcollective pages 1-2, sveen2024evolutionarymodeand pages 1-2).

Spheroid formation and ECM biology (2023 experimental model): Micek et al. developed an in vitro model distinguishing spheroids formed by single-cell aggregation vs collective detachment. Key data: - In vitro spheroids and ascites spheroids were similar in size (51 vs 55 μm, p>0.05) (micek2023modelofcollective pages 1-2). - Spheroids incorporate multiple ECM proteins; inhibiting RGD-based adhesion or fibronectin assembly reduced mesothelial adhesion strength under shear (micek2023modelofcollective pages 1-2).

Spheroid dispersion and mesothelial clearance (2023 mechanistic study): Sivakumar et al. identify BCAM (including soluble sBCAM shed by ADAM10) as a regulator of spheroid architecture and invasion.

Direct quote: - “…promotes the dispersion of OC cell spheroids by regulating LAMA5-integrin-β1-dependent compaction and thereby facilitating invasion of metastatic target sites.” (sivakumar2023basalcelladhesion pages 1-3)

2.6 Tumor microenvironment (TME) and immune ecosystems

Transcriptomic subtypes correspond to distinct microenvironmental states and clinical outcomes.

Carey et al. analyzed four mRNA subtypes (immunoreactive, differentiated, proliferative, mesenchymal) and immune infiltration: - Immunoreactive subtype: high immune infiltration including M1 (p<0.0001), M2 macrophages (p<0.01), Th1 cells (p<0.01) and extremely strong association with LAIR‑1 expression (p=1.63e‑101) (carey2024subtypespecificanalysisof pages 1-2). - Mesenchymal subtype: enriched for fibroblasts (p<0.0001) (carey2024subtypespecificanalysisof pages 1-2).

Balan et al. summarize the clinical backdrop for immune-directed strategies and highlight the role of immune evasion in limiting checkpoint blockade efficacy; they also note standard first-line response rates of ~80–90% yet frequent relapse with 5‑year survival ~35% in their overview (balan2024unlockingovariancancer pages 1-2).

3) Key molecular players (genes/proteins), chemicals, cell types, anatomy

Table: Overview of critical genes, pathways, and cellular processes identified as central to high-grade serous ovarian carcinoma pathophysiology in 2023–2025 literature.

3.1 Genes/proteins (HGNC)

Core annotated drivers and effectors include: - TP53, BRCA1, BRCA2, CCNE1, and frequent copy-number perturbations (e.g., PTEN, RB1, NF1 losses) (wang2024biologydriventherapyadvances pages 1-2, haagsma2025theroleof pages 20-24). - Metastasis/TME modules include BCAM–ADAM10–LAMA5–ITGB1 (spheroid dispersion, mesothelial clearance) (sivakumar2023basalcelladhesion pages 1-3). - Dissemination evolution includes recurrent alterations across sites in TP53, BRCA1/2, DNMT3A and PI3K/AKT pathway members (sveen2024evolutionarymodeand pages 1-2).

3.2 Chemical entities / drugs (CHEBI / pharmacologic)

Evidence-supported clinically deployed agents: - Platinum agents (carboplatin) + taxanes (paclitaxel) are standard first-line therapy (villatoro2025tumormicroenvironmentand pages 16-19). - PARP inhibitors: olaparib, rucaparib, niraparib (maintenance paradigms) (talbot2023amplifiedtherapeutictargets pages 1-2, arcieri2024howbrcaand pages 1-2). - Anti‑VEGF therapy (bevacizumab) in maintenance/combination contexts (villatoro2025tumormicroenvironmentand pages 16-19, wang2024biologydriventherapyadvances pages 1-2).

3.3 Key cell types (CL)

• Fallopian tube secretory epithelial lineage (origin), ciliated cells (protective/decline with age), tumor epithelial cells, mesothelial cells, macrophages (M1/M2), Th1 cells, B cells, fibroblasts/CAFs (wang2024biologydriventherapyadvances pages 1-2, fleskennikitin2024preciliatedtubalepithelial pages 1-2, carey2024subtypespecificanalysisof pages 1-2, sivakumar2023basalcelladhesion pages 1-3).

3.4 Anatomical locations (UBERON)

• Fallopian tube fimbria, ovary, peritoneum, omentum, and ascitic fluid/peritoneal fluid (sveen2024evolutionarymodeand pages 1-2, wang2024biologydriventherapyadvances pages 1-2, yoon2024genomiccatastrophe(chromothripsis pages 1-3, micek2023modelofcollective pages 1-2).

Table: A structured mapping of key genes, biological processes, cell types, and anatomical locations involved in High-Grade Serous Ovarian Carcinoma pathophysiology to standard ontology domains, supported by recent literature.

4) Biological processes disrupted (GO Biological Process targets)

Key disrupted processes for GO annotation (supported by the above sources): - DNA damage response / homologous recombination (HRD) (arcieri2024howbrcaand pages 1-2, sveen2024evolutionarymodeand pages 1-2) - Chromosome organization and chromosomal instability including chromothripsis/polyploidy (yoon2024genomiccatastrophe(chromothripsis pages 1-3) - Cell cycle regulation and replication stress (e.g., CCNE1-mediated G1/S dysregulation) (wang2024biologydriventherapyadvances pages 1-2, talbot2023amplifiedtherapeutictargets pages 1-2) - Cell adhesion and extracellular matrix remodeling in spheroids and peritoneal colonization (micek2023modelofcollective pages 1-2, sivakumar2023basalcelladhesion pages 1-3) - Angiogenesis / vascular permeability (VEGF-driven) (wang2024biologydriventherapyadvances pages 1-2) - Immune regulation and immune evasion with subtype-specific immune infiltration (carey2024subtypespecificanalysisof pages 1-2, balan2024unlockingovariancancer pages 1-2)

5) Cellular components (GO Cellular Component context)

Major cellular compartments implicated by mechanism: - Nucleus / chromatin (TP53, BRCA1/2, genomic instability) (wang2024biologydriventherapyadvances pages 1-2, arcieri2024howbrcaand pages 1-2) - DNA replication machinery / replication forks (replication stress; CCNE1) (wang2024biologydriventherapyadvances pages 1-2) - Plasma membrane (integrins, BCAM) and extracellular matrix (LAMA5, fibronectin/collagens in spheroids) (sivakumar2023basalcelladhesion pages 1-3, micek2023modelofcollective pages 1-2) - Tumor–stroma interface as a spatial functional unit in immune outcomes (subtype/TIME associations) (carey2024subtypespecificanalysisof pages 1-2)

6) Disease progression: sequence of events (initiation → clinical disease)

A consensus progression model supported by recent reviews and genomic studies: 1. Initiation in fimbrial fallopian tube epithelium: TP53 mutation and DNA damage accumulate; p53 signatures detectable (wang2024biologydriventherapyadvances pages 1-2). 2. Precursor lesions (STIC): share TP53 mutation; progress toward invasive carcinoma (wang2024biologydriventherapyadvances pages 1-2). 3. Genomic instability escalation: HRD in ~50% yields structural variation and copy-number complexity (arcieri2024howbrcaand pages 1-2, sveen2024evolutionarymodeand pages 1-2). 4. Dissemination via ascites: exfoliated tumor cells seed peritoneal cavity; diagnosis often stage III/IV (sveen2024evolutionarymodeand pages 1-2). 5. Spheroid-mediated peritoneal implantation: spheroids produce ECM and engage integrin-mediated adhesion; factors like BCAM modulate compaction and invasion (micek2023modelofcollective pages 1-2, sivakumar2023basalcelladhesion pages 1-3). 6. Metastatic colonization and ecosystem formation: omentum/peritoneum niches; subtype-specific immune ecosystems (carey2024subtypespecificanalysisof pages 1-2, sveen2024evolutionarymodeand pages 1-2).

Visual support: Wang et al. provide a schematic of this tubal origin and progression framework (wang2024biologydriventherapyadvances media 021dd764).

7) Phenotypic manifestations (clinical phenotypes linked to mechanisms)

7.1 Key clinical phenotypes

• Late-stage presentation with peritoneal dissemination: ~two-thirds stage III/IV at diagnosis (sveen2024evolutionarymodeand pages 1-2).
• High relapse frequency: recurrence in ~70% within 3 years after first-line chemotherapy (arcieri2024howbrcaand pages 1-2).
• Ascites and spheroids: ascites contributes to dissemination and therapy resistance; ascites present in a substantial fraction at diagnosis (nearly 40% of ovarian cancer patients at diagnosis in the provided synthesis) (haagsma2025theroleof pages 20-24).

7.2 Mechanistic linkage

• HRD → platinum/PARP sensitivity; HR-proficient/CCNE1-amplified → poorer chemotherapy response (wang2024biologydriventherapyadvances pages 1-2, arcieri2024howbrcaand pages 1-2).
• Mesenchymal subtype → stromal/ECM remodeling and poorer prognosis; immunoreactive subtype → higher immune infiltration and better prognosis (carey2024subtypespecificanalysisof pages 1-2).

8) Recent developments and latest research (2023–2024 emphasis)

8.1 Refining the cell-of-origin: lineage and cell-state susceptibility

Flesken‑Nikitin et al. (Nat Commun 2024) identify a transitional “pre‑ciliated” cell state in tubal epithelium as cancer-prone under Trp53/Rb1 pathway perturbations, suggesting initiation susceptibility may not be limited to mature secretory cells (fleskennikitin2024preciliatedtubalepithelial pages 1-2).

8.2 Genome evolution and dissemination timing at multisite resolution

Sveen et al. (JCI Insight 2024) quantify low TMB, high CNA burden, and multiple dissemination modes; chemotherapy exposure is associated with higher genomic diversity in disseminated clones (sveen2024evolutionarymodeand pages 1-2).

8.3 Catastrophic genomic events and tumor distribution

Yoon et al. (Am J Surg Pathol 2024) provide strong quantitative evidence that CGE (chromothripsis/polyploidy) is common and correlates with ovarian parenchymal involvement, supporting heterogeneous evolutionary trajectories and possibly multiple “routes” to extensive disease (yoon2024genomiccatastrophe(chromothripsis pages 1-3).

8.4 Functional metastasis mechanisms in spheroids

2023 mechanistic studies emphasize spheroids as metastasis units, including ECM production post-detachment and BCAM-dependent modulation of compaction and invasion (micek2023modelofcollective pages 1-2, sivakumar2023basalcelladhesion pages 1-3).

8.5 Immune microenvironment stratification

Carey et al. (2024) provide subtype-specific immune associations with extremely strong p-values (e.g., LAIR‑1 p=1.63e‑101), illustrating that subtype classification may be operationalized for immune stratification (carey2024subtypespecificanalysisof pages 1-2).

9) Current applications and real-world implementations

9.1 Molecular testing in practice

European and American guidelines recommend BRCA testing for all new high‑grade ovarian cancer diagnoses, and HRD testing to guide PARP inhibitor use (arcieri2024howbrcaand pages 1-2).

9.2 Targeted therapies and biomarker-linked benefit

• PARP inhibitor maintenance benefits (trial summary values as reported in 2023 review):
• Olaparib: PFS improvement 13.6 months in BRCA1/2-mut maintenance setting; OS difference 12.9 months in final unadjusted analysis (not statistically significant) (talbot2023amplifiedtherapeutictargets pages 1-2).
• Rucaparib: PFS benefit 9.2 months in BRCA-mut and 5.4 months in ITT (talbot2023amplifiedtherapeutictargets pages 1-2).
• Niraparib: PFS benefit 11.5 months (first-line HRD group) and 5.6 months overall (talbot2023amplifiedtherapeutictargets pages 1-2).
• VEGF-driven angiogenesis is a therapeutic dependency; bevacizumab improves PFS in maintenance in standard-of-care frameworks (villatoro2025tumormicroenvironmentand pages 16-19, wang2024biologydriventherapyadvances pages 1-2).

9.3 Translational directions

• Targeting spheroid adhesion/ECM interactions (integrin, fibronectin assembly) and regulators of spheroid architecture (BCAM/ADAM10 axis) represent testable metastasis-focused strategies (micek2023modelofcollective pages 1-2, sivakumar2023basalcelladhesion pages 1-3).

10) Evidence items (knowledge base–oriented)

10.1 Mechanistic evidence highlights (with direct quotes)

• TP53 universality and early event: “Somatic mutation of TP53 is thought to be the first mutagenic event in the fimbria…” (wang2024biologydriventherapyadvances pages 1-2).
• TP53 frequency: TP53 alterations are “identified in more than 95% of cases of HGSOC” (wang2024biologydriventherapyadvances pages 1-2).
• Copy-number driven cancer definition: “High-grade serous ovarian carcinoma is a unique cancer characterised by universal TP53 mutations and widespread copy number alterations.” (talbot2023amplifiedtherapeutictargets pages 1-2).
• Spheroid invasion mechanism: “…promotes the dispersion of OC cell spheroids by regulating LAMA5-integrin-β1-dependent compaction…” (sivakumar2023basalcelladhesion pages 1-3).

10.2 Quantitative/statistical anchors

• US 2023 burden (review-cited): 19,710 new diagnoses and 13,270 deaths projected in 2023 (wang2024biologydriventherapyadvances pages 1-2).
• Global burden: >150,000 OC-related deaths annually worldwide (wang2024biologydriventherapyadvances pages 1-2).
• HRD frequency: ~50% (arcieri2024howbrcaand pages 1-2, sveen2024evolutionarymodeand pages 1-2).
• Dissemination: ~two-thirds stage III/IV at diagnosis (sveen2024evolutionarymodeand pages 1-2).
• Catastrophic genomic events: 57.7% overall; chromothripsis-like 50%; polyploidy 23.1% (yoon2024genomiccatastrophe(chromothripsis pages 1-3).
• Multisite WES: median TMB 1.1 nonsilent/Mb (sveen2024evolutionarymodeand pages 1-2).

10.3 Limitations of this extraction

• PMIDs were not explicitly present in the retrieved text excerpts; therefore, citations are provided via DOIs and journal metadata. Where PubMed IDs exist in the broader literature, they were not exposed in the present tool-retrieved text segments.
• Some ontology IDs are provided as examples; where IDs were not resolvable from the current context, this is explicitly indicated in artifact-01.

Figure evidence

A schematic figure depicting the tubal origin model and progression from TP53-mutant FTE/p53 signature → STIC → carcinoma/metastasis was extracted from Wang et al. (JCI 2024) (wang2024biologydriventherapyadvances media 021dd764).

References

1. (arcieri2024howbrcaand pages 1-2): Martina Arcieri, Veronica Tius, Claudia Andreetta, Stefano Restaino, Anna Biasioli, Elena Poletto, Giuseppe Damante, Alfredo Ercoli, Lorenza Driul, Anna Fagotti, Domenica Lorusso, Giovanni Scambia, and Giuseppe Vizzielli. How brca and homologous recombination deficiency change therapeutic strategies in ovarian cancer: a review of literature. Frontiers in Oncology, Mar 2024. URL: https://doi.org/10.3389/fonc.2024.1335196, doi:10.3389/fonc.2024.1335196. This article has 36 citations.

2. (wang2024biologydriventherapyadvances pages 1-2): Yinu Wang, Alexander James Duval, Mazhar Adli, and Daniela Matei. Biology-driven therapy advances in high-grade serous ovarian cancer. The Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci174013, doi:10.1172/jci174013. This article has 69 citations.

3. (sveen2024evolutionarymodeand pages 1-2): Anita Sveen, Bjarne Johannessen, Solveig M.K. Klokkerud, Sigrid M. Kraggerud, Leonardo A. Meza-Zepeda, Merete Bjørnslett, Katharina Bischof, Ola Myklebost, Kjetil Taskén, Rolf I. Skotheim, Anne Dørum, Ben Davidson, and Ragnhild A. Lothe. Evolutionary mode and timing of dissemination of high-grade serous carcinomas. JCI Insight, Jan 2024. URL: https://doi.org/10.1172/jci.insight.170423, doi:10.1172/jci.insight.170423. This article has 5 citations and is from a domain leading peer-reviewed journal.

4. (yoon2024genomiccatastrophe(chromothripsis pages 1-3): Ju-Yoon Yoon, Aarti Sharma, Azra H. Ligon, Rebecca G. Ramesh, T. Rinda Soong, Wa Xian, David B. Chapel, and Christopher P. Crum. Genomic catastrophe (chromothripsis and polyploidy) correlates with tumor distribution in extrauterine high-grade serous carcinoma. The American Journal of Surgical Pathology, 48:1017-1023, Apr 2024. URL: https://doi.org/10.1097/pas.0000000000002229, doi:10.1097/pas.0000000000002229. This article has 0 citations.

5. (fleskennikitin2024preciliatedtubalepithelial pages 1-2): Andrea Flesken-Nikitin, Coulter Q. Ralston, Dah-Jiun Fu, Andrea J. De Micheli, Daryl J. Phuong, Blaine A. Harlan, Amanda P. Armstrong, David McKellar, Sangeeta Ghuwalewala, John C. Schimenti, Benjamin D. Cosgrove, and Alexander Yu. Nikitin. Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma. Nature Communications, Dec 2024. URL: https://doi.org/10.1038/s41467-024-52984-1, doi:10.1038/s41467-024-52984-1. This article has 21 citations and is from a highest quality peer-reviewed journal.

6. (talbot2023amplifiedtherapeutictargets pages 1-2): Thomas Talbot, Haonan Lu, and Eric O. Aboagye. Amplified therapeutic targets in high-grade serous ovarian carcinoma – a review of the literature with quantitative appraisal. Cancer Gene Therapy, 30:955-963, Feb 2023. URL: https://doi.org/10.1038/s41417-023-00589-z, doi:10.1038/s41417-023-00589-z. This article has 8 citations and is from a peer-reviewed journal.

7. (micek2023modelofcollective pages 1-2): Hannah M. Micek, Lauren Rosenstock, Yicheng Ma, Caitlin Hielsberg, Lauren Montemorano, Metti K. Gari, Suzanne M. Ponik, and Pamela K. Kreeger. Model of collective detachment in high-grade serous ovarian cancer demonstrates that tumor spheroids produce ecm to support metastatic processes. APL Bioengineering, Feb 2023. URL: https://doi.org/10.1063/5.0132254, doi:10.1063/5.0132254. This article has 4 citations.

8. (sivakumar2023basalcelladhesion pages 1-3): Suresh Sivakumar, Sonja Lieber, Damiano Librizzi, Corinna Keber, Leah Sommerfeld, Florian Finkernagel, Katrin Roth, Silke Reinartz, Jörg W. Bartsch, Johannes Graumann, Sabine Müller‐Brüsselbach, and Rolf Müller. Basal cell adhesion molecule promotes metastasis‐associated processes in ovarian cancer. Clinical and Translational Medicine, Jan 2023. URL: https://doi.org/10.1002/ctm2.1176, doi:10.1002/ctm2.1176. This article has 7 citations and is from a peer-reviewed journal.

9. (carey2024subtypespecificanalysisof pages 1-2): Kaylin M. Carey, Corey D. Young, Alexis J. Clark, Eric B. Dammer, Rajesh Singh, and James W. Lillard. Subtype-specific analysis of gene co-expression networks and immune cell profiling reveals high grade serous ovarian cancer subtype linkage to variable immune microenvironment. Journal of Ovarian Research, Dec 2024. URL: https://doi.org/10.1186/s13048-024-01556-4, doi:10.1186/s13048-024-01556-4. This article has 5 citations and is from a peer-reviewed journal.

10. (balan2024unlockingovariancancer pages 1-2): Dharvind Balan, Nirmala Chandralega Kampan, Magdalena Plebanski, and Nor Haslinda Abd Aziz. Unlocking ovarian cancer heterogeneity: advancing immunotherapy through single-cell transcriptomics. Frontiers in Oncology, May 2024. URL: https://doi.org/10.3389/fonc.2024.1388663, doi:10.3389/fonc.2024.1388663. This article has 15 citations.

11. (haagsma2025theroleof pages 20-24): J Haagsma. The role of tp53 mutation in reducing inflammatory signaling and promoting precursor cell spheroid survival in ovarian high-grade serous carcinoma. Unknown journal, 2025.

12. (villatoro2025tumormicroenvironmentand pages 16-19): FP Villatoro. Tumor microenvironment and genomic biomarkers for precision oncology in high-grade serous ovarian cancer. Unknown journal, 2025.

13. (micoli2025decodingthegenomic pages 1-2): Giulia Micoli, Kari Lavikka, Yilin Li, Anna Pirttikoski, Daria Afenteva, Wojciech Senkowski, Giovanni Marchi, Anna Vaharautio, Taru A. Muranen, Titta Joutsiniemi, Sakari Hietanen, Anni Virtanen, Krister Wennerberg, Johanna Hynninen, Jaana Oikkonen, and Sampsa Hautaniemi. Decoding the genomic and functional landscape of emerging subtypes in ovarian cancer. Cancer discovery, Jul 2025. URL: https://doi.org/10.1158/2159-8290.cd-25-0652, doi:10.1158/2159-8290.cd-25-0652. This article has 2 citations and is from a highest quality peer-reviewed journal.

14. (haagsma2025theroleof pages 24-27): J Haagsma. The role of tp53 mutation in reducing inflammatory signaling and promoting precursor cell spheroid survival in ovarian high-grade serous carcinoma. Unknown journal, 2025.

15. (wang2024biologydriventherapyadvances media 021dd764): Yinu Wang, Alexander James Duval, Mazhar Adli, and Daniela Matei. Biology-driven therapy advances in high-grade serous ovarian cancer. The Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci174013, doi:10.1172/jci174013. This article has 69 citations.

Ovarian High-Grade Serous Carcinoma Manual Research Notes

Date: 2026-04-12

Scope

This note distills the literature and modeling decisions used for the kb/disorders/Ovarian_High-Grade_Serous_Carcinoma.yaml curation.

Cancer Modeling Decisions

• Applied issue #1198 guidance before rewriting the disease entry.
• Kept one disease-level mechanism graph for HGSOC instead of splitting BRCA-associated, HRD-positive, or platinum-response contexts into separate dismech pages.
• Kept the disease anchor MONDO-first. OLS search returned MONDO:0005211 (ovarian serous adenocarcinoma) as the closest MONDO concept, but not a separate high-grade ovarian serous MONDO leaf.
• Used NCIT to recover oncology specificity where the schema supports it: NCIT:C105555 Ovarian High Grade Serous Adenocarcinoma for disease-alignment context, NCIT:C213446 High Grade Serous Adenocarcinoma and NCIT:C126449 Serous Tubal Intraepithelial Carcinoma for histopathology, and NCIT drug/biomarker terms for olaparib, bevacizumab, carboplatin, paclitaxel, HRD, CCNE1 amplification, CA-125, and HE4.
• Treated subtype handling as a flat facet axis rather than as separate causal programs. In the YAML, BRCA-associated versus BRCA-wild-type HGSOC is represented as a disease facet inside one graph, not as separate disease pages. I did not force a subtype_term for the BRCA-associated facet once review confirmed that MONDO:0003582 denotes a predisposition syndrome rather than a carcinoma subtype.
• Kept pathophysiology nodes atomic. The old entry bundled origin, TP53, HRD, and genomic instability into broad blocks; the revised entry separates tubal origin, early TP53-mutant precursor state, STIC, HRD, copy-number instability, and CCNE1-linked replication stress.
• Important schema constraint: the current dismech schema exposes MONDO/ICD disease mapping containers, but not a dedicated ncit_mappings disease slot. Because of that, NCIT disease alignment is recorded in the curation notes and expressed structurally through histopathology, biomarker, regimen, and therapeutic-agent terms.

Ontology Grounding Used

• Disease anchor: MONDO:0005211 ovarian serous adenocarcinoma
• Disease-level oncology counterpart: NCIT:C105555 Ovarian High Grade Serous Adenocarcinoma
• Precursor lesion: NCIT:C126449 Serous Tubal Intraepithelial Carcinoma
• Defining histology: NCIT:C213446 High Grade Serous Adenocarcinoma
• Key biomarker state: NCIT:C120465 Homologous Recombination Deficiency
• Key copy-number biomarker: NCIT:C36682 CCNE1 Gene Amplification
• Candidate regimen concept not retained in final YAML because the current RegimenTerm enum rejected it during validation: NCIT:C63402 Carboplatin/Paclitaxel Regimen

Primary Claims Used In YAML

1. Tubal origin and precursor sequence

• PMID:33011111 supports the tubal-origin model and the TP53-to-STIC-to-HGSOC sequence.
• Used for:
• tubal cell-of-origin node
• TP53 as earliest recurrent lesion
• STIC as precursor histopathology and pathophysiology node
• Evidence type in YAML: OTHER
• This paper is a review/synthesis, not a direct cohort study.

2. Near-universal TP53 mutation and core genomic architecture

• PMID:21720365 (TCGA) remains the foundational human study for HGSOC.
• Used for:
• TP53 near-universality
• HRD in about half of tumors
• recurrent BRCA1/2 alteration
• recurrent CCNE1 amplification
• focal copy-number burden
• Evidence type in YAML: HUMAN_CLINICAL
• The study is based on clinically annotated human HGSOC tumors.

3. Pre-ciliated tubal epithelial susceptibility

• PMID:39366996 adds recent mechanistic depth beyond the older secretory-cell-only origin model.
• Used for:
• the atomic node describing a cancer-prone pre-ciliated tubal epithelial state
• Evidence type in YAML: MODEL_ORGANISM
• The key mechanistic evidence is mouse-based lineage tracing and transformation work.

4. Copy-number-driven disease framing

• PMID:36804485 gives a compact recent synthesis of the defining HGSOC genomic pattern: universal TP53 alteration plus widespread copy-number change.
• Used for:
• the copy-number-driven chromosomal instability node
• Evidence type in YAML: OTHER
• This paper is a review.

5. Clinical presentation and first-line management context

• PMID:40690248 is a recent JAMA review of ovarian cancer.
• Used for:
• ascites, abdominal pain, abdominal distention presentation context
• cytoreductive surgery and carboplatin/paclitaxel first-line treatment framing
• Evidence type in YAML: OTHER
• The paper is a review and not HGSOC-exclusive, but it is recent and clinically aligned with HGSOC-dominant advanced ovarian cancer care.

6. Maintenance olaparib

• PMID:36082969 (SOLO1 7-year follow-up) is the clearest long-term randomized evidence tied to the BRCA-associated HGSOC facet.
• Used for:
• olaparib maintenance treatment entry
• Evidence type in YAML: HUMAN_CLINICAL

7. Bevacizumab benefit enrichment

• PMID:36252167 (GOG-0218 validation) supports biomarker-informed bevacizumab use.
• Used for:
• bevacizumab treatment entry
• Evidence type in YAML: HUMAN_CLINICAL

8. CA-125 and HE4 biomarker context

• PMID:30917847 supports CA-125 and HE4 as practical biomarker entries.
• Evidence type in YAML: OTHER
• Review article summarizing diagnostic biomarker performance.

Literature Not Fully Expanded Into YAML

• The existing research/Ovarian_High-Grade_Serous_Carcinoma-deep-research-falcon.md already captures additional 2023-2025 literature on dissemination timing, spheroid biology, and tumor microenvironment variation.
• I did not turn every one of those claims into YAML because the issue called for a coherent disease-level curation, not a maximal import of every published HGSC detail.
• In particular, dissemination-mode, stromal subtype, and immune-ecosystem papers were treated as background unless they cleanly sharpened an atomic disease mechanism node.

Remaining Curation Judgment Calls

• The subtype list is intentionally narrow. Under the #1198 guidance, I did not encode multiple orthogonal axes (BRCA status, HRD status, stage, platinum sensitivity, site of spread) as if they were one subtype tree.
• The current schema does not yet provide a structured disease-level NCIT mapping slot. If that slot is added later, NCIT:C105555 should be promoted from curation notes into a first-class disease mapping.
• The current RegimenTerm dynamic enum also rejected NCIT:C63402 and NCIT:C160097, so the final YAML keeps oncology specificity through NCIT therapeutic agents rather than regimen descriptors.