graph LR
Recurrent_Acinar_Cell_Injury["Recurrent Acinar Cell Injury"]
Alcohol_Consumption["Alcohol Consumption"]
Endocrine_Insufficiency["Endocrine Insufficiency"]
Exocrine_Insufficiency["Exocrine Insufficiency"]
Diabetes_Mellitus["Diabetes Mellitus"]
Steatorrhea["Steatorrhea"]
Weight_Loss["Weight Loss"]
Smoking["Smoking"]
Exocrine_Insufficiency --> Steatorrhea
Exocrine_Insufficiency --> Weight_Loss
Endocrine_Insufficiency --> Diabetes_Mellitus
Alcohol_Consumption --> Recurrent_Acinar_Cell_Injury
Smoking --> Recurrent_Acinar_Cell_Injury
style Recurrent_Acinar_Cell_Injury fill:#dbeafe
style Alcohol_Consumption fill:#dcfce7
style Endocrine_Insufficiency fill:#dbeafe
style Exocrine_Insufficiency fill:#dbeafe
style Diabetes_Mellitus fill:#fef3c7
style Steatorrhea fill:#fef3c7
style Weight_Loss fill:#fef3c7
style Smoking fill:#dcfce7
graph LR
Acinar_to_Ductal_Metaplasia["Acinar-to-Ductal Metaplasia"]
KRAS_GM_CSF_Myeloid_Immunosuppression["KRAS-GM-CSF Myeloid Immunosuppression"]
Adaptive_CD24_Antiphagocytic_Signaling["Adaptive CD24 Antiphagocytic Signaling"]
Desmoplastic_Stroma["Desmoplastic Stroma"]
Acquired_RASON_Inhibitor_Resistance["Acquired RAS(ON) Inhibitor Resistance"]
Early_Dissemination_and_EMT["Early Dissemination and EMT"]
Exocrine_Pancreatic_Insufficiency["Exocrine Pancreatic Insufficiency"]
KRAS_Oncogene_Activation["KRAS Oncogene Activation"]
Obstructive_Jaundice["Obstructive Jaundice"]
Weight_Loss["Weight Loss"]
KRAS_Regulated_Glutamine_Redox_Metabolism["KRAS-Regulated Glutamine Redox Metabolism"]
Pancreatic_Precursor_Progression_and_Invasive_Growth["Pancreatic Precursor Progression and Invasive Growth"]
PDAC_Immunotherapy_PhysiCell_Model["PDAC Immunotherapy PhysiCell Model"]
Antigen_Presentation_Restoration["Antigen Presentation Restoration"]
MYC_Amplification_Driven_RAS_Independent_Proliferation["MYC Amplification-Driven RAS-Independent Proliferation"]
PDAC_CAF_Mediated_Invasion_PhysiCell_Model["PDAC CAF-Mediated Invasion PhysiCell Model"]
Basal_State_GM_CSF_Immunosuppressive_Circuit["Basal-State GM-CSF Immunosuppressive Circuit"]
Human_PDAC_Cell_and_Organoid_RAS_Response_Models["Human PDAC Cell and Organoid RAS-Response Models"]
USP20_Cholesterol_Metabolism_CD8_Exhaustion_Checkpoint["USP20 Cholesterol-Metabolism CD8 Exhaustion Checkpoint"]
RAS_Independent_Cell_Cycle_Uncoupling["RAS-Independent Cell-Cycle Uncoupling"]
Immunosuppressive_TME_Reversibility_under_RASON_Inhibition["Immunosuppressive TME Reversibility under RAS(ON) Inhibition"]
Daraxonrasib_RASON_Multiselective_Inhibitor["Daraxonrasib (RAS(ON) Multiselective Inhibitor)"]
Matrix_Associated_Hypoperfusion["Matrix-Associated Hypoperfusion"]
KPC_RMC_7977_Acquired_Resistance_Models["KPC RMC-7977 Acquired-Resistance Models"]
Metastatic_Dissemination_and_Colonization["Metastatic Dissemination and Colonization"]
Pancreatic_Exocrine_Functional_Loss["Pancreatic Exocrine Functional Loss"]
Tumor_Cell_FAS_Induction_and_CD8_Mediated_Killing["Tumor-Cell FAS Induction and CD8-Mediated Killing"]
Hepatic_Metastases["Hepatic Metastases"]
Autophagy_Lysosome_Growth_Support["Autophagy-Lysosome Growth Support"]
NBR1_Mediated_MHC_I_Autophagic_Degradation["NBR1-Mediated MHC-I Autophagic Degradation"]
Myeloid_Suppression_Relief_and_CD8_Effector_Infiltration["Myeloid Suppression Relief and CD8 Effector Infiltration"]
Adaptive_mTOR_and_JUN_AP1_Transcriptional_Program["Adaptive mTOR and JUN-AP1 Transcriptional Program"]
KRAS_Dependent_Anabolic_Glucose_Metabolism["KRAS-Dependent Anabolic Glucose Metabolism"]
Macropinocytic_Protein_Scavenging["Macropinocytic Protein Scavenging"]
Immunocompetent_Mouse_PDAC_RAS_Inhibition_Models["Immunocompetent Mouse PDAC RAS-Inhibition Models"]
FAK_Mediated_Antigen_Presentation_Suppression["FAK-Mediated Antigen-Presentation Suppression"]
Cyclophilin_A_Loss_and_Reduced_Tri_Complex_Engagement["Cyclophilin A Loss and Reduced Tri-Complex Engagement"]
Biliary_Drainage["Biliary Drainage"]
KRAS["KRAS"]
IL1_LIF_JAK_STAT_Inflammatory_Fibroblast_Programming["IL1-LIF-JAK-STAT Inflammatory Fibroblast Programming"]
CAF_Mediated_T_Cell_Exclusion["CAF-Mediated T Cell Exclusion"]
CDK8_CXCL2_Adaptive_Immune_Reversal["CDK8-CXCL2 Adaptive Immune Reversal"]
On_Target_RAS_Reactivation_and_KRAS_Amplification["On-Target RAS Reactivation and KRAS Amplification"]
Regulatory_T_Cell_Recruitment_after_KRAS_Inhibition["Regulatory T-Cell Recruitment after KRAS Inhibition"]
Experimental_KRAS_Inhibition_with_Immune_Checkpoint_Blockade["Experimental KRAS Inhibition with Immune Checkpoint Blockade"]
Senescent_Myofibroblast_Immunosuppression["Senescent Myofibroblast Immunosuppression"]
Exosome_MIF_Liver_Premetastatic_Niche["Exosome-MIF Liver Premetastatic Niche"]
Immune_Evasion["Immune Evasion"]
Chronic_Pancreatic_Inflammation["Chronic Pancreatic Inflammation"]
IL6_CAF_and_Myeloid_Rebound_after_SOS1_MEK_Inhibition["IL6-CAF and Myeloid Rebound after SOS1-MEK Inhibition"]
Tumor_Restraining_Fibroblast_Programs["Tumor-Restraining Fibroblast Programs"]
Experimental_RAS_EGFR_STAT3_Combination["Experimental RAS-EGFR-STAT3 Combination"]
Pancreatic_Enzyme_Replacement["Pancreatic Enzyme Replacement"]
Tumor_Suppressor_Inactivation["Tumor Suppressor Inactivation"]
RTK_and_Feedback_Pathway_Reactivation["RTK and Feedback Pathway Reactivation"]
Chronic_Pancreatic_Inflammation --> Acinar_to_Ductal_Metaplasia
Chronic_Pancreatic_Inflammation --> Early_Dissemination_and_EMT
Acinar_to_Ductal_Metaplasia --> Pancreatic_Precursor_Progression_and_Invasive_Growth
KRAS_Oncogene_Activation --> Acinar_to_Ductal_Metaplasia
KRAS_Oncogene_Activation --> KRAS_Dependent_Anabolic_Glucose_Metabolism
KRAS_Oncogene_Activation --> KRAS_Regulated_Glutamine_Redox_Metabolism
KRAS_Oncogene_Activation --> Macropinocytic_Protein_Scavenging
KRAS_Oncogene_Activation --> KRAS_GM_CSF_Myeloid_Immunosuppression
KRAS_Oncogene_Activation --> USP20_Cholesterol_Metabolism_CD8_Exhaustion_Checkpoint
Tumor_Suppressor_Inactivation --> Pancreatic_Precursor_Progression_and_Invasive_Growth
Pancreatic_Precursor_Progression_and_Invasive_Growth --> Desmoplastic_Stroma
Pancreatic_Precursor_Progression_and_Invasive_Growth --> Metastatic_Dissemination_and_Colonization
Pancreatic_Precursor_Progression_and_Invasive_Growth --> IL1_LIF_JAK_STAT_Inflammatory_Fibroblast_Programming
Pancreatic_Precursor_Progression_and_Invasive_Growth --> Tumor_Restraining_Fibroblast_Programs
Pancreatic_Precursor_Progression_and_Invasive_Growth --> Pancreatic_Exocrine_Functional_Loss
Pancreatic_Precursor_Progression_and_Invasive_Growth --> Obstructive_Jaundice
Desmoplastic_Stroma --> CAF_Mediated_T_Cell_Exclusion
Desmoplastic_Stroma --> Matrix_Associated_Hypoperfusion
CAF_Mediated_T_Cell_Exclusion --> Immune_Evasion
KRAS_Dependent_Anabolic_Glucose_Metabolism --> Pancreatic_Precursor_Progression_and_Invasive_Growth
KRAS_Regulated_Glutamine_Redox_Metabolism --> Pancreatic_Precursor_Progression_and_Invasive_Growth
Macropinocytic_Protein_Scavenging --> Pancreatic_Precursor_Progression_and_Invasive_Growth
Autophagy_Lysosome_Growth_Support --> Pancreatic_Precursor_Progression_and_Invasive_Growth
KRAS_GM_CSF_Myeloid_Immunosuppression --> Immune_Evasion
NBR1_Mediated_MHC_I_Autophagic_Degradation --> Immune_Evasion
FAK_Mediated_Antigen_Presentation_Suppression --> Immune_Evasion
Exosome_MIF_Liver_Premetastatic_Niche --> Metastatic_Dissemination_and_Colonization
Metastatic_Dissemination_and_Colonization --> Hepatic_Metastases
Cyclophilin_A_Loss_and_Reduced_Tri_Complex_Engagement --> Acquired_RASON_Inhibitor_Resistance
RAS_Independent_Cell_Cycle_Uncoupling --> Acquired_RASON_Inhibitor_Resistance
On_Target_RAS_Reactivation_and_KRAS_Amplification --> Acquired_RASON_Inhibitor_Resistance
RTK_and_Feedback_Pathway_Reactivation --> Acquired_RASON_Inhibitor_Resistance
Adaptive_mTOR_and_JUN_AP1_Transcriptional_Program --> Acquired_RASON_Inhibitor_Resistance
MYC_Amplification_Driven_RAS_Independent_Proliferation --> Acquired_RASON_Inhibitor_Resistance
Myeloid_Suppression_Relief_and_CD8_Effector_Infiltration --> Immunosuppressive_TME_Reversibility_under_RASON_Inhibition
Tumor_Cell_FAS_Induction_and_CD8_Mediated_Killing --> Immunosuppressive_TME_Reversibility_under_RASON_Inhibition
Antigen_Presentation_Restoration --> Immunosuppressive_TME_Reversibility_under_RASON_Inhibition
USP20_Cholesterol_Metabolism_CD8_Exhaustion_Checkpoint --> Immune_Evasion
USP20_Cholesterol_Metabolism_CD8_Exhaustion_Checkpoint --> Autophagy_Lysosome_Growth_Support
CDK8_CXCL2_Adaptive_Immune_Reversal --> Immune_Evasion
IL6_CAF_and_Myeloid_Rebound_after_SOS1_MEK_Inhibition --> Immune_Evasion
Basal_State_GM_CSF_Immunosuppressive_Circuit --> Immune_Evasion
Pancreatic_Exocrine_Functional_Loss --> Exocrine_Pancreatic_Insufficiency
Pancreatic_Exocrine_Functional_Loss --> Weight_Loss
Adaptive_CD24_Antiphagocytic_Signaling --> Immune_Evasion
Senescent_Myofibroblast_Immunosuppression --> Immune_Evasion
Daraxonrasib_RASON_Multiselective_Inhibitor --> KRAS_Oncogene_Activation
Daraxonrasib_RASON_Multiselective_Inhibitor --> Immunosuppressive_TME_Reversibility_under_RASON_Inhibition
Daraxonrasib_RASON_Multiselective_Inhibitor --> Regulatory_T_Cell_Recruitment_after_KRAS_Inhibition
Experimental_KRAS_Inhibition_with_Immune_Checkpoint_Blockade --> Immunosuppressive_TME_Reversibility_under_RASON_Inhibition
Pancreatic_Enzyme_Replacement --> Exocrine_Pancreatic_Insufficiency
Biliary_Drainage --> Obstructive_Jaundice
Experimental_RAS_EGFR_STAT3_Combination --> KRAS_Oncogene_Activation
Experimental_RAS_EGFR_STAT3_Combination --> Acquired_RASON_Inhibitor_Resistance
Human_PDAC_Cell_and_Organoid_RAS_Response_Models --> KRAS_Oncogene_Activation
Immunocompetent_Mouse_PDAC_RAS_Inhibition_Models --> Immunosuppressive_TME_Reversibility_under_RASON_Inhibition
KPC_RMC_7977_Acquired_Resistance_Models --> MYC_Amplification_Driven_RAS_Independent_Proliferation
PDAC_CAF_Mediated_Invasion_PhysiCell_Model --> Desmoplastic_Stroma
PDAC_Immunotherapy_PhysiCell_Model --> Immune_Evasion
KRAS --> KRAS_Oncogene_Activation
style Acinar_to_Ductal_Metaplasia fill:#dbeafe
style KRAS_GM_CSF_Myeloid_Immunosuppression fill:#dbeafe
style Adaptive_CD24_Antiphagocytic_Signaling fill:#dbeafe
style Desmoplastic_Stroma fill:#dbeafe
style Acquired_RASON_Inhibitor_Resistance fill:#dbeafe
style Early_Dissemination_and_EMT fill:#dbeafe
style Exocrine_Pancreatic_Insufficiency fill:#fef3c7
style KRAS_Oncogene_Activation fill:#dbeafe
style Obstructive_Jaundice fill:#fef3c7
style Weight_Loss fill:#fef3c7
style KRAS_Regulated_Glutamine_Redox_Metabolism fill:#dbeafe
style Pancreatic_Precursor_Progression_and_Invasive_Growth fill:#dbeafe
style PDAC_Immunotherapy_PhysiCell_Model fill:#ecfccb
style Antigen_Presentation_Restoration fill:#dbeafe
style MYC_Amplification_Driven_RAS_Independent_Proliferation fill:#dbeafe
style PDAC_CAF_Mediated_Invasion_PhysiCell_Model fill:#ecfccb
style Basal_State_GM_CSF_Immunosuppressive_Circuit fill:#dbeafe
style Human_PDAC_Cell_and_Organoid_RAS_Response_Models fill:#ccfbf1
style USP20_Cholesterol_Metabolism_CD8_Exhaustion_Checkpoint fill:#dbeafe
style RAS_Independent_Cell_Cycle_Uncoupling fill:#dbeafe
style Immunosuppressive_TME_Reversibility_under_RASON_Inhibition fill:#dbeafe
style Daraxonrasib_RASON_Multiselective_Inhibitor fill:#fce7f3
style Matrix_Associated_Hypoperfusion fill:#dbeafe
style KPC_RMC_7977_Acquired_Resistance_Models fill:#ede9fe
style Metastatic_Dissemination_and_Colonization fill:#dbeafe
style Pancreatic_Exocrine_Functional_Loss fill:#dbeafe
style Tumor_Cell_FAS_Induction_and_CD8_Mediated_Killing fill:#dbeafe
style Hepatic_Metastases fill:#fef3c7
style Autophagy_Lysosome_Growth_Support fill:#dbeafe
style NBR1_Mediated_MHC_I_Autophagic_Degradation fill:#dbeafe
style Myeloid_Suppression_Relief_and_CD8_Effector_Infiltration fill:#dbeafe
style Adaptive_mTOR_and_JUN_AP1_Transcriptional_Program fill:#dbeafe
style KRAS_Dependent_Anabolic_Glucose_Metabolism fill:#dbeafe
style Macropinocytic_Protein_Scavenging fill:#dbeafe
style Immunocompetent_Mouse_PDAC_RAS_Inhibition_Models fill:#ede9fe
style FAK_Mediated_Antigen_Presentation_Suppression fill:#dbeafe
style Cyclophilin_A_Loss_and_Reduced_Tri_Complex_Engagement fill:#dbeafe
style Biliary_Drainage fill:#fce7f3
style KRAS fill:#f3e8ff
style IL1_LIF_JAK_STAT_Inflammatory_Fibroblast_Programming fill:#dbeafe
style CAF_Mediated_T_Cell_Exclusion fill:#dbeafe
style CDK8_CXCL2_Adaptive_Immune_Reversal fill:#dbeafe
style On_Target_RAS_Reactivation_and_KRAS_Amplification fill:#dbeafe
style Regulatory_T_Cell_Recruitment_after_KRAS_Inhibition fill:#dbeafe
style Experimental_KRAS_Inhibition_with_Immune_Checkpoint_Blockade fill:#fce7f3
style Senescent_Myofibroblast_Immunosuppression fill:#dbeafe
style Exosome_MIF_Liver_Premetastatic_Niche fill:#dbeafe
style Immune_Evasion fill:#dbeafe
style Chronic_Pancreatic_Inflammation fill:#dbeafe
style IL6_CAF_and_Myeloid_Rebound_after_SOS1_MEK_Inhibition fill:#dbeafe
style Tumor_Restraining_Fibroblast_Programs fill:#dbeafe
style Experimental_RAS_EGFR_STAT3_Combination fill:#fce7f3
style Pancreatic_Enzyme_Replacement fill:#fce7f3
style Tumor_Suppressor_Inactivation fill:#dbeafe
style RTK_and_Feedback_Pathway_Reactivation fill:#dbeafe
name: com_Chronic_Pancreatitis__Pancreatic_Ductal_Adenocarcinoma
creation_date: "2026-08-27T00:00:00Z"
curation_status: CANDIDATE
notes: >-
Split out of the former `kb/disorders/Metastatic_Pancreatic_Adenocarcinoma.yaml`'s
(since folded into `Pancreatic_Ductal_Adenocarcinoma`, design decisions §3a)
`environmental:` block (dismech#8296, dismech#8551). That entry listed
`Chronic pancreatitis` as an exposure, but chronic pancreatitis is a
first-class `Disease` entry in its own right
(`kb/disorders/Chronic_Pancreatitis.yaml`) rather than something external to
the organism acting on it.
`disease_b` is `Pancreatic_Ductal_Adenocarcinoma`, not the
`Metastatic_Pancreatic_Adenocarcinoma` entry this row came from. The cohort
evidence measures incident pancreatic cancer in a chronic pancreatitis
population without reference to stage at presentation, and nothing cited here
addresses the metastatic entity specifically. Attaching a directed risk edge
to the metastatic entry would assert more than the sources support -- the same
correction the review of dismech#8195 applied to
`com_Liver_Cirrhosis__Hepatocellular_Carcinoma`.
The signal below uses the standardized incidence ratio computed after
excluding the first two years of follow-up, 16.5 rather than the headline
26.3. The unrestricted figure is inflated by cancers already present when
pancreatitis was diagnosed, which is reverse causation rather than risk.
PMID:35142721 is the more recent and more cancer-specific source and is cited
in the hypothesis below, but the signal metric stays the 1993 cohort's SIR
because a standardized incidence ratio measured forward from a defined
pancreatitis cohort against expected population rates is a directed A_BEFORE_B
quantity, which is what this slot holds; the meta-analysis reports incidence
rising with disease duration rather than a single ratio.
`kb/disorders/Pancreatic_Ductal_Adenocarcinoma.yaml` keeps its own
`Chronic Pancreatitis` entry under `environmental:` rather than folding it in
here, and the two divide the labour deliberately: that row carries the
mechanistic route into the pathograph, which a comorbidity entry cannot
express, and this entry carries the disease-disease epidemiology. Its `notes:`
cross-references this file.
disease_a:
slug: Chronic_Pancreatitis
preferred_term: chronic pancreatitis
term:
id: MONDO:0005003
label: chronic pancreatitis
disease_b:
slug: Pancreatic_Ductal_Adenocarcinoma
preferred_term: pancreatic ductal adenocarcinoma
term:
id: MONDO:0005184
label: pancreatic ductal adenocarcinoma
directionality: A_BEFORE_B
effect_direction: RISK
hypotheses:
- description: >-
Sustained pancreatic inflammation and the fibrotic, regenerative response to
it provide the context from which pancreatic ductal adenocarcinoma arises,
in the same way cirrhosis does for hepatocellular carcinoma.
evidence:
- reference: PMID:38408777
reference_title: Management of chronic pancreatitis.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The disease is manifested by abdominal pain, deterioration in quality of life, food maldigestion and malabsorption, diabetes, and an increased risk for pancreatic adenocarcinoma."
explanation: >-
Names increased pancreatic adenocarcinoma risk among the established
consequences of chronic pancreatitis, in a clinical management review.
- reference: PMID:35142721
reference_title: "Chronic Pancreatitis Is a Risk Factor for Pancreatic Cancer, and Incidence Increases With Duration of Disease: A Systematic Review and Meta-analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "There is an increased risk of PDAC in patients with CP, and incidence rates increase with CP disease duration."
explanation: >-
The cancer-specific anchor for this pair, and the strongest of the two:
a systematic review and meta-analysis reporting not just elevated risk but
a dose-response in disease duration, which is the pattern expected if the
inflammation is causal rather than merely co-occurring.
association_signals:
- source: LITERATURE
method: LITERATURE_ASSOCIATION
population: >-
International Pancreatitis Study Group multicentre historical cohort, 2015
subjects with chronic pancreatitis recruited across six countries, mean
follow-up 7.4 years, with observed pancreatic cancers compared against
country-specific incidence adjusted for age and sex.
directionality: A_BEFORE_B
effect_direction: RISK
statistics:
metrics:
- metric_type: OTHER
metric_value: 16.5
notes: >-
Standardized incidence ratio of pancreatic cancer among subjects with at
least two years of follow-up, and 14.4 at five years. The unrestricted
ratio of 26.3 is deliberately not used: excluding early follow-up
removes cancers that were already present when pancreatitis was
diagnosed. Metric type is OTHER because the enum has no standardized
incidence ratio value.
evidence:
- reference: PMID:8479461
reference_title: Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "For subjects with a minimum of two or five years of follow-up, the respective standardized incidence ratios were 16.5 (95 percent confidence interval, 11.1 to 23.7) and 14.4 (95 percent confidence interval, 8.5 to 22.8)."
explanation: >-
Measures incident pancreatic cancer forward from a defined chronic
pancreatitis cohort against expected population rates, which is what a
directed A_BEFORE_B risk signal requires, and reports the lag-adjusted
ratios that exclude reverse causation.