graph LR
Exocrine_Insufficiency["Exocrine Insufficiency"]
Recurrent_Acinar_Cell_Injury["Recurrent Acinar Cell Injury"]
Smoking["Smoking"]
Alcohol_Consumption["Alcohol Consumption"]
Endocrine_Insufficiency["Endocrine Insufficiency"]
Weight_Loss["Weight Loss"]
Diabetes_Mellitus["Diabetes Mellitus"]
Steatorrhea["Steatorrhea"]
Exocrine_Insufficiency --> Steatorrhea
Exocrine_Insufficiency --> Weight_Loss
Endocrine_Insufficiency --> Diabetes_Mellitus
Alcohol_Consumption --> Recurrent_Acinar_Cell_Injury
Smoking --> Recurrent_Acinar_Cell_Injury
style Exocrine_Insufficiency fill:#dbeafe
style Recurrent_Acinar_Cell_Injury fill:#dbeafe
style Smoking fill:#dcfce7
style Alcohol_Consumption fill:#dcfce7
style Endocrine_Insufficiency fill:#dbeafe
style Weight_Loss fill:#fef3c7
style Diabetes_Mellitus fill:#fef3c7
style Steatorrhea fill:#fef3c7
graph LR
USP20_Cholesterol_Metabolism_CD8_Exhaustion_Checkpoint["USP20 Cholesterol-Metabolism CD8 Exhaustion Checkpoint"]
Tumor_Suppressor_Inactivation["Tumor Suppressor Inactivation"]
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"]
Regulatory_T_Cell_Relief["Regulatory T-Cell Relief"]
Tumor_Cell_FAS_Induction_and_CD8_Mediated_Killing["Tumor-Cell FAS Induction and CD8-Mediated Killing"]
Early_Dissemination_and_EMT["Early Dissemination and EMT"]
Desmoplastic_Stroma["Desmoplastic Stroma"]
Chronic_Pancreatic_Inflammation["Chronic Pancreatic Inflammation"]
Perineural_Invasion["Perineural Invasion"]
Mitochondrial_Remodeling_and_Ferroptosis_Vulnerability["Mitochondrial Remodeling and Ferroptosis Vulnerability"]
Acquired_RASON_Inhibitor_Resistance["Acquired RAS(ON) Inhibitor Resistance"]
PDAC_Immunotherapy_PhysiCell_Model["PDAC Immunotherapy PhysiCell Model"]
RTK_and_Feedback_Pathway_Reactivation["RTK and Feedback Pathway Reactivation"]
CDK8_CXCL2_Adaptive_Immune_Reversal["CDK8-CXCL2 Adaptive Immune Reversal"]
Acinar_to_Ductal_Metaplasia["Acinar-to-Ductal Metaplasia"]
Mutant_KRAS_Vaccine_Immunologic_Interception["Mutant KRAS Vaccine (Immunologic Interception)"]
CAF_Mediated_T_Cell_Exclusion["CAF-Mediated T Cell Exclusion"]
Daraxonrasib_RASON_Multiselective_Inhibitor["Daraxonrasib (RAS(ON) Multiselective Inhibitor)"]
Obesity_and_Diet["Obesity and Diet"]
Immunosuppressive_TME_Reversibility_under_RASON_Inhibition["Immunosuppressive TME Reversibility under RAS(ON) Inhibition"]
Cyclophilin_A_Loss_and_Reduced_Tri_Complex_Engagement["Cyclophilin A Loss and Reduced Tri-Complex Engagement"]
Immune_Evasion["Immune Evasion"]
Antigen_Presentation_Restoration["Antigen Presentation Restoration"]
Chronic_Pancreatitis["Chronic Pancreatitis"]
MYC_Amplification_Driven_RAS_Independent_Proliferation["MYC Amplification-Driven RAS-Independent Proliferation"]
PDAC_CAF_Mediated_Invasion_PhysiCell_Model["PDAC CAF-Mediated Invasion PhysiCell Model"]
KRAS_Oncogene_Activation["KRAS Oncogene Activation"]
Tobacco_Smoking["Tobacco Smoking"]
On_Target_RAS_Reactivation_and_KRAS_Amplification["On-Target RAS Reactivation and KRAS Amplification"]
RAS_Independent_Cell_Cycle_Uncoupling["RAS-Independent Cell-Cycle Uncoupling"]
Extracellular_Vesicle_Mediated_Immune_Escape["Extracellular Vesicle-Mediated Immune Escape"]
Chronic_Pancreatic_Inflammation --> Acinar_to_Ductal_Metaplasia
Acinar_to_Ductal_Metaplasia --> Tumor_Suppressor_Inactivation
KRAS_Oncogene_Activation --> Immunosuppressive_TME_Reversibility_under_RASON_Inhibition
KRAS_Oncogene_Activation --> Acquired_RASON_Inhibitor_Resistance
KRAS_Oncogene_Activation --> Early_Dissemination_and_EMT
KRAS_Oncogene_Activation --> Acinar_to_Ductal_Metaplasia
KRAS_Oncogene_Activation --> Tumor_Suppressor_Inactivation
Tumor_Suppressor_Inactivation --> Desmoplastic_Stroma
Tumor_Suppressor_Inactivation --> Extracellular_Vesicle_Mediated_Immune_Escape
Desmoplastic_Stroma --> CAF_Mediated_T_Cell_Exclusion
CAF_Mediated_T_Cell_Exclusion --> Immune_Evasion
Extracellular_Vesicle_Mediated_Immune_Escape --> Immune_Evasion
Early_Dissemination_and_EMT --> Perineural_Invasion
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
Mitochondrial_Remodeling_and_Ferroptosis_Vulnerability --> 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
Regulatory_T_Cell_Relief --> Immunosuppressive_TME_Reversibility_under_RASON_Inhibition
USP20_Cholesterol_Metabolism_CD8_Exhaustion_Checkpoint --> Immunosuppressive_TME_Reversibility_under_RASON_Inhibition
CDK8_CXCL2_Adaptive_Immune_Reversal --> Acquired_RASON_Inhibitor_Resistance
Tobacco_Smoking --> KRAS_Oncogene_Activation
Tobacco_Smoking --> Chronic_Pancreatic_Inflammation
Chronic_Pancreatitis --> Chronic_Pancreatic_Inflammation
Obesity_and_Diet --> Chronic_Pancreatic_Inflammation
Daraxonrasib_RASON_Multiselective_Inhibitor --> KRAS_Oncogene_Activation
Mutant_KRAS_Vaccine_Immunologic_Interception --> KRAS_Oncogene_Activation
PDAC_CAF_Mediated_Invasion_PhysiCell_Model --> Desmoplastic_Stroma
PDAC_Immunotherapy_PhysiCell_Model --> Immune_Evasion
style USP20_Cholesterol_Metabolism_CD8_Exhaustion_Checkpoint fill:#dbeafe
style Tumor_Suppressor_Inactivation fill:#dbeafe
style Myeloid_Suppression_Relief_and_CD8_Effector_Infiltration fill:#dbeafe
style Adaptive_mTOR_and_JUN_AP1_Transcriptional_Program fill:#dbeafe
style Regulatory_T_Cell_Relief fill:#dbeafe
style Tumor_Cell_FAS_Induction_and_CD8_Mediated_Killing fill:#dbeafe
style Early_Dissemination_and_EMT fill:#dbeafe
style Desmoplastic_Stroma fill:#dbeafe
style Chronic_Pancreatic_Inflammation fill:#dbeafe
style Perineural_Invasion fill:#dbeafe
style Mitochondrial_Remodeling_and_Ferroptosis_Vulnerability fill:#dbeafe
style Acquired_RASON_Inhibitor_Resistance fill:#dbeafe
style PDAC_Immunotherapy_PhysiCell_Model fill:#ecfccb
style RTK_and_Feedback_Pathway_Reactivation fill:#dbeafe
style CDK8_CXCL2_Adaptive_Immune_Reversal fill:#dbeafe
style Acinar_to_Ductal_Metaplasia fill:#dbeafe
style Mutant_KRAS_Vaccine_Immunologic_Interception fill:#fce7f3
style CAF_Mediated_T_Cell_Exclusion fill:#dbeafe
style Daraxonrasib_RASON_Multiselective_Inhibitor fill:#fce7f3
style Obesity_and_Diet fill:#dcfce7
style Immunosuppressive_TME_Reversibility_under_RASON_Inhibition fill:#dbeafe
style Cyclophilin_A_Loss_and_Reduced_Tri_Complex_Engagement fill:#dbeafe
style Immune_Evasion fill:#dbeafe
style Antigen_Presentation_Restoration fill:#dbeafe
style Chronic_Pancreatitis fill:#dcfce7
style MYC_Amplification_Driven_RAS_Independent_Proliferation fill:#dbeafe
style PDAC_CAF_Mediated_Invasion_PhysiCell_Model fill:#ecfccb
style KRAS_Oncogene_Activation fill:#dbeafe
style Tobacco_Smoking fill:#dcfce7
style On_Target_RAS_Reactivation_and_KRAS_Amplification fill:#dbeafe
style RAS_Independent_Cell_Cycle_Uncoupling fill:#dbeafe
style Extracellular_Vesicle_Mediated_Immune_Escape 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.