Pancreatic ductal adenocarcinoma (PDAC) develops from somatic driver mutations that accumulate in steps, on a background of inherited and acquired predisposition. Four genes make up the core molecular signature of PDAC. The first is an activating KRAS mutation, found in about 85–95% of tumors. The other three are tumor suppressor genes that are inactivated: CDKN2A, TP53, and SMAD4. These alterations are acquired one after another as precursor lesions progress to invasive cancer.^[1][2][3][4] About 5–10% of unselected patients carry a pathogenic germline variant, most often in DNA damage repair genes. The proportion rises to about 30% in early-onset disease.^[5][2][6] Most PDAC is sporadic. Established acquired risk factors include cigarette smoking, obesity, long-standing type 2 diabetes, and chronic pancreatitis.^[2][7][8][9] The cause of a patient’s PDAC now shapes management. Universal germline testing is recommended for every patient with PDAC, and tumor profiling finds a minority with targetable alterations.^{[8][10][11][12]}

Exome and whole-genome sequencing consistently find four recurrently altered driver genes in PDAC, often called the genomic “mountains.” Alongside them is a long tail of low-frequency “hills.” The average PDAC exome carries only about 40 somatic mutations, which is a low burden for an adenocarcinoma.^[1][4][13]

Several low-frequency drivers are biologically and clinically important:^[1][4][13]

• Homologous recombination repair genes: BRCA1, BRCA2, PALB2, and ATM
• Chromatin remodeling genes: ARID1A, KDM6A, PBRM1, and SMARCA4
• TGF-β pathway components: TGFBR2, ACVR1B, and ACVR2A
• GNAS and RNF43: characteristic of PDAC that arises from intraductal papillary mucinous neoplasms (IPMNs)

These drivers fit together into a small number of core signaling pathways. That pathway-level map has replaced older descriptions of nonspecific “deregulation” of signaling molecules.^[17][18] Whole-genome analyses also detect large-scale structural events. These include copy-number changes, chromothripsis, and kataegis, which are clusters of substitutions associated with APOBEC enzymes.^[13] Prognosis and treatment selection can be refined beyond single-gene status in two further ways. Transcriptomic subtyping separates classical from basal-like tumors. Whole-genome structural classes divide tumors into stable, scattered, and unstable groups.^[2][8]

About 85–95% of PDACs arise from pancreatic intraepithelial neoplasia (PanIN). About 15–20% arise from macroscopic cystic precursors, most often IPMNs.^[14][4][7] The cell of origin is still debated. Genetic and mouse-model data support acinar-to-ductal metaplasia triggered by oncogenic KRAS activation.^[14][4] The classic sequence starts with KRAS mutation in low-grade PanIN. CDKN2A inactivation follows, and TP53 and SMAD4 loss occur in high-grade lesions.^[2][19][8] Low-grade PanINs are present in 75–85% of adult pancreata, and nearly all of them harbor KRAS mutations, yet very few progress. Progression requires tumor suppressors to be lost one after another over decades. The lesion must also escape immune surveillance and overcome a stroma that does not support tumor growth.^[2]

About 5–10% of unselected PDAC patients carry a pathogenic germline variant. The figure is about 30% in early-onset disease.^[5][2][6] About half of carriers have no family history of the disease.^[10]

Most PDAC is sporadic. The established acquired risk factors are summarized below; see Pancreatic cancer risk factors for more detail.^[2][7][8][9]

• Universal germline testing: NCCN and ASCO recommend germline testing for every patient with newly diagnosed PDAC, whether or not there is a family history. Testing should use a multigene panel that includes BRCA1/2, PALB2, ATM, CDKN2A, STK11, and the mismatch repair genes (NCCN category 2A).^{[8][10][11][12]} Testing only patients with a family history misses about half of carriers.^[10]
• Somatic tumor profiling: Recommended in locally advanced or metastatic disease to look for actionable alterations. These include BRCA1/2 and PALB2 (platinum or PARP inhibitors), MSI-H/dMMR (immunotherapy), KRAS G12C, and rare NTRK or other fusions. KRAS wild-type tumors should be profiled with particular care.^[11][8][18] Even so, matched targeted therapy applies to fewer than 5% of PDACs.^[18]
• Risk modification: Counsel patients on quitting smoking. In adults aged 50 or older with new-onset diabetes and other suggestive features, evaluate for an occult malignancy.^[2][7]
• Cascade testing and surveillance: Refer high-risk germline carriers for surveillance; see Pancreatic cancer screening.^[12][20]

• Whether PDAC originates from acinar or ductal cells remains unresolved.^[14][4]
• It is disputed whether heavy alcohol use is an independent risk factor or acts only through pancreatitis.^[8][9]
• Guidelines differ on surveillance eligibility for BRCA1, ATM, and PALB2 carriers who have no family history.^[20][12]
• Germline risk profiles vary by ancestry. For example, BRCA1/2, ATM, and CDKN2A variants are less frequent in Asian cohorts, which limits how widely a single panel applies.^[21]