A 62-year-old presents with painless obstructive jaundice and a 2.5 cm mass in the pancreatic head. CT shows duct dilation ('double duct sign'). Biopsy confirms pancreatic ductal adenocarcinoma (PDAC). Molecular analysis would most likely show which combination of driver mutations?

• A KRAS mutation + CDKN2A loss + SMAD4 loss + TP53 mutation ✓
• B BRAF V600E + MLH1 methylation + APC mutation
• C IDH1 mutation + ATRX loss + TERT promoter mutation
• D VHL deletion + mTOR activation + PTEN loss

Explanation

PDAC follows a defined genetic progression from PanIN (pancreatic intraepithelial neoplasia) to invasive carcinoma driven by sequential mutations: KRAS mutation (>95% of PDAC, early event in PanIN-1), followed by CDKN2A (p16/INK4a) loss (PanIN-2), then TP53 mutation and SMAD4 loss (PanIN-3). SMAD4 (DPC4) loss, found in ~55% of PDACs, predicts early hematogenous metastasis and poor prognosis; SMAD4 loss can be detected immunohistochemically. IDH mutations are characteristic of intrahepatic cholangiocarcinoma; VHL/mTOR mutations characterize clear cell renal carcinoma; BRAF/MLH1 is the colorectal pathway.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.