A 55-year-old man presents with obstructive jaundice and a periampullary mass. CT shows a 'double duct sign' (dilatation of both common bile duct and pancreatic duct). Surgery reveals a firm, gray-white mass in the head of pancreas. Histology shows abundant desmoplastic stroma with malignant glands expressing CK7, CA19-9, and CEA. What mutation is MOST commonly the earliest genetic event in pancreatic ductal adenocarcinoma?

• A TP53 mutation — late event causing genomic instability
• B KRAS point mutation (codon 12) — present in >90% of cases, earliest initiating event ✓
• C SMAD4 (DPC4) deletion — loss of TGF-beta signaling
• D CDKN2A (p16) deletion — early event but preceded by KRAS

Explanation

KRAS point mutations at codon 12 (predominantly G12D, G12V) are found in over 90% of pancreatic ductal adenocarcinomas and represent the earliest initiating genetic event, detectable even in PanIN-1 (the earliest precursor lesion). The sequential progression model is: KRAS → CDKN2A loss → TP53 mutation → SMAD4 deletion (late event correlating with metastasis). This makes KRAS the primary therapeutic target and molecular marker of interest in pancreatic cancer.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.