In pancreatic ductal adenocarcinoma (PDAC), the molecular progression from normal duct epithelium to carcinoma follows a well-characterized PanIN sequence. Which of the following correctly sequences the key driver mutations in order of acquisition?

• A TP53 mutation → RB1 loss → KRAS activation → BRCA2 loss
• B APC mutation → beta-catenin nuclear translocation → KRAS activation → CDKN2A loss
• C SMAD4 loss → KRAS mutation → TP53 mutation → MSI-H development
• D KRAS mutation (early, PanIN 1) → CDKN2A/p16 loss (PanIN 2) → SMAD4/DPC4 and TP53 loss (PanIN 3/carcinoma) ✓

Explanation

PDAC follows a stepwise PanIN progression: activating KRAS mutations occur in >90% of PanIN-1 lesions (earliest); CDKN2A (encoding p16 tumor suppressor) inactivation occurs in PanIN-2; TP53 and SMAD4 (DPC4, a TGF-β pathway mediator) mutations are late events in PanIN-3 and invasive carcinoma. This sequence is distinct from colorectal cancer (APC first) and does not involve MSI-H as a primary 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.