Pancreatic ductal adenocarcinoma characteristically shows near-universal mutation in KRAS. Beyond KRAS, what is the correct sequence of additional driver mutations in the PDAC precursor PanIN progression?

• A TP53 loss first → then KRAS activation → then CDKN2A loss
• B APC mutation → β-catenin accumulation → MSI development
• C CDKN2A loss (PanIN-2) → TP53 and SMAD4/DPC4 loss (PanIN-3/invasive) ✓
• D RB1 loss → followed by BRCA2 loss → then TP53 inactivation

Explanation

The PanIN-to-PDAC progression follows a characteristic mutational sequence: KRAS activation is near-universal and the initiating event (PanIN-1); CDKN2A (p16/p14ARF) deletion accumulates in PanIN-2, releasing cell-cycle arrest; TP53 mutation and SMAD4/DPC4 loss (abrogating TGF-β growth suppression) occur late (PanIN-3 and invasive carcinoma). BRCA2 mutation is a less frequent but important event. APC/β-catenin mutations characterize colorectal (Vogelstein), not pancreatic, adenocarcinoma progression. RB1 is not a primary driver in PDAC PanIN sequence. MSI pathway (microsatellite instability) occurs in ~2% of PDAC only.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.