Pancreatic intraepithelial neoplasia (PanIN) grades 1, 2, and 3 are now unified as 'low-grade PanIN' and 'high-grade PanIN' per the 2019 WHO classification. Which molecular event occurs earliest in the PanIN progression sequence, even in PanIN-1/low-grade lesions?
- A KRAS mutation (predominantly KRAS G12D or G12V) — present in >90% of even low-grade PanIN lesions ✓
- B SMAD4/DPC4 homozygous deletion — present in early PanIN lesions as an initiating event
- C TP53 mutation with nuclear p53 accumulation — occurs in transition from PanIN-1 to PanIN-2
- D CDKN2A (p16) inactivation by promoter hypermethylation — occurs exclusively in high-grade PanIN
Correct answer: A. KRAS mutation (predominantly KRAS G12D or G12V) — present in >90% of even low-grade PanIN lesions
Explanation
KRAS mutation (G12D, G12V, G12R) is the earliest and most prevalent molecular event in pancreatic ductal adenocarcinoma development, detectable in >90% of low-grade PanIN-1 lesions. The sequence is: KRAS → p16/CDKN2A loss (PanIN-1 to 2) → TP53 mutation (PanIN-2 to 3) → SMAD4/DPC4 loss and BRCA2 mutation (high-grade PanIN to invasive carcinoma). SMAD4 loss correlates with metastatic potential and occurs late in progression; TP53 mutations occur at the intermediate transition, not earliest.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.