A 55-year-old with pancreatic ductal adenocarcinoma undergoes molecular profiling. The tumor shows KRAS G12D mutation, homozygous CDKN2A deletion, TP53 mutation, and SMAD4 deletion. Which of these alterations is most commonly ACQUIRED LATEST in the progression model of PDAC (PanIN → invasive carcinoma)?
- A SMAD4 (DPC4) deletion ✓
- B KRAS mutation
- C CDKN2A (p16) deletion
- D TP53 mutation
Correct answer: A. SMAD4 (DPC4) deletion
Explanation
The molecular progression model of PDAC follows a defined temporal sequence: KRAS mutation is the earliest event (occurring in PanIN-1A/B, >90% of cases); CDKN2A (p16) loss occurs in PanIN-2; TP53 mutation occurs in PanIN-3 (high-grade); SMAD4/DPC4 deletion is the latest event, occurring at or near the transition to invasive carcinoma. SMAD4 loss correlates with widespread metastasis. Loss of SMAD4 IHC staining in ~55% of PDAC and is used as a diagnostic marker on core biopsy; its presence distinguishes PDAC from autoimmune pancreatitis (SMAD4 preserved).
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.