A 68-year-old man presents with progressive painless jaundice, pruritus, and dark urine for 3 weeks. On examination, a non-tender, palpable gallbladder is noted. Contrast-enhanced pancreas-protocol CT shows a firm, ill-defined grey-white mass in the pancreatic head with concurrent dilatation of the common bile duct and pancreatic duct. The structure marked **B** in the diagram is suspected. Which of the following molecular alterations is the EARLIEST and MOST FREQUENT in the pathogenesis of this lesion?
A. CDKN2A/p16 deletion
B. KRAS mutation (present in >90% of cases)
C. SMAD4/DPC4 inactivation
D. TP53 mutation with loss of p53 function
Explanation
Why KRAS mutation (present in >90% of cases) is right
KRAS mutation is the earliest and near-universal molecular alteration in pancreatic ductal adenocarcinoma (PDAC), occurring in >90% of cases and present even in early PanIN-1 lesions. According to Sabiston Textbook of Surgery 21e and NCCN guidelines, KRAS is the initiating event in the multi-step progression through pancreatic intraepithelial neoplasia (PanIN-1 → PanIN-3) to invasive PDAC. This makes it the most frequent and earliest mutation in the adenocarcinoma marked B.
Why each distractor is wrong
TP53 mutation with loss of p53 function: While TP53 mutations are common in PDAC (occurring in ~50-70% of cases), they occur LATER in the progression sequence, typically at the PanIN-3 stage or during malignant transformation, not as the initiating event.
SMAD4/DPC4 inactivation: SMAD4 loss is a late event in PDAC pathogenesis, associated with advanced disease and poor prognosis. It is present in only ~30% of cases and occurs after KRAS and TP53 alterations.
CDKN2A/p16 deletion: CDKN2A inactivation occurs early but is NOT the earliest event; it typically follows KRAS mutation in the PanIN progression and is present in ~90% of cases but is secondary to KRAS.
High-YieldNEET PG
KRAS is the "gatekeeper" mutation in PDAC—present in >90%, earliest event, and found in PanIN-1 lesions; TP53 and SMAD4 are late events associated with progression to invasive disease.
Sabiston Textbook of Surgery 21e; NCCN Pancreatic Adenocarcinoma 2024
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