S3287 Genomic Stability Interrupted: A Case of CHEK2 I157T Mutation in Metastatic Pancreatic Adenocarcinoma

Introduction: Exocrine pancreatic cancer is considered the fourth leading cause of cancer-related deaths in the United States. Ductal adenocarcinomas account for approximately 85% of pancreatic neoplasms. The CHEK2 mutation is associated with an increased risk of breast, stomach, and prostate cancers; however, it is rarely observed in patients with pancreatic cancer. This report highlights a case of pancreatic adenocarcinoma with a CHEK2 mutation. Case Description/Methods: A 45-year-old man with history of hypertension presented to the hospital with 2 weeks of jaundice, diarrhea, and decreased appetite. He expressed episodic abdominal discomfort 6 months ago with associated 45 lb weight loss; computed tomography abdomen/pelvis was negative at that time. Lab workup on admission revealed elevated GGT 1352, AST 256, ALT 204, total bilirubin 11.4, direct bilirubin 8.6. Hepatitis screening was negative. Computed tomography and magnetic resonance cholangiopancreatography (MRCP) revealed a 3.2 cm pancreatic head mass encasing the superior mesenteric artery with multiple liver lesions up to 3.3 cm, and intra- and extrahepatic bile duct dilation. Staging PET scan that confirmed a hypermetabolic pancreatic head mass, peripancreatic lymph nodes, and liver metastasis. Endoscopic ultrasound and fine needle aspiration of peripancreatic node was positive for stage 4 pancreatic adenocarcinoma. Patient underwent endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy, biliary stenting, and brushing for liver decompression with findings of ampullary stenosis, and intrapancreatic common bile duct strictures. He was started on FOLFIRINOX chemotherapy. NGS testing revealed TP53, KRAS with tumor mutation burden of 8.6, but no actionable targets or high MSI. Germline testing revealed a p.l157T (C.470T > C) moderate risk mutation in CHEK2 gene. Discussion: The CHEK2 protein maintains genomic stability by controlling the cell cycle, repairing damaged DNA, and participating in apoptosis. One major pathogenic CHEK2 mutation identified is I175T. The I175T mutation is a missense mutation where Isoleucine at position 157 is changed to Threonine. This genetic variant poses an increased risk for multi-organ cancers such as breast cancer, colon cancer, kidney cancer, prostate cancer, and thyroid cancer [1]. Few studies have shown CHEK2 I175T mutation contributing to Familial Pancreatic Cancer and minimal involvement in sporadic cases. Our case highlights CHEK2 I175T mutation in metastatic pancreatic cancer in a patient without risk factors or family history. The CHEK2 I175T mutation is associated with low penetrance of disease and studies linking this variant to hereditary pancreatic cancer remain limited.