Next-Generation Strategies for Hereditary Colorectal Cancer Risk Assessment

An asymptomatic 36-year-old woman was recommended by her primary care physician to undergo her first-ever screening colonoscopy because of her family history (Fig 1). Her brother died of metastatic microsatellite stable rectal adenocarcinoma at age 45 years. Her 70-year-old father had a lifetime total of eight colorectal adenomas beginning at age 50 years. After a high-quality bowel preparation, colonoscopy successfully visualized the entire colon with intubation of the ileocecal valve; it revealed a 1-cm adenoma in the ascending colon, two 5-mm adenomas in the descending colon, a 4-mm rectal hyperplastic polyp, and a 4-cm ulcerated mass in the sigmoid colon. Biopsy of the mass showed low-grade invasive adenocarcinoma. Immunohistochemistry (IHC) of the adenocarcinoma revealed intact staining of the MLH1, MSH2, MSH6, and PMS2 proteins. Molecular testing identified a somatic KRAS G12C mutation and revealed stability at five of five mononucleotide microsatellite markers (BAT25, BAT26, NR21, NR24, and NR27) by polymerase chain reaction. Computed tomography showed no evidence of metastatic disease in the chest, abdomen, or pelvis. Laboratory testing demonstrated a carcinoembryonic antigen level of 4.3 ng/mL. Before undergoing surgical resection, she was referred for consideration of genetic testing to evaluate for an underlying hereditary cancer predisposition syndrome.