A 50-year-old man is scheduled to undergo a colonoscopy for routine colorectal cancer screening. He has no abdominal pain, gross blood in the stool, constipation, change in stool caliber, or unintentional weight loss. He also has no family history of colon cancer. The procedure is uncomplicated, but the patient is found to have a small mucosal lesion (~1 cm) in his sigmoid colon. The lesion is biopsied and its histology is shown in the image below. The pathogenesis of this patient's lesion most likely began with a mutation involving which of the following genes?

Question

A 50-year-old man is scheduled to undergo a colonoscopy for routine colorectal cancer screening.  He has no abdominal pain, gross blood in the stool, constipation, change in stool caliber, or unintentional weight loss.  He also has no family history of colon cancer.  The procedure is uncomplicated, but the patient is found to have a small mucosal lesion (~1 cm) in his sigmoid colon.  The lesion is biopsied and its histology is shown in the image below.  The pathogenesis of this patient's lesion most likely began with a mutation involving which of the following genes?

Quizplus · Accepted Answer

11ec160b_39f2_8889_9249_8d2b1d1167fc_MD0001_00 The image above shows a tubular adenoma, a precursor of colorectal carcinoma. Tubular adenomas are composed of tubular glands lined by dysplastic columnar epithelial cells, which are characteristic of colonic adenomatous polyps. The malignant potential of an adenomatous polyp is partly determined by the degree of dysplasia. Mildly dysplastic cells are elongated and hyperchromatic and show loss of mucin from the cytoplasm. With continued proliferation, dysplastic cells display increased variation in shape/size (pleomorphism) as well as loss of polarity. Other findings include an increase in number/size of nucleoli, nuclear-to-cytoplasmic ratio, and number of mitotic figures. Most cases of sporadic colorectal carcinoma arise via the classic adenoma-to-carcinoma sequence (APC/beta-catenin pathway). The first mutation in this pathway usually involves the APC tumor suppressor gene, which is responsible for regulating cell growth/adhesion (patients with familial adenomatous polyposis inherit an APC gene mutation and exhibit tumorigenesis at an early age). Mutations in K-RAS, DCC (Deleted in Colon Cancer), and p53 occur later in the adenoma-to-carcinoma sequence (Choices B, C, and E). K-RAS proto-oncogene and DCC gene mutations lead to unregulated cell proliferation and avoidance of apoptosis, respectively. They are usually observed in larger adenomas (>1 cm) or carcinomas. The p53 tumor suppressor gene regulates the cell cycle and promotes repair of damaged DNA; mutations are found in most colon carcinomas but rarely adenomas. (Choice D) Mutations in DNA mismatch repair genes such as MLH1 and MSH2 result in microsatellite instability and an accumulation of genetic errors in many of the other genes implicated in colorectal carcinogenesis. Mutations in MLH1 and MSH2 cause hereditary nonpolyposis colorectal cancer (Lynch syndrome) but are not frequently associated with sporadic colorectal carcinoma. Educational objective: Mutation of the APC tumor suppressor gene is the first step in the classic adenoma-to-carcinoma sequence; it is found in most cases of sporadic colon cancer and in all patients with familial adenomatous polyposis. The microsatellite instability pathway is characterized by mutations in DNA mismatch repair genes and is implicated in the development of hereditary nonpolyposis colorectal cancer (Lynch syndrome). __________ References: Colorectal cancer: molecular features and clinical opportunities. (http://www.ncbi.nlm.nih.gov/pubmed/20498827)

A 50-Year-Old Man Is Scheduled to Undergo a Colonoscopy for Routine