A 21-year-old woman is hospitalized for elective subtotal colectomy with ileo-rectal anastomosis due to abnormal colonoscopic findings. She underwent screening colonoscopy because of family history of colon cancer. Her maternal grandfather died of metastatic colon cancer, and her mother was also recently diagnosed with colon cancer. The patient has no other medical problems, takes no medications, and does not use tobacco, alcohol, or illicit drugs. The surgery is performed with no operative complications. Numerous lesions are present throughout the resected colon, some of which are shown in the histopathology exhibit below. Genetic testing is most likely to reveal a germline mutation resulting in which of the following effects?

Question

A 21-year-old woman is hospitalized for elective subtotal colectomy with ileo-rectal anastomosis due to abnormal colonoscopic findings.  She underwent screening colonoscopy because of family history of colon cancer.  Her maternal grandfather died of metastatic colon cancer, and her mother was also recently diagnosed with colon cancer.  The patient has no other medical problems, takes no medications, and does not use tobacco, alcohol, or illicit drugs.  The surgery is performed with no operative complications.  Numerous lesions are present throughout the resected colon, some of which are shown in the histopathology exhibit below.  Genetic testing is most likely to reveal a germline mutation resulting in which of the following effects?

Quizplus · Accepted Answer

11ec160b_39f4_5d4e_9249_ddeedb050dbd_MD0001_00 This young patient has evidence of multiple adenomas on histopathologic examination of the colon, raising strong suspicion for the autosomal dominant disorder familial adenomatous polyposis (FAP). Patients with FAP usually develop innumerable colonic polyps in the second or third decade of life. The lifetime risk that ≥1 of these polyps will transform to invasive colon cancer is nearly 100%. Therefore, prophylactic colectomy is usually advised. FAP is caused by a germline mutation in the tumor suppressor gene adenomatous polyposis coli (APC). Although it is an autosomal dominant disorder, a spontaneous mutation to the other (wild-type) APC gene is required for expression (which usually occurs in the patient's teens or twenties). APC encodes for a protein that degrades beta-catenin. Loss of function of the APC protein increases cellular concentrations of beta-catenin, which activates transcriptional proteins that lead to intestinal crypt hyperproliferation; accumulation of subsequent mutations leads to development of polyps. APC plays a crucial role in generation of both hereditary and spontaneous forms of colon cancer. Nearly 80% of spontaneous colon cancer has spontaneous mutations to both sets of APC genes; the remainder typically has activating mutations to downstream products of the APC pathway. (Choice A) RAS oncogene mutations lead to constitutively active growth signal transduction. RAS mutations (particularly KRAS) are present in approximately 50% of sporadic colon cancers. However, FAP is not caused by an initial mutation in RAS. (Choice B) TP53 acts as a transcriptional activator of genes that inhibit cellular growth. TP53 mutations are the most common genetic abnormality seen in all cancers, and they are present in approximately 75% of colorectal cancers. Germline mutation to TP53 is associated with Li Fraumeni syndrome; these patients have increased risk of many tumor types but, for unclear reasons, are not at particularly increased risk for colorectal cancer. (Choice C) Lynch syndrome is associated with hereditary nonpolyposis colorectal cancer due to germline mutation to one of the DNA mismatch repair genes (eg, MSH2/6, MLH1). These patients do not have extensive polyposis in the colon but are very likely to develop colon cancer (from dysplasia in flat colonic mucosa). (Choice D) Telomerase prevents the shortening of telomeres during cellular division, which extends the life of the cell. Telomerase activity is increased in many cancer types but is not especially linked to colorectal cancer. Educational objective: Familial adenomatous polyposis is an autosomal-dominant hereditary disorder that results in the formation of innumerable colonic polyps and a nearly 100% risk of colorectal cancer. It arises due to germline mutation in the adenomatous polyposis coli tumor suppressor gene.

A 21-Year-Old Woman Is Hospitalized for Elective Subtotal Colectomy with Ileo-Rectal