WBR0095

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D. and Rim Halaby, M.D. [1])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Gastrointestinal
Prompt	[[Prompt::A 17-year-old girl presents to her primary care physician complaining of fatigue and gastrointestinal pain. Her menstrual cycle is regular with no menorrhagia or dysmenorrhea. She denies an association of her pain with food intake or bowel movements. The patient reports she has no sexual activity. Further questioning reveals that she has a strong family history of colon cancer at young age. Following appropriate work-up, flexible sigmoidoscopy reveals thousands of polyps lining her colon. The patient is referred for genetic studies. A defect in which of the following genes is most likely responsible for the patient's condition?]]
Answer A	AnswerA::''APC'' gene
Answer A Explanation	[[AnswerAExp::Tens to thousands of colonic polyps in a young adolescent patient with a positive family history of colon cancer or colectomy at young age strongly suggests a diagnosis of familial adenomatous polyposis (FAP). FAP is caused by mutations in the APC gene.]]
Answer B	AnswerB::''STK11'' gene
Answer B Explanation	[[AnswerBExp::STK11 mutations cause Peutz-Jeghers syndrome. Peutz–Jeghers syndrome, also known as hereditary intestinal polyposis syndrome, is an autosomal dominant genetic disease characterized by the development of benign hamartomatous polyps in the gastrointestinal tract and hyperpigmented macules on the lips and oral mucosa.]]
Answer C	AnswerC::''RB'' gene
Answer C Explanation	[[AnswerCExp::RB gene mutations cause familial retinoblastoma, a syndrome characterized by the development of tumors in the eyes of affected infants.]]
Answer D	AnswerD::''WNT'' gene
Answer D Explanation	[[AnswerDExp::Unlike APC, Wnt promotes the stability of proteins that contain beta-catenin. Wnt protein binds to extracellular receptors that can induce beta-catenin signaling, which can cause uncontrolled cell growth. However, inability to degrade beta-catenin is achieved in familial adenomatous polyposis via mutations in the ''APC'' gene in the presence of Wnt; whereas beta-catenin is normally degraded in the presence of a normally functioning APC protein and/or an absent Wnt signal.]]
Answer E	AnswerE::''Beta-catenin'' gene
Answer E Explanation	[[AnswerEExp::Beta catenin protein becomes dysregulated in familial adenomatous polyposis due to loss-of-function mutations of APC gene. APC protein is a negative regulator of beta-catenin protein. In the absence of a normally functioning APC protein, beta-catenin enters the nucleus and leads to the expression of proto-oncogenes involved in FAP.]]
Right Answer	RightAnswer::A
Explanation	[[Explanation::Familial adenomatous polyposis (FAP) syndrome is a genetic disorder in which tens to thousands of polyps form mainly in the epithelium of the rectum and colon during the second decade of life. While these polyps start out benign, malignant transformation into colon cancer occurs almost invariably approximately 10 years after the appearance of the polyps. FAP most commonly results from mutations in the ''APC'' gene, which normally functions to inhibit the activity of the beta-catenin transcription factor that targets c-myc and downstream proto-oncogenes. APC gene mutations in FAP may be deletions, insertions, nonsense mutations, or even missense mutations, that occur at the level of the "mutation cluster region" (MCR) of the gene. This region coincides with another region of the APC gene, which functions to regulate the degradation of beta-catenin. Absence of APC protein within the Wnt signaling pathway allows the entry of beta-catenin into the cell nucleus leading to the promotion of gene expression and polyamine metabolism in the colonic epithelium. On the other hand, the presence of APC allows colonic epithelial proteasomal degradation via ubiquitin-mediated destruction. FAP is inherited in an autosomal dominant pattern. Thus, one copy of the altered gene is sufficient to cause the disorder. It does not have a gender predominance and accounts for less than 1% of cases of colon cancer. Because mutation of the APC gene may occur spontaneously, patients may not be aware of the diagnosis until symptoms manifest. Most commonly, patients present during adolescence with constipation, diarrhea, abdominal pain, palpable abdominal masses, and weight loss. Prophylactic surgery is generally recommended before the age of 25 to prevent the development of colon cancer. There are several surgical options that involve the removal of either the colon or both the colon and rectum for patients with FAP. Extra-intestinal non-malignant tumors that may be associated with FAP include: fibromas, lipomas, sebaceous cysts, epidermoid cysts, osteomas, nasopharyngeal adenomas, and soft-tissue desmoid tumors. Extra-colonic cancers may also be associated with FAP, such as pancreatic mucinous adenocarcinomas, hepatoblastomas, and brain tumors. Gardner syndrome is a subtype of FAP that is characterized by the presence of colonic polyps, osteomas, soft tissue tumors, congenital hypertrophy of retinal pigment epithelium (CHRPE), and supernumerary teeth. Also, Turcot syndrome is characterized by FAP and the presence of malignant CNS tumors. Educational Objective: Familial adenomatous polyposis is caused by loss-of-function mutations in the APC gene. References: Half E, Bercovich D, Rozen P. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009;4:22. First Aid 2014 page 87, 359]]
Approved	Approved::Yes
Keyword	WBRKeyword::Colon, WBRKeyword::Colon cancer, WBRKeyword::Colonoscopy, WBRKeyword::Familial adenomatous polyposis, WBRKeyword::Tumor suppressor, WBRKeyword::Cancer, WBRKeyword::Colorectal cancer, WBRKeyword::Genetics, WBRKeyword::APC, WBRKeyword::protein, WBRKeyword::gene, WBRKeyword::wnt, WBRKeyword::signaling, WBRKeyword::pathway, WBRKeyword::beta, WBRKeyword::catenin, WBRKeyword::gardner, WBRKeyword::turcot, WBRKeyword::Gardner, WBRKeyword::Turcot, WBRKeyword::syndrome, WBRKeyword::syndromes, WBRKeyword::Syndrome, WBRKeyword::Syndromes, WBRKeyword::beta-catenin
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