WBR0247

Author	[[PageAuthor::Rim Halaby, M.D. [1], Alison Leibowitz [2] (Reviewed by Alison Leibowitz)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pathology
Sub Category	SubCategory::Gastrointestinal
Prompt	[[Prompt::A 45-year-old male patient, whose father had colon cancer at the age of 55, presents to the physician's office for an annual checkup. You recommend that he undergoes a screening colonoscopy, 10 years prior to the age his father had colon cancer. You explain that most cases of colon cancer are sporadic, while some are familial and are related to gene mutations. A mutation in which of the following genes is most likely associated with familial colon cancer?]]
Answer A	AnswerA::C-kit
Answer A Explanation	[[AnswerAExp::The C-kit oncogene is associated with GIST.]]
Answer B	AnswerB::Ret
Answer B Explanation	[[AnswerBExp::The Ret oncogene is associated with MEN syndrome, type IIa and IIb.]]
Answer C	AnswerC::Abl
Answer C Explanation	[[AnswerCExp::The Abl oncogene is associated with CML.]]
Answer D	AnswerD::Ras
Answer D Explanation	[[AnswerDExp::The Ras oncogene is associated with colon carcinoma.]]
Answer E	AnswerE::C-myc
Answer E Explanation	[[AnswerEExp::The C-myc is associated with Burkitt's lymphoma.]]
Right Answer	RightAnswer::D
Explanation	[[Explanation::Familial adenomatosis polyposis (FAP) is an inherited condition, with an autosomal dominant mutation of the APC gene on chromosome 5q. FAP is often characterized by the excessive growth of polyps that progress to colon cancer in affected individuals. The genetic and clinical evolution of colon cancer proceeds through a well characterized adenoma-to-carcinoma” sequence. In normal individuals, two functioning copies of the APC gene exist in all of the cells of their bodies at birth. To biallelically inactivate the APC gene, both copies must be mutated or deleted. However, in individuals with FAP, one copy of the gene has already been inactivated since birth, thereby shortening the somatic process of biallelic inactivation to one "hit". Loss-of-function of the APC genes leads to hyperactivation of the beta-catenin pathway, a crucial signaling pathway governing growth control in the colonic epithelium. Therefore, loss of APC leads to the formation of a small polyp. However, inactivation of APC alone is not sufficient to lead to frank carcinoma. Secondary oncogenic genetic alterations must occur, the most common of which is mutation of a single amino acid in the KRAS gene. This mutation in KRAS leads to uncontrolled MAP Kinase signaling of the colonic epithelium. Further loss of the tumor suppressor genes p53 and SMAD4, lead to the transformation of an adenoma into a carcinoma. The cooperation of the APC, KRAS and TP53 genes in colon cancer is the best documented instance of "oncogene cooperation" in cancer biology and was originally described by Bert Vogelstein in 1990. Note: Some USMLE texts report that DCC is the tumor suppressor gene involved in colon cancer on chromosome 18, this is wrong. Most cancer biologists now agree that the gene on chromosome 18 whose deletion provides a fitness advantage is SMAD4. Educational Objective: Mutations in K-ras oncogene are implicated in the carcinogenesis of colon cancer. References: First Aid 2014 page 359 Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-67.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Cancer, WBRKeyword::Colon cancer, WBRKeyword::Polyp, WBRKeyword::FAP, WBRKeyword::Familial adenomatous polyposis
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