WBR0247

Author	[[PageAuthor::Rim Halaby, M.D. [1] (Reviewed by William J Gibson and Yazan Daaboul, M.D.)]]
Exam Type	USMLE Step 1
Main Category	Pathology
Sub Category	Gastrointestinal
Prompt	A 45-year-old man presents to the physician's office for an annual check-up. His father was diagnosed with colon cancer at the age of 55, and the physician now recommends that the patient undergoes a screening colonoscopy. The physician then explains that the majority of colon cancer cases are due to sporadic development, but familial forms are also present. A mutation in which gene is most likely associated with familial colon cancer?
Answer A	C-KIT
Answer A Explanation	[[AnswerAExp::C-KIT oncogene is associated with gastrointestinal stromal tumors (GIST).]]
Answer B	RET
Answer B Explanation	[[AnswerBExp::The RET oncogene is associated with multiple endocrine neoplasia (MEN) syndromes 2A and 2B]]
Answer C	BRAF
Answer C Explanation	The BRAF oncogene is associated with melanoma.
Answer D	KRAS
Answer D Explanation	[[AnswerDExp::The KRAS oncogene is associated with colorectal cancer.]]
Answer E	C-MYC
Answer E Explanation	[[AnswerEExp::The C-MYC oncogene is associated with Burkitt's lymphoma.]]
Right Answer	D
Explanation	[[Explanation::Familial adenomatosis polyposis (FAP) is an autosomal dominant genetic disease caused by a mutation in the APC gene on chromosome 5q. FAP is often characterized by the development of hundreds of polyps that ultimately 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 cells. To bi-allelically 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 bi-allelic inactivation to one "hit". Loss-of-function of the APC gene leads to hyperactivation of the beta-catenin pathway, a crucial signaling pathway that governs growth control in the colonic epithelium. Therefore, loss of APC leads to the formation of small polyps. However, inactivation of APC alone is insufficient to cause carcinoma. Secondary oncogenic genetic alterations must occur, the most common of which is mutation of a single amino acid in the KRAS gene. KRAS mutation leads to uncontrolled MAP kinase signaling of the colonic epithelium. Further loss of the tumor suppressor genes TP53 and SMAD4 lead to the transformation of the tumor from 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. Educational Objective: Mutations in KRAS oncogene are implicated in the tumorigenesis of colon cancer. KRAS mutation leads to uncontrolled MAP kinase signaling of the colonic epithelium. References: Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-67. First Aid 2014 page 359 ]]
Approved	Yes
Keyword	Cancer, Colon cancer, Polyp, FAP, Familial adenomatous polyposis, CRC, Colorectal cancer
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