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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor={{Rim}}, {{AJL}} {{Alison}}
|QuestionAuthor={{Rim}} (Reviewed by William J Gibson and {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Pathology
|MainCategory=Pathology
Line 21: Line 21:
|MainCategory=Pathology
|MainCategory=Pathology
|SubCategory=Gastrointestinal
|SubCategory=Gastrointestinal
|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?
|Prompt=A 45-year-old man presents to the physician's office for an annual checkup. 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?
|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.
|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.


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".
|AnswerA=C-KIT
 
|AnswerAExp=''[[C-KIT]]'' oncogene is associated with gastrointestinal stromal tumors ([[GIST]]).
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.
|AnswerB=RET
 
|AnswerBExp=The ''[[Ret gene|RET oncogene]]'' is associated with [[multiple endocrine neoplasia]] (MEN) syndromes 2A and 2B
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.
|AnswerC=ABL
 
|AnswerCExp=The ''[[Abl gene|ABL oncogene]]'' is associated with [[chronic myelogenous leukemia]] ([[CML]]).
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.
|AnswerD=KRAS
|AnswerA=C-kit
|AnswerDExp=The [[KRAS]] oncogene is associated with colorectal cancer.
|AnswerAExp=The [[C-kit]] oncogene is associated with [[GIST]].
|AnswerE=C-MYC
|AnswerB=Ret
|AnswerEExp=The [[C-MYC]] oncogene is associated with [[Burkitt's lymphoma]].
|AnswerBExp=The [[Ret gene|Ret oncogene]] is associated with [[MEN|MEN syndrome]], type IIa and IIb.
|EducationalObjectives=Mutations in [[Ras|KRAS]] oncogene are implicated in the tumorigenesis of [[colon cancer]]. ''KRAS'' mutation leads to uncontrolled MAP Kinase signaling of the colonic epithelium.
|AnswerC=Abl
|References=Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-67.<br>
|AnswerCExp=The [[Abl gene|Abl oncogene]] is associated with CML.
First Aid 2014 page 359 <br>
|AnswerD=Ras
|AnswerDExp=The [[Ras]] oncogene is associated with colon carcinoma.
|AnswerE=C-myc
|AnswerEExp=The [[C-myc]] is associated with [[Burkitt's lymphoma]].
|EducationalObjectives=Mutations in [[Ras|K-ras]] oncogene are implicated in the carcinogenesis of [[colon cancer]].
|References=First Aid 2014 page 359 <br> Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-67.
|RightAnswer=D
|RightAnswer=D
|WBRKeyword=Cancer, Colon cancer, Polyp, FAP, Familial adenomatous polyposis,
|WBRKeyword=Cancer, Colon cancer, Polyp, FAP, Familial adenomatous polyposis, CRC, Colorectal cancer
|Approved=Yes
|Approved=Yes
}}
}}

Revision as of 21:56, 7 November 2014
Author [[PageAuthor::Rim Halaby, M.D. [1] (Reviewed by William J Gibson and Yazan Daaboul, M.D.)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Pathology
Sub Category SubCategory::Gastrointestinal
Prompt [[Prompt::A 45-year-old man presents to the physician's office for an annual checkup. 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 AnswerA::C-KIT
Answer A Explanation [[AnswerAExp::C-KIT oncogene is associated with gastrointestinal stromal tumors (GIST).]]
Answer B AnswerB::RET
Answer B Explanation [[AnswerBExp::The RET oncogene is associated with multiple endocrine neoplasia (MEN) syndromes 2A and 2B]]
Answer C AnswerC::ABL
Answer C Explanation [[AnswerCExp::The ABL oncogene is associated with chronic myelogenous leukemia (CML).]]
Answer D AnswerD::KRAS
Answer D Explanation [[AnswerDExp::The KRAS oncogene is associated with colorectal cancer.]]
Answer E AnswerE::C-MYC
Answer E Explanation [[AnswerEExp::The C-MYC oncogene is associated with Burkitt's lymphoma.]]
Right Answer RightAnswer::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 Approved::Yes
Keyword WBRKeyword::Cancer, WBRKeyword::Colon cancer, WBRKeyword::Polyp, WBRKeyword::FAP, WBRKeyword::Familial adenomatous polyposis, WBRKeyword::CRC, WBRKeyword::Colorectal cancer
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