Genetic Testing for Colon Cancer

Andrew M. Kaz; Teresa A. Brentnall

Nat Clin Pract Gastroenterol Hepatol. 2006;3(12):670-679.

Summary and Introduction

Summary

Colon cancer remains the third leading cause of death due to cancer in the US, where it affected more than 145,000 individuals in 2005. Up to 30% of these cases exhibit familial clustering, which means that tens of thousands of individuals have a disease with a potentially definable genetic component. Approximately 3-5% of colon cancers are associated with high-risk, inherited colon cancer syndromes. Identification of the genes that cause these colon cancer syndromes, coupled with additional insights into their clinical course, has led to the development of specific management guidelines—and genetic tests—that can diagnose these familial disorders. These guidelines can be life-saving, not only for the affected patient, but also for their family members.

Introduction

Colon cancer is the third leading cause of death due to cancer in the US, and the cumulative lifetime risk of developing colorectal cancer is approximately 5-6%.^[1] Almost one-third of these cases exhibit familial clustering. Although the specific genetic defects involved in most moderate-risk familial colon cancers have not yet been elucidated, the molecular genetics of several high-risk, inherited, colon cancer syndromes have been determined. The clinical presentation and genetics of the major inherited colon cancer syndromes are addressed in this article, with particular attention paid to genetic testing, including its indications, methods, and potential pitfalls. Finally, the fundamental role of the genetic counselor is explored.

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Cite this: Genetic Testing for Colon Cancer - Medscape - Dec 01, 2006.

Box 1. How to Recognize an Individual With an Inherited Colon Cancer Syndrome
Colon cancer diagnosed under the age of 45 Adenomas >2 cm diagnosed under the age of 40 Multiple colonic malignancies present, either synchronous or metachronous Multiple primary cancers diagnosed, either colonic or extracolonic 10 or more adenomas present over a lifetime, along with a family history of colon cancer Multiple, closely related family members who have been diagnosed with colon cancer Colon cancer in more than one generation of the individual's family Clustering of extracolonic cancers in family members (especially gastric, breast, thyroid, and uterine)

Box 2. Amsterdam Criteria for the Diagnosis of HNPCC^[22,23]
Amsterdam I Criteria^a Three or more relatives with colorectal cancer, one of whom is a first-degree relative of the other two (FAP should be excluded) Cancer in at least two generations of the same family At least one cancer case diagnosed before the age of 50 Amsterdam II Criteria^a Three or more relatives with HNPCC-associated cancer (i.e. colorectal, endometrial, renal pelvis, small-bowel, ureteral cancers), one of whom is a first-degree relative of the other two (FAP should be excluded) Cancer in at least two generations of the same family At least one cancer case diagnosed before the age of 50 ^aAll criteria must be met. Abbreviations: FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis colorectal cancer

Box 3. Bethesda Guidelines for DNA Microsatellite Instability Testing of Colorectal Tumors^[24]
Individuals with cancer whose family meets the Amsterdam criteria Individuals with two HNPCC-associated cancers^a including synchronous and metachronous colorectal cancers or associated extracolonic cancers Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or an extracolonic HNPCC-associated cancer^a and/or a colorectal adenoma; one of these cancers diagnosed at <45 years of age, and the adenoma diagnosed at <40 years of age Individuals with colorectal cancer or endometrial cancer diagnosed at <45 years of age Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid or cribiform) on histology, diagnosed at <45 years of age Individuals with signet-ring-cell colorectal cancer diagnosed at <45 years of age Individuals with adenoma diagnosed at <40 years of age Meeting any one of these criteria is sufficient to proceed with microsatellite instability testing. ^aHNPCC-associated cancers include endometrial, gastric, ovarian, hepatobiliary, small bowel, or transitional cell cancers of the renal pelvis or ureter. Abbreviation: HNPCC = hereditary nonpolyposis colorectal cancer

Box 3. Bethesda Guidelines for DNA Microsatellite Instability Testing of Colorectal Tumors^[24]
Individuals with cancer whose family meets the Amsterdam criteria Individuals with two HNPCC-associated cancers^a including synchronous and metachronous colorectal cancers or associated extracolonic cancers Individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or an extracolonic HNPCC-associated cancer^a and/or a colorectal adenoma; one of these cancers diagnosed at <45 years of age, and the adenoma diagnosed at <40 years of age Individuals with colorectal cancer or endometrial cancer diagnosed at <45 years of age Individuals with right-sided colorectal cancer with an undifferentiated pattern (solid or cribiform) on histology, diagnosed at <45 years of age Individuals with signet-ring-cell colorectal cancer diagnosed at <45 years of age Individuals with adenoma diagnosed at <40 years of age Meeting any one of these criteria is sufficient to proceed with microsatellite instability testing. ^aHNPCC-associated cancers include endometrial, gastric, ovarian, hepatobiliary, small bowel, or transitional cell cancers of the renal pelvis or ureter. Abbreviation: HNPCC = hereditary nonpolyposis colorectal cancer

Table 1. Inherited Colon Cancer Syndromes, Their Causative Genes, and the Indications for, and Costs and Sensitivity of Genetic Testing
Syndrome	Causative gene or genes	Indications for genetic testing	Cost of genetic testing (US$)^a	Sensitivity of genetic testing in an index case (%)^b
FAP and AFAP	APC	>100 colon adenomas; first-degree relative of patients with FAP >10-20 cumulative colon adenomas (suspect AFAP); first-degree relative of patients with AFAP	285-1,650	80-90
HNPCC	MLH1, MLH2, MLH6, PMS2	Amsterdam Criteria or any of the first three revised Bethesda guidelines met; first-degree relative with a known mutation in DNA mismatch repair genes; patients with MSI-high tumor test result	200-2,900	50-70
JPS	SMAD4, BMPR1A	Clinical criteria for JPS met; first-degree relative of person with known MADH4 or BMPR1A mutation	200-1,625	40-60
PJS	STK11	Clinical criteria for PJS met; first-degree relative of person with known STK11 mutation	200-1,400	30-70
MAP	MUTYH	>15 colon adenomas in an individual who tested negative for APC mutations; first-degree relative of patient with MAP	375-1,250	Up to 98

^aData from laboratories identified on the GeneTests website.^[20]
^bMore information has been published elsewhere.^[1,56]
Abbreviations: AFAP = attenuated familial adenomatous polyposis; FAP = familial adenomatous polyposis; HNPCC = hereditary nonpolyposis colorectal cancer; JPS = juvenile polyposis syndrome; MAP = MUTYH-associated polyposis; MSI = microsatellite instability; PJS = Peutz-Jeghers syndrome

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Genetic Testing for Colon Cancer

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