INTRODUCTION

Hereditary colorectal cancer is underdiagnosed. In the United States as many as 1 in 400 people carry a mutation in one of the genes responsible for hereditary nonpolyposis colorectal cancer, yet most of them do not know it. Without proper screening most of these mutation carriers will develop colorectal cancer (CRC) during their lifetime. Genetic testing is available to accurately identify mutation carriers.

The most common type of inherited colorectal cancer is hereditary nonpolyposis colorectal cancer (HNPCC). The majority of HNPCC is due to mutations in one of three genes: MLH1, MSH2 or MSH6. HNPCC mutation carriers have up to an 82% chance to develop colorectal cancer by age 70. Women with an HNPCC mutation have up to a 71% chance to develop endometrial cancer and a up to a 12% chance to develop ovarian cancer by age 70. In addition, individuals with HNPCC have an increased risk for other cancers, including gastric, ureter/renal pelvis, biliary tract, small bowel, pancreatic, brain, and sebaceous adenoma. However, HNPCC mutation carriers can reduce their risk and preempt cancer by altering their surveillance strategies. It is recommended that HNPCC mutation carriers start colonoscopies at an earlier age (20-25 years) and have them more frequently (every 1-2 years). Studies have shown that with appropriate preventative measures in HNPCC, there can be up to a 56% reduction of risk in colorectal cancer and a similar reduction in colorectal cancer mortality. Women with an HNPCC mutation must also undergo increased screening for their risks of endometrial and ovarian cancers. They may also want to consider surgical intervention to remove the uterus and ovaries once childbearing is complete.

Individuals who should be offered genetic risk assessment are those with a personal or family history of:

	Colorectal cancer diagnosed before age 50
	Endometrial cancer diagnosed before age 50
	2 or more HNPCC-related cancers in an individual or family
	Relatives of an HNPCC mutation carrier

Mutations in MLH1, MSH2 and MSH6 are inherited in an autosomal dominant pattern. First degree relatives are at 50% risk to carry the same mutation. Once a mutation has been detected in a family, other family members can be tested for the specific family mutation. Those family members testing positive for the known mutation are managed more aggressively. By contrast, individuals who did not inherit the family mutation may adhere to general population screening guidelines.

You can determine the chance of an MLH1 or MSH2 mutation based upon your patient's personal and family history by using the HNPCC Mutation Prevalence Tables. Prevalence data for MSH6 mutations are not yet available.

Click here to open the HNPCC Mutation Prevalence Table in PDF format.

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