Lynch syndrome

Ed Michaud, PhD

July 29, 2011

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CONDITION 

Lynch syndrome 

CLINICAL BOTTOM LINE 

• Lynch syndrome (LS), formerly called hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal dominant disorder caused by a germline mutation in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) that predisposes the patient to an increased risk of colorectal, endometrial, and other cancers. Subsequent somatic loss of function of the second normal copy of the gene is required for cancer to develop. 

• LS is the most common form of inherited colorectal and endometrial cancers, yet it remains underdiagnosed in clinical practice. Patients with LS are also at increased risk for cancers of the ovary, stomach, small intestine, pancreas, upper urinary tract, hepatobiliary tract, brain, skin, and prostate. 

• Diagnosis of LS includes a thorough review of family cancer history; screening of colorectal tumor samples for indications of LS; genetic counseling referral for patients suspected of having LS based on family history and/or positive tumor screening; and genetic testing of persons with positive tumor samples to identify the causative DNA mutation in one of four MMR genes. 

• If LS is diagnosed, the patient should receive enhanced surveillance for colorectal, endometrial, GI, and urinary tract cancers. 

• Detecting a causative mutation in one of the DNA MMR genes in a patient with LS enables predictive testing of at-risk family members and targeted surveillance of presymptomatic mutation carriers.^1-3 

WHAT IS LYNCH SYNDROME? 

LS is caused by the autosomal dominant inheritance of a mutation in an MMR gene that carries a high risk of colorectal, endometrial, and other cancers. 

Colorectal cancer 

–The estimated worldwide incidence of colorectal cancer (CRC) is 1 million people annually. 

–Approximately 3% to 5% of all persons with CRC have LS. 

–Patients with LS develop colorectal polyps in numbers similar to persons in the general population, but polyps appear at a younger age and are at a much greater risk of becoming cancerous. 

–The mean age of onset of CRC in patients with LS is 44 years. 

–Those with LS have an estimated 30% to 80% risk of developing colon cancer by age 70 years. 

–More than two-thirds of CRCs in patients with LS occur in the proximal colon. 

–Multiple synchronous or metachronous colorectal and other  LS-associated cancers may  develop. 

Endometrial cancer 

–The lifetime risk of endometrial cancer in women with LS is 20% to 60% by age 70 years. 

–Women with LS have a risk for endometrial cancer that is greater than or equal to the risk for CRC, with a mean age of onset of 46 years. 

–Half of women with LS who have both colon and endometrial cancer present with endometrial cancer first.^1-3 