Cancer Risk with the Lynch Syndrome PMS2 Gene

Lynch syndrome, which accounts for 4% or more of colorectal cancer (CRC) in the West, is due to autosomal dominant mutations in the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, or EPCAM. Routine testing of CRC pathology for deficiency of these proteins is advocated to identify high-risk patients for genetic counseling and more intensive cancer screening. However, potential variation in cancer risk by specific mutation has not been clearly defined.

To determine cancer risks associated with the PMS2 mutation, European investigators conducted a large multicenter cohort study involving 98 PMS2 families and 377 proven mutation carriers, 97% of whom had heterozygous mutations.

The cumulative risks to age 70 for CRC were 19% in men and 11% in women with PMS2 mutations, and the risk for endometrial cancer to age 70 was 12%; these risks are lower than estimates for patients with the more common MLH1 and MSH2 mutations. CRC diagnosis occurred at a younger age in probands versus family members (mean age, 47 vs. 58 years; P<0.001). Other Lynch-related cancers observed — including small bowel, ovarian, breast, and renal pelvis cancer — were uncommon but present at higher rates than in the general population. Cancer risk varied among families and was suggestive of other potential environmental or genetic modulating risk factors.