Cancer Risk Associated With Lynch Syndrome PMS2 Mutation in European Cohort


Key Points

  • Carriers of PMS2 were at increased risk of colorectal cancer and endometrial cancers compared with noncarriers.
  • Risk associated with the mutation was lower than that associated with other Lynch-related mismatch repair gene mutations.

The effects of PMS2 germline mutations are less well understood than those of other Lynch syndrome–associated mismatch repair gene mutations. In a European cohort study reported in the Journal of Clinical Oncology, ten Broeke et al found that risks of colorectal cancer and endometrial cancer in mutation carriers were elevated compared with noncarriers but were lower than those associated with other Lynch syndrome mismatch repair gene mutations.

The study involved data from 98 PMS2 families including 2,548 family members and 377 proven mutation carriers. The cumulative risk of colorectal cancer for male mutation carriers by age 70 years was 19% (hazard ratio (HR) vs noncarriers = 6.92) and the cumulative risks for female carriers by this age were 11% for colorectal cancer (HR = 4.71) and 12% for endometrial cancer (HR = 8.74).

The mean age of colorectal cancer diagnosis was 52 years, with a significant difference (P < .001) observed between probands (47 years, range = 26–68 years) and other family members with PMS2 mutation (58 years, range = 31–86 years).  

Standardized incidence ratios for mutation carriers vs noncarriers were significant for overall cancer (2.2, P < .001) and cancers of the small bowel (118.9, P < .001), ovaries (12.0, P < .001), breast (3.8, P < .001), and renal pelvis (50.5, P = .0015).

As noted by the investigators, cumulative cancer risks by age 70 reported for Lynch-associated MLH1 and MSH2 mutations range from 52% to 97% for colorectal cancer and 21% to 54% for endometrial cancer and those for MSH6 mutations range from 22% to 69% for colorectal cancer and 16% to 71% for endometrial cancer.

The investigators concluded: “[Colorectal cancer] and [endometrial cancer] risks were found to be markedly lower than those previously reported for the other [mismatch repair genes]. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.”

Sanne W. ten Broeke, MD, of Leiden University Medical Center, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by the Dutch Cancer Society. For full disclosures of the study authors, visit

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