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PMS2-Associated Lynch Syndrome and Cancer Risks

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Key Points

  • PMS2 mutation carriers were at increased risk of colorectal cancer and endometrial cancer.
  • No clear increase in risk was observed for ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer.

In a study reported in the Journal of Clinical Oncology, ten Broeke et al found that patients with Lynch syndrome associated with PMS2 mutation are at increased risk of colorectal and endometrial cancers but not other cancers associated with the syndrome. As noted by the investigators, Lynch syndrome associated with pathogenic variants in the DNA mismatch–repair genes MLH1, MSH2, and MSH6 is associated with colorectal and endometrial cancers, but other cancers have also been reported as part of the Lynch syndrome tumor spectrum.

Study Details

The study involved analysis of a large data set from a worldwide collaboration to determine the risk for cancers among carriers of heterozygous pathogenic PMS2 variants. In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis, with the population containing 513 confirmed carriers.

Cancer Risks

The estimated cumulative risk of colorectal cancer to age 80 years for PMS2 mutation carriers was approximately 13% for male carriers and 12% for female carriers, vs 6.6% and 4.7% in the general population, respectively. Hazard ratios were 6.51 (95% confidence interval [CI] = 2.03–20.9) for males younger than 40 years, 1.70 (95% CI = 0.89–3.24) for males older than 70 years, 6.48 (95% CI = 2.24–18.8) for females younger than 40 years, and 2.23 (95% CI = 1.21–4.12) for females older than 70 years. The estimated cumulative risk of endometrial cancer to age 80 years for PMS2 mutation carriers was approximately 13% compared with 2.4% in the general population, with a hazard ratio of 5.73 (95% CI = 2.98–11.0). PMS2 mutation carriers had no clear increase in risk for ovarian cancer or for gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer.

The investigators concluded, “Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer, but not for any other Lynch syndrome–associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.”

The study was supported by grants from the the Dutch Cancer Society, the National Cancer Institute, and others.

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

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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