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. 2018 Oct;20(10):1167-1174.
doi: 10.1038/gim.2017.254. Epub 2018 Jan 18.

MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer

Maegan E Roberts  1 , Sarah A Jackson  2 , Lisa R Susswein  2 , Nur Zeinomar  3 , Xinran Ma  3 , Megan L Marshall  2 , Amy R Stettner  2 , Becky Milewski  2 , Zhixiong Xu  2 , Benjamin D Solomon  2 , Mary Beth Terry  3 , Kathleen S Hruska  2 , Rachel T Klein  2 , Wendy K Chung  4
Affiliations

MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer

Maegan E Roberts et al. Genet Med. 2018 Oct.

Abstract

Purpose: An association of Lynch syndrome (LS) with breast cancer has been long suspected; however, there have been insufficient data to address this question for each of the LS genes individually.

Methods: We conducted a retrospective review of personal and family history in 423 women with pathogenic or likely pathogenic germ-line variants in MLH1 (N = 65), MSH2 (N = 94), MSH6 (N = 140), or PMS2 (N = 124) identified via clinical multigene hereditary cancer testing. Standard incidence ratios (SIRs) of breast cancer were calculated by comparing breast cancer frequencies in our study population with those in the general population (Surveillance, Epidemiology, and End Results 18 data).

Results: When evaluating by gene, the age-standardized breast cancer risks for MSH6 (SIR = 2.11; 95% confidence interval (CI), 1.56-2.86) and PMS2 (SIR = 2.92; 95% CI, 2.17-3.92) were associated with a statistically significant risk for breast cancer whereas no association was observed for MLH1 (SIR = 0.87; 95% CI, 0.42-1.83) or MSH2 (SIR = 1.22; 95% CI, 0.72-2.06).

Conclusion: Our data demonstrate that two LS genes, MSH6 and PMS2, are associated with an increased risk for breast cancer and should be considered when ordering genetic testing for individuals who have a personal and/or family history of breast cancer.

Keywords: Lynch syndrome; MSH6; PMS2; breast cancer; mismatch repair.

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Conflict of interest statement

M.E.R., S.A.J., L.R.S., M.L.M., A.R.S., B.M., and Z.X. are employed by GeneDx/BioReference Laboratories and have a salary as the only disclosure. W.K.C. is a former employee of BioReference Laboratories. K.S.H., R.T.K., and B.D.S. disclose stock and employment with GeneDx/BioReference Laboratories/Opko. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Personal and family history.
(a) Personal history of breast and Lynch syndrome (LS)-associated cancers. Women with multiple cancers are counted more than once. Fallopian tube and primary peritoneal cancer were both included as ovarian cancer. Unaffected: no history of cancer but could have a history of colorectal polyps. (b) Personal history: breast cancer only versus other histories. Individuals are counted only once. Breast only: breast cancer, but no history of a LS-associated or any other cancer; Breast and Lynch: breast cancer plus a LS-associated tumor; Breast and other: breast cancer and possibly another non-LS-associated tumor; Lynch: LS-associated tumor and possibly other cancers; Other cancer: history of cancer that is not breast or a LS-associated tumor. (c) Family history: average number of cancer cases per family. Includes family history data only, not probands. Seven individuals were related to someone else in our cohort, but their families were only counted once. Total families = 416.
Figure 2
Figure 2. Cumulative incidence of breast cancer.
All study participants with breast cancer and a prior cancer diagnosis were assessed to see if there were any potential treatment-related risks that could have contributed to their breast cancer. It was determined that no study participants needed to be excluded based on previous treatment.
Figure 3
Figure 3. Clinical criteria.
Each family is only counted once. Total families = 416. NCCN HBOC, National Comprehensive Cancer Network Hereditary Breast and Ovarian Cancer.
See this image and copyright information in PMC

Comment in

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