Certain Lynch syndrome mutations may up risk of breast and ovarian cancer

Last Updated: 2017-06-01

By Marilynn Larkin

NEW YORK (Reuters Health) - Although Lynch syndrome is thought to increase the risk of colorectal and/or uterine cancer, certain mutations may confer an increased risk of breast or ovarian cancer, researchers say.

Most studies describe Lynch syndrome as a hereditary condition caused by mutations in the mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2, and large deletions in EPCAM. Most cases are thought to be due to mutations in MLH1 and MSH2, raising the risk of colorectal and endometrial, as well as gastric and ovarian cancers.

To get a more complete picture of Lynch syndrome patients, Carin Espenschied of Ambry Genetics in Aliso Viejo, California and colleagues analyzed data from close to 35,000 patients who underwent multigene panel testing between 2012 to 2015.

As reported in the Journal of Clinical Oncology, online May 17, mutations in MSH6 were most frequent (29.3% of patients), followed by PMS2 (24.2%), MSH2 (23.7%), MLH1 (21.6%) and EPCAM (1.2%) - a distribution that is statistically significantly different from previous studies, according to the authors.

Of 528 patients with MMR mutations, 11.9% had breast cancer and 27.3% had colorectal cancer, with MSH6 and PMS2 mutations more frequent than MLH1 and MSH2 mutations.

Twenty-two percent of the patients with MMR mutations met BRCA1 and BRCA2 testing criteria, but not Lynch syndrome criteria, and 5.1% met neither criteria.

Among those who met BRCA1/2 but not Lynch syndrome testing criteria, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations.

“These results provide a new perspective on Lynch syndrome and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer phenotype,” the authors say.

Espenschied told Reuters Health by email, “One particularly important finding is that over 25% of mutation carriers did not meet current Lynch syndrome testing criteria, most of whom did meet NCCN guidelines for BRCA1/2 gene testing.”

“When individuals with Lynch syndrome receive the appropriate management,” she noted, “their cancer risks can be reduced significantly, so identifying individuals with increased risk is key.”

Coauthor Heather Hampel of the Ohio State University Comprehensive Cancer Center in Columbus, added, “This study suggests that it might be prudent to include the Lynch syndrome genes when ordering genetic testing for families based on a history of breast and ovarian cancer.”

Dr. Elena Stoffel, director of the University of Michigan Cancer Genetics Clinic in Ann Arbor, told Reuters Health, “This study demonstrates the significant variability in clinical presentations of individuals with genetic predisposition to cancer.”

“The high prevalence of breast cancer diagnoses among Lynch Syndrome mutation carriers may be a reflection of current referral biases for who is offered genetic testing,” she said by email. “However, it also illustrates the potential for phenotypic overlap among the various hereditary cancer syndromes.”

“Multigene panel tests are efficient when the differential diagnosis encompasses more than one syndrome,” she concluded.

Dr. Zsofia Stadler, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City, told Reuters Health, “While the results are interesting, and highlight the increased prevalence of MSH6 and PMS2 mutations, it is important to note that it remains unknown whether the observed PMS2 and MSH6 mutations are truly responsible for the breast cancers in the study population.”

“Alternatively,” she said by email, “the observed mutation in PMS2 and MSH6 may be incidental findings in women with a diagnosis of breast cancer.”

“In fact,” she observed, “in prior studies of Lynch syndrome patients with a diagnosis of breast cancer, only about 50% of breast tumors exhibited a defective DNA mismatch repair, the tumor signature observed in Lynch-associated cancers (PMC3672741).”

“The authors also note that 22% of patients with Lynch syndrome met clinical genetic testing criteria for hereditary breast and ovarian cancer (BRCA1 and BRCA2 testing),” she continued. “However, this seemingly high rate may have been a reflection of the tested population, consisting largely of individuals undergoing genetic testing due to a family or personal history of breast and/or ovarian cancer.”

“More precise and direct estimates of gene-specific risks for breast cancer in the setting of Lynch syndrome are needed,” Dr. Stadler concluded. “Whether cancer risks in individuals with an incidental diagnosis of Lynch syndrome are equivalent to cancer risk in Lynch syndrome patients with a strong family history of Lynch-associated cancers remains an important clinical question.”

Espenschied and four coauthors are employees of Ambry Genetics. Hampel received research funding from Myriad Genetics and has stock or other sources of income from other genomics companies.

SOURCE: http://bit.ly/2qEYKoh

J Clin Oncol 2017.