Two Genetic Mutations Implicated in Breast Cancer Emerge From Study of Lynch Syndrome

Key Points

  • Women with a mutation in two Lynch syndrome–specific genes—MSH6 and PMS2—had a twofold higher risk of breast cancer compared to women in the general population.
  • About 31% to 38% of women with cancer-causing MSH6 and PMS2 variants will develop breast cancer, compared to around 15% of women in the general population.

Researchers at Columbia University Irving Medical Center (CUIMC) and GeneDx, a genetic testing company, have identified two new genetic mutations associated with breast cancer: MSH6 and PMS2. The researchers’ study—published by Roberts et al in Genetics in Medicinesuggests that each gene approximately doubles a woman’s risk of developing breast cancer by age 60.

The two genes were previously known to cause Lynch syndrome, an inherited condition that raises the risk of colorectal, ovarian, stomach, and endometrial cancer. The new study shows that some women with Lynch syndrome are also more likely to develop breast cancer.

Study Findings

The researchers analyzed a database of more than 50,000 women who had undergone multigene hereditary cancer testing between 2013 and 2015. Of these, 423 women had a mutation in 1 of the 4 genes that cause Lynch syndrome: MLH1, MSH2, MSH6, and PMS2.

Additional analyses revealed that women with a mutation in two Lynch syndrome–specific genes—MSH6 and PMS2—had a twofold higher risk of breast cancer compared to women in the general population. Based on the incidence of cancer in the study population, the researchers calculate that about 31% to 38% of women with cancer-causing MSH6 and PMS2 variants will develop breast cancer, compared to around 15% of women in the general population.

Women With Lynch Syndrome

Lynch syndrome is a genetic disorder that raises the risk of developing several types of cancer, particularly colon cancer. Lynch syndrome is the most common inherited form of colorectal cancer, accounting for roughly 3% of newly diagnosed cases. One in 440 Americans carries a gene variant that causes Lynch syndrome.

Researchers have been unsure whether genes that cause Lynch syndrome also raise the risk of breast cancer. Some studies found a link; others did not. These previous studies looked at the risk of breast cancer among women with any type of Lynch syndrome.

The new study, which looked at the risk associated with each different gene, showed that two Lynch syndrome genes do raise the risk of breast cancer, but two others do not. The finding means that women with Lynch syndrome who have MSH6 or PMS2 variants, but not MLH1 and MSH2 variants, may benefit from increased breast cancer screening, though the researchers caution that the findings need to be replicated in another study.

“People with Lynch syndrome aren’t thinking they may also be at risk for breast cancer,” said Wendy Chung, MD, PhD, Director of Columbia’s Clinical Genetics Program and the study’s senior author. “Given the fact that genomic analysis is becoming more common in patients with a personal or family history of cancer, we have an opportunity to do more targeted breast cancer screening in women who carry any of the genes associated with risk for this disease.”

Breast Cancer Screening

Women with a family history of breast cancer often undergo genetic testing for mutated BRCA1 and BRCA2 genes, which increase the risk of breast cancer over a woman’s lifetime to 50% to 60%. The new study suggests MSH6 and PMS2 should be added to the list of genes to screen for when there is a history of breast cancer. Screening for these genes would give these families potentially life-saving information to prevent colon cancer by increasing the frequency of colonoscopies. Currently, testing for Lynch syndrome genes is generally only done when someone has a personal or family history of colon or uterine cancer.

“Given that Lynch syndrome is not rare in the general population, this finding has the potential to impact tens of thousands of people in the United States and could change standard practice related to one of the most common cancer predisposition syndromes,” said researchers.

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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