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Two New Genetic Mutations Linked to Higher Risk of Breast Cancer

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About 5% to 10% of breast cancers are thought to be hereditary, caused by abnormal genes passed from parent to child.

Genes are particles in cells, contained in chromosomes, and made of DNA (deoxyribonucleic acid). DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.

Think of your genes as an instruction manual for cell growth and function. Changes or mistakes in the DNA are like typographic errors. They may provide the wrong set of instructions, leading to faulty cell growth or function. In any one person, if there is an error in a gene, that same mistake will appear in all the cells that contain the same gene. This is like having an instruction manual in which all the copies have the same typographical error.

There are two types of DNA changes or mutations: those that are inherited and those that happen over time. Inherited DNA changes are passed down from parent to child. Inherited DNA changes are called germ-line alterations.

DNA changes that happen over the course of lifetime, as a result of the natural aging process or exposure to chemicals in the environment, are called somatic alterations.

Some DNA changes are harmless, but others can cause disease or other health issues.

Many inherited cases of breast cancer are associated with two genetic mutations: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two). But changes in other genes also are linked to breast cancer.

A study has found that mutations in the MSH6 and PMS2 genes are linked to higher-than-average breast cancer risk.

The research was published online on Jan. 18, 2018 by the journal Genetics in Medicine. Read MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer.”

The MSH6 gene provides instructions for making a protein that helps repair DNA damage. Other studies have found that mutations in the MSH6 gene are linked to Lynch syndrome and a higher risk of ovarian cancer. Having Lynch syndrome increases the risk of many types of cancer, particularly colorectal, endometrial, ovarian, stomach, small intestine, liver, gallbladder, upper urinary tract, and brain.

The PMS2 gene also provides instructions for making a protein that helps repair DNA damage. Mutations in the PMS2 gene are also linked to Lynch syndrome and ovarian cancer.

Researchers have suspected that the genetic mutations linked to Lynch syndrome also were linked to breast cancer, but previous research results have been mixed.

In this study, the researchers analyzed a database of information from more than 50,000 women who had had multi-gene genetic testing for hereditary cancer between 2013 and 2015. Of these women, 423 had a mutation in one of the four genes linked to Lynch syndrome:

  • 15.4% had a MLH1 mutation
  • 22.2% had an MSH2 mutation
  • 33.1% had an MSH6 mutation
  • 29.3% had a PMS2 mutation

In total, 107 of the 423 women (25.3%) had been diagnosed with breast cancer; six women had been diagnosed with more than one primary breast cancer.

The researchers then compared the number of breast cancer cases in the women with each genetic mutation to the number expected in the general population.

Women with a MSH6 or PMS2 mutation were more likely to be diagnosed with breast cancer compared to women with a MLH1 or MSH2 mutation.

The analysis found that women with a MSH6 or PMS2 mutation had about double the breast cancer risk of the average women. The researchers calculated that about 31% to 38% of women with a MSH6 or PMS2 mutation would be diagnosed with breast cancer, compared to about 15% of women in the general population.

"People with Lynch syndrome aren't thinking they may also be at risk for breast cancer," said Wendy Chung, M.D., Ph.D., the Kennedy Family professor of pediatrics at Columbia University Irving Medical Center 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. 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."

If you have a strong family history of breast cancer, yet you and your family members have tested negative for a BRCA1 or BRCA2 mutation, you may want to talk to your doctor about this study and ask if being screened for MSH6 and PMS2 mutations makes sense for you.

Likewise, if you have a family history of Lynch syndrome, you also may want to talk to your doctor about this study and ask about ways to determine your personal risk of breast cancer and what steps you might take if your risk turns out to be higher than average.

For more information on genetics and breast cancer risk, visit the Genetics page in the Lower Your Risk section.

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