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Study: Mutations in Lynch syndrome genes MSH6 and PMS2 may be associated with breast cancer

Some women with mutations in MSH6 and PMS2, two Lynch syndrome genes, may have a modest (2 to 3-fold) increased risk for breast cancer. (6/14/18 updated 09/25/19)

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Most relevant for: Women with an MSH6 or PMS2 mutation.

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people with a genetic mutation linked to cancer risk
people with breast cancer

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Strength of Science: Medium-High

Research Timeline: Human Research

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Two new breast cancer genes emerge from lynch syndrome gene study: The findings suggest that genetic screening for breast cancer should be expanded to include MSH6 and PMS2
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At a glance	Clinical trials
Findings	In-depth
What does this mean for me?	Limitations
Questions for your doctor	Resources

STUDY AT A GLANCE

This study is about:

The risk of breast cancer associated with gene mutations.

Why is this study important?

This study is the first to address gene-specific breast cancer risk for four Lynch syndrome genes in a single group of women.

Study background:

Lynch syndrome (LS), also known as hereditary non-polyposis colorectal cancer (), is a syndrome. LS is associated with multiple types of cancers, particularly colon, ovarian and endometrial/uterine cancer, as well as many other cancers.

LS is caused by inherited mutations in , , , or particular mutations in the related gene. Previous studies have found mixed results on the association between LS and breast cancer risk.

Study findings:

The researchers retrospectively identified 423 women who carried a mutation in one of 4 LS genes (MLH1, MSH2, MSH6 or PMS2).

MLH1 and MSH2 carriers did not have an increased risk of breast cancer.
MSH6 and PMS2 carriers had a modestly increased risk of breast cancer compared to the general population:
- MSH6 carriers had 2.11-fold more cases of breast cancer.
- PMS2 carriers had 2.92-fold more cases of breast cancer.
The estimated cumulative incidence of breast cancer was significantly greater for MSH6 and PMS2 carriers:
- MSH6 carriers: 31.1% predicted to have breast cancer by age 60.
- PMS2 carriers: 37.7% predicted to have breast cancer by age 60.
11.1% of women with a LS mutation had no personal or family history of colorectal, endometrial or ovarian cancer.
- Families with MSH6 or PMS2 pathogenic variants report breast cancer most often. In contrast, families with MSH2 or MLH1 pathogenic variants report colorectal cancer most often.

What does this mean for me?

Women whose personal or family history is limited to breast cancer may carry a MSH6 or PMS2 mutation. These mutations may be undetected if only the common breast cancer genes are examined. If you have breast cancer and you have a personal or family history of colorectal, endometrial or ovarian cancer, genetic counseling and testing for LS gene mutations may be warranted. If you have a family history of breast cancer and you do not have a mutation in a known breast cancer predisposing gene, you might have a mutation in a different gene. A genetic counselor can help determine if additional genetic testing is right for you.

If you have a mutation in MSH6 or PMS2 genes, you have increased risk endometrial, ovarian colorectal and other cancers. Among experts, there is a lot of uncertainty about Lynch Syndrome and breast cancer risk. Additional studies to confirm the risk for breast cancer are needed. Currently, the National Comprehensive Cancer Network (NCCN) Guidelines for breast surveillance for people with LS are based on family history and do not include increased surveillance based on a LS gene mutation alone. Screening for other Lynch syndrome-related cancers is warranted. For additional information regarding management guidelines for Lynch syndrome, visit our information page on LS.

Posted 6/14/18 and updated 09/25/19

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References

Roberts ME, Jackson SA, Susswein LR, et al. "MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer." Genetics in Medicine. Jan. 18, 2018. doi: 10.1038/gim.2017.254.

ten Broeke SW, Suerink M, Nielsen M, "Response to Roberts et al. 2018: Is breast cancer truly caused by MSH6 and PMS2 variants or is it simply due to a high prevalence of these variants in the population?" Genetics in Medicine. May 24, 2018. doi: 10.1038/s41436-018-0029-1.

Roberts ME, Zeinomar N, Solomon BD, et al. "Response to ten Broeke et al." Genetics in Medicine. May 24, 2018. doi:10.1038/s41436-018-0031-7

Win AK, Lindor NM, Jenkins MA. "Risk of breast cancer in Lynch syndrome: a systematic review." 2013.15(2):R27.

Disclosure

FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

This article is also relevant for:

previvors
people with a genetic mutation linked to cancer risk
people with breast cancer

IN-DEPTH REVIEW OF RESEARCH

Study background:

Lynch syndrome (LS) is an syndrome also known as hereditary non-polyposis colorectal cancer (HNPCC). It is associated with multiple types of cancers, particularly colon and endometrial/uterine cancer. LS accounts for 3-5% of all colorectal cases annually. LS occurs in people with mutations in genes of the mismatch repair system. These genes include MLH1, MSH2, MSH6, PMS2 genes and related EPCAM gene. LS gene mutations are not uncommon. About 1 in 440 people carry a mutation in a LS gene.

Past studies grouped all of the LS genes together to evaluate the cancer incidence. A 2013 review found that 13 studies showed no association between LS genes and breast cancer while 8 studies found an increased risk of breast cancer among LS carriers. In this study, researchers wanted to clarify whether each of the LS genes was or was not associated with breast cancer.

Researchers of this study wanted to know:

The risk of breast cancer among women who carry a mutation in one of the Lynch syndrome genes: MLH1, MSH2, MSH6 or PMS2.

Populations looked at in this study:

The researchers retrospectively identified 423 women from over 50,000 women who had multigene hereditary cancer panel testing at GeneDx between 2013 and 2016. These women carried a mutation in one of 4 genes (MLH1, MSH2, MSH6 or PMS2). They were at least 18 years old and were diagnosed with invasive breast cancer or ductal carcinoma in situ. Researchers limited their study to women carrying mutations that were classified as pathogenic or likely pathogenic according to 2015 guidelines by the American College of Medical Genetics and Genomics/Association for Molecular Pathology. They collected demographic information, clinical history and family history from genetic test requests.

Study findings:

Breast cancer was not uncommon among these LS carriers.

25.3% of women with a LS mutation had a history of breast cancer; 1.4% had more than one primary breast cancer.
Average age at first breast cancer diagnosis was 50.

Breast cancer occurred in women with a pathogenic mutation in MSH6 or PMS2 in the absence of other LS associated cancers:

18.6 % of MSH6 carriers had breast cancer only.
29.0% with PMS2 carriers had breast cancer only.

Families with MSH6 or PMS2 pathogenic variants report breast cancer most often. In contrast, families with MSH2 or MLH1 pathogenic variants report colorectal cancer most often.

11.1% of women with a LS mutation had no personal or family history of colorectal, endometrial or ovarian cancer.

To determine the risk of breast cancer for these carriers, researchers compared the number of women with breast cancer to the number of women they expected would have breast cancer based on incidence in the general population (using the national cancer registry data).

MLH1 and MSH2 carriers did not have an increased risk of breast cancer.
MSH6 and PMS2 carriers had a modest, but significantly increased, risk of breast cancer as compared to the general population:
- MSH6 carriers had 2.11-fold more cases of breast cancer.
- PMS2 carriers had 2.92-fold more cases of breast cancer.
The estimated cumulative incidence of breast cancer was significantly greater for PMS2 and MSH6 carriers.
- PMS2 carriers: 37.7 % predicted to have breast cancer by age 60.
- MSH6 carriers: 31.1 % predicted to have breast cancer by age 60.
- MSH2 carriers: 16.1 % predicted to have breast cancer by age 60.
- MLH1 carriers: 15.5 % predicted to have breast cancer by age 60.

These observations suggest that women whose personal or family history is limited to breast cancer may carry MSH6 or PMS2 mutations. These mutations may be undetected if only the common breast cancer genes are examined.

As expected, women with pathogenic mutations in a Lynch syndrome gene had higher risks of other cancers than the general population: colorectal cancer was 3 to 19-fold higher, endometrial cancer was 7 to 18-fold higher, and ovarian cancer was 3 to 12-fold higher.

Researchers wanted to know which genetic testing criteria would best detect LS mutations prospectively. They examined the personal and family histories of these women with known LS mutations retrospectively. They applied three established clinical or testing criteria (Amsterdam II and Revised Bethesda guidelines for Lynch syndrome and NCCN BRCA1/2 testing guidelines). Women with pathogenic mutations in an LS gene met NCCN BRCA1/2 guidelines for genetic testing more often (58% of the time) than the other two testing criteria (23, 24% of the time). They concluded that genetic test criteria should be continuously reevaluated.

Limitations:

Women in this study were retrospectively selected because they had genetic testing that identified a mutation in one of the Lynch syndrome genes. The decision to have genetic testing may reflect an individual’s personal and family cancer history, therefore this group of women may not be representative of all LS carriers.

Researchers had access only to clinical information provided at the time of genetic testing request; information about subsequent cancers was unknown.

Researchers acknowledge that the demographic makeup of the women in this study may not be racially or ethnically representative.

Researchers acknowledge that cumulative survival time is difficult to determine with a study. For these reasons, the study limited estimation of breast cancer incidence to age 60.

Importantly, MSH6 and PMS2 are the most common genes in which mutations can be found in the general population. Breast cancer is also common in the general population of women. This makes it difficult to determine if mutations in these genes are what is causing breast cancer in these patients. testing of potential Lynch syndrome mutation carriers will help clarify these issues.

Conclusions:

Women with mutations in MSH6 and PMS2 and have increased risk for cancers associated with Lynch syndrome. They may also have a 2-3-fold increased risk of breast cancer compared to the general population.

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Posted 6/14/18 and updated 09/25/19

Expert Guidelines

The National Comprehensive Cancer Network (NCCN) provides risk management guidelines for people with Lynch syndrome mutations.

Colorectal cancer

Colonoscopy every 1-2 years. Speak with your doctor about whether you should be screened yearly or every two years. Men, people over age 40 and individuals with a personal history of colon cancer or colon may benefit most from yearly screenings.
- For people with MLH1, MSH2 or EPCAM:
  - beginning between ages 20-25 (or 2-5 years before the earliest age of colon cancer in the family, if diagnosed before age 25).
- For people with MSH6 or PMS2:
  - beginning between ages 30-35 (or 2-5 years before the earliest age of colon cancer in the family, if diagnosed before age 35).
Daily aspirin can decrease the risk of colorectal cancer. The best dose and timing for aspirin are unknown. Speak with your doctor about the benefits, risks, best timing and dose.

Endometrial and ovarian cancer

Be aware of endometrial and ovarian cancer symptoms.
Consider endometrial biopsy every 1-2 years beginning between ages 30-35.
Discuss the benefits and risks of oral contraceptives.
Consider risk-reducing hysterectomy; discuss risk-reducing removal of ovaries and with your doctor (EPCAM, MLH1, MSH2 and MSH6 gene mutations).

Other cancers

Consider annual cancer screening with testing and digital rectal exam.
For people with a family history of urothelial cancer and men with an MSH2 mutation:
- Consider annual urinalysis beginning between ages 30-35.
Consider baseline esophagogastroduodenoscopy with random stomach biopsy at age 40.
- consider continuing this surveillance every 3-5 years for people in a high-risk category for gastric cancer.
Consider testing for H. pylori and treating if the test is positive.
For people with a family history of pancreatic cancer:
- Consider annual cholangiopancreatography (MRCP) and/or endoscopic (EUS) beginning at age 50.
- Consider participating in a pancreatic cancer screening study.

Consider annual physical and neurological exams.

Updated: 03/09/2023

Questions To Ask Your Doctor

Should I consider genetic counseling or genetic testing for Lynch syndrome mutations given my personal and family history?
My family has a history of Lynch syndrome, should I consider genetic counseling and testing?
As a Lynch syndrome mutation carrier, what breast cancer screening options should I consider? What are my risks for other cancers?
As a Lynch syndrome mutation carrier, what preventive measures should I consider?
Can you refer me to a genetics expert?

Open Clinical Trials

The following screening and prevention studies are open to people with Lynch syndrome.

Colorectal cancer

NCT03831698: Omega 3 Fatty Acids in Colorectal Cancer (CRC) Prevention in Patients With Lynch Syndrome (COLYNE). This study assesses the effects of omega-3 acid ethyl esters capsules (generic Lovaza) on molecular and intestinal microbiota changes in participants at high risk for colorectal cancer.
NCT04379999: Atorvastatin ± Aspirin in Lynch Syndrome Syndrome. This study investigates whether a common cholesterol-lowering agent (atorvastatin) alone or combined with a nonsteroidal anti-inflammatory drug (aspirin) reduces the risk of colorectal cancer in high-risk individuals with Lynch syndrome.

Gynecologic cancers

NCT05257057: Frequency of Endometrial Cancer Precursors Associated With Lynch Syndrome. This study examines endometrial hyperplasia specimens and compares the frequency of Lynch syndrome gene mutations between people with endometrial hyperplasia and those with endometrial cancer.
NCT00508573: Registry for Women Who Are At Risk Or May Have Lynch Syndrome. This study facilitates the study of gynecologic cancer risks by creating a registry of information about women who have or are at risk for Lynch syndrome, to facilitate study of gynecologic cancer risks.
Validating a Blood Test for Early Ovarian Cancer Detection in High-risk Women and Families: MicroRNA Detection Study (MiDE). The goal of this effort is to develop a clinical diagnostic test to detect early-onset ovarian cancer, as currently, no reliable screening or early-detection tests are available.

Prostate cancer

NCT03805919: Men at High Genetic Risk for Prostate Cancer. This is a prostate cancer screening study using in high-risk men is open to men with Lynch syndrome and other mutations.
NCT05129605: Prostate Cancer Genetic Risk Evaluation and Screening Study (PROGRESS). This study looks at how well prostate MRI works as a screening tool for men at high risk for prostate cancer. Enrollment is open to men with an in , , , , , EPCAM, , MLH1, MSH2, MSH6, , , PMS2, , , and other genes.

Pancreatic cancer

NCT02206360: Pancreatic Cancer Early Detection Program. This pancreatic cancer screening study uses esophageal ultrasound to screen for pancreatic cancer in high-risk people. The study is open to people who have a family history of pancreatic cancer and an MLH1 mutation or other mutation linked to increased cancer risk.
NCT03568630: Blood Markers of Early Pancreas Cancer. This pancreatic cancer study involves blood samples taken over time to identify biomarkers of pancreatic cancer in high-risk people. Enrollment is open to people with an MLH1 mutation or other mutation linked to increased cancer risk.
NCT03250078: A Pancreatic Cancer Screening Study in Hereditary High-Risk Individuals. The main goal of this study is to screen and detect pancreatic cancer and precursor lesions in individuals with a strong family history or genetic predisposition to pancreatic cancer. MRI and magnetic cholangiopancreatography (MRI/MRCP) will be utilized to screen for pancreatic lesions.

Other clinical trials for patients with endometrial cancer can be found here.

Updated: 03/09/2023