Get notified of page updates

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

Printer Friendly Page

Read the article that we reviewed

Contents

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 genes in a single group of women. 

Study background:

(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 (, , or ).

  • and carriers did not have an increased risk of breast cancer.
  • and carriers had a modestly increased risk of breast cancer compared to the general population:
    • carriers had 2.11-fold more cases of breast cancer.
    • carriers had 2.92-fold more cases of breast cancer.
  • The estimated cumulative incidence of breast cancer was significantly greater for and carriers:
    • carriers: 31.1% predicted to have breast cancer by age 60.
    • 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 or pathogenic variants report breast cancer most often. In contrast, families with or 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 or 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 or genes, you have increased risk endometrial, ovarian colorectal and other cancers. Among experts, there is a lot of uncertainty about 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 , visit our information page on LS.

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

Share your thoughts on this XRAYS article by taking our brief survey.
 

References

Roberts ME, Jackson SA, Susswein LR, et al. " and germ-line pathogenic variants implicated in 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 and 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 relevant for:

Women with an MSH6 or PMS2 mutation

This article is also relevant for:

Previvors

People with a genetic mutation linked to cancer risk

Breast cancer survivors

Women under 45

Women over 45

Be part of XRAY:

IN-DEPTH REVIEW OF RESEARCH

Study background:

(LS) is an syndrome also known as hereditary non-polyposis colorectal cancer (). 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 , , , genes and related 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 genes: , , or .

Populations looked at in this study:

The researchers retrospectively identified 423 women from over 50,000 women who had multigene panel testing at GeneDx between 2013 and 2016. These women carried a mutation in one of 4 genes (, , or ). 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 or in the absence of other LS associated cancers:

  • 18.6 % of carriers had breast cancer only.
  • 29.0% with carriers had breast cancer only.

Families with or pathogenic variants report breast cancer most often. In contrast, families with or 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).

  • and carriers did not have an increased risk of breast cancer.
  • and carriers had a modest, but significantly increased, risk of breast cancer as compared to the general population:
    • carriers had 2.11-fold more cases of breast cancer.
    • carriers had 2.92-fold more cases of breast cancer.
  • The estimated cumulative incidence of breast cancer was significantly greater for and carriers.
    • carriers: 37.7 % predicted to have breast cancer by age 60.
    • carriers: 31.1 % predicted to have breast cancer by age 60.
    • carriers: 16.1 % predicted to have breast cancer by age 60.
    • 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 or mutations. These mutations may be undetected if only the common breast cancer genes are examined.

As expected, women with pathogenic mutations in a 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 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 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, and 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 mutation carriers will help clarify these issues.

Conclusions:

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

Share your thoughts on this XRAYS article by taking our brief survey.

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

Expert Guidelines Expert Guidelines

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

Colorectal cancer 

  • Colonoscopy every 1-2 years. Speak with your doctor about whether your screenings should be yearly or every two years. Men, people over age 40, and people with a personal history of colon cancer or colon polyps may benefit most from yearly screenings. 
    • For people with , 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 or PMS2: 
      • beginning between the ages of 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 for colorectal cancer. The best dose and timing for aspirin is not known. Speak with your doctor about the benefits and 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 at age 30-35.
  • Discuss the benefits and risks of oral contraceptives.
  • Consider risk-reducing hysterectomy; discuss risk-reducing removal of ovaries and with your doctor (, , and ).

Other cancers

  • Consider annual cancer screening with testing and digital rectal exam.
  • For people with a family history of urethelial cancer and men with an mutation:
    • Consider annual urinalysis beginning at age 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 catgory for gastric cancer. 
  • Consider testing for H. pylori and treating if positive. 
  • For people with a family history of pancreatic cancer:
    • Consider annual cholangiopancreatography (MRCP) and/or endoscopic (EUS) beginning at age 5-. 
    • Consider participating in a pancreatic cancer screening study. 
  • Consider annual physical and neurological exam. 

Updated: 12/22/2021

Questions to Ask Questions to Ask Your Doctor

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

Open Clinical Trials Open Clinical Trials

The following screening and prevention studies are open to people with

Multiple cancers

Colorectal cancer

Gynecologic cancers

 cancer

  • NCT03805919: Men at High Genetic Risk for  Cancer. This is a  cancer screening study using  in high risk men. This study is open to men with  and other mutations.
  • NCT05129605: Cancer Genetic Risk Evaluation and Screening Study (PROGRESS).  This study will look at how well  MRI works as a screening tool for men at high risk for cancer. This study is open to men with inherited mutations in , , , , , , HOXB13, , , , , , , , , and other genes. 

Pancreatic cancer

  • NCT02206360: Pancreatic Cancer Early Detection Program. This pancreatic cancer screening study uses esopheal  to screen for pancreatic cancer in high risk people. The study is open to people with a  mutation or other mutation linked to increased cancer risk who also have a family history of pancreatic cancer.
  • NCT03568630: Blood Markers of Early Pancreas Cancer.  This pancreatic cancer study involves blood samples over time to look for biomarkers of pancreatic cancer in high risk people. The study is open to people with an  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.  and Magnetic cholangiopancreatography (MRI/MRCP) will be utilized to screen for early  pancreatic lesions.

A number of other clinical trials for patients with endometrial cancer can be found here.

Updated: 03/14/2022

Peer Support Peer Support

FORCE offers many peer support programs for people with inherited mutations. 

Updated: 08/06/2022

Back to XRAY Home