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Study: Cancer risk associated with inherited mutations in Lynch syndrome genes

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Contents

At a glance                  Questions for your doctor
What does this mean for me? In-depth            
Clinical trials Limitations
Guidelines Resources


STUDY AT A GLANCE

This study is about:

Determining cancer risks linked to different genes by age, gender and organ and survival rates after cancer.

Why is this study important?

Lynch syndrome is caused by mutations in one of several genes. Although these genes are often discussed together, research show that mutations in , , , and have different cancer risks. The risk of cancer in different organs and the average age when cancer occurs may differ between the Lynch syndrome genes and between men and women. In this study, researchers wanted to determine the risk of cancer, average age of cancer and survival associated with Lynch syndrome mutations.

Study findings: 

Of the 6350 participants with a mutation in a Lynch syndrome gene, 1808 (28%) had cancers during the study time period.

  • The most common cancers seen for mutations in any Lynch syndrome gene were colon (31%), skin (12%), endometrial (10%) and rectal cancers (7%).
  • The average age at diagnosis of cancer at each organ was reported for mutations in any Lynch syndrome gene:
    • brain cancer: average age 56
    • endometrial cancer: average age 51
    • colon cancer:  average age 53
    • ovarian cancer: average age 47
    • pancreatic cancer: average age 61
    • cancer: average age 62
    • rectal cancer: average age 56
    • skin cancer : average age 61
    • stomach cancer: average age 62
  • Men were more likely than women to have colon, stomach, small bowel, gallbladder and pancreatic cancer.

Mutations in different Lynch syndrome genes have different lifetime risks of cancer. MLH1 and MSH2 had higher rates of cancer than MSH6 or PMS2.

  • MLH 1 patients were estimated to have 71-81% risk of a cancer by age 75.
  • MSH 2 patients were estimated to have 75-84% risk of a cancer by age 75.
  • MSH 6 patients were estimated to have 42-62% risk of a cancer by age 75.
  • PMS 2 patients were estimated to have 34 % risk of a cancer by age 75.

Women with MSH6 mutations had a significantly increased risk of ovarian cancer (11%) and uterine/endometrial cancer (41%). In U.S., ovarian and endometrial cancer occur in 3% of women in the general population.

  • Researchers note that with only a 20% risk of colorectal cancer for people with MSH6 mutations, families may go unrecognized as having Lynch syndrome despite the much higher risk (41%) of endometrial cancer for women with MSH6 mutations.

There was only a slight increase in breast cancer risk associated with participants in this study who had Lynch syndrome mutations. Women with MSH2, MSH6 or PMS2 mutations had a 14-15% breast cancer risk by age 75. This is a very small increase in  risk compared to the general U.S. population (13% lifetime risk).

Survival among participants diagnosed with cancer differed depending on the cancer site:

  • The majority of patients with Lynch syndrome mutations survived colorectal, endometrial, ovarian, prostate, breast, urinary tract and bladder cancers 10 or more years.
  • The majority of patients with pancreatic (29%), bile duct (42%) and brain cancer (15%) survived less than 10 years after diagnosis.

Different cancer risks are associated with each of the Lynch syndrome genes. These researchers suggest that recommendations for genetic counseling, surveillance and clinical management may need to differ for patients depending on which gene is affected.

*Note: Most EPCAM mutations associated with Lynch syndrome are thought to affect how the MSH2 gene works. Although mutations in EPCAM were not part of this study, experts believe cancer risks for people with these EPCAM mutations may be similar to MSH2.

What does this mean for me?

Different cancer risks are associated with mutations in each of the Lynch syndrome genes. These findings suggest that recommendations for genetic counseling, surveillance and clinical management may need to be tailored for patients and family members depending on which gene is affected.

If you have a mutation in a Lynch syndrome gene, you may have an increased risk of colorectal, pancreatic or stomach cancers. If you are female you may also have increased risk of ovarian and endometrial cancers and a slightly elevated risk of breast cancer. If you are male you may have increased risk of prostate cancer. You will want to consider regular screening and prompt evaluation by a health care provider of concerning symptoms.

Blood relatives may have an increased risk of cancer if they have inherited a mutation in a Lynch syndrome gene. Genetic counseling and consideration of genetic testing is recommended for at risk-relatives.

Posted 2/21/20

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References

Dominguez-Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Lynch Syndrome Database. Genetics in Medicine. 2020. 22: 20-25 

Stoll J, Rosenthal E, Cummings S, et al. No evidence of increased risk of breast cancer in women with Lynch syndrome identified by multi-gene panel testing. JCO Precision Oncology. 2020. 4:51-60. https://doi.org/10.1200/PO.19.0027

 

This article is relevant for:

People with Lynch syndrome mutations

This article is also relevant for:

people with breast cancer

people with ovarian cancer

people with a genetic mutation linked to cancer risk

previvors

people newly diagnosed with cancer

people with pancreatic cancer

people with a family history of cancer

Be part of XRAY:

Expert Guidelines
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 prostate 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
Questions To Ask Your Doctor

  • I have a mutation in a Lynch syndrome gene, what cancer screening tests do you recommend?
  • My family has a history of colorectal, pancreatic, stomach, ovarian or other cancers, should I consider genetic testing?
  • What are the preventive options for reducing my cancer risk?
  • What are the signs or symptoms of cancers that I am most at risk for and when should I seek evaluation from my healthcare provider?
  • I have Lynch syndrome and I’ve been diagnosed with cancer. Does my Lynch syndrome mutation affect my treatment options?

Open Clinical Trials
Open Clinical Trials

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

Colorectal cancer

Gynecologic cancers

Prostate cancer

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

Peer Support
Peer Support

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

Updated: 08/06/2022

Who covered this study?

Genome Web

Also published in:

The same article also appeared in Precision Oncology News.

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