Study: Cancer risk associated with inherited mutations in Lynch syndrome genes
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:
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).
- For people with MLH1, MSH2 or EPCAM:
- 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
- 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?
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
FORCE offers many peer support programs for people with inherited mutations.
- Our Message Boards allow people to connect with others who share their situation. Once registered, you can post on the Diagnosed With Cancer board to connect with other people who have been diagnosed.
- Our Peer Navigation Program will match you with a volunteer who shares your mutation and situation.
- Our moderated, private Facebook group allows you to connect with other community members 24/7.
- Check out our virtual and in-person support meeting calendar.
- Join one of our Zoom community group meetings.
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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