What Is an MSH2 Mutation? What You Need to Know

What Is an Inherited MSH2 Mutation? General Information for Carriers

• The name MSH2 comes from "MutS homolog 2." The gene is located on chromosome 2, and the MSH2 gene protein plays an important role in repairing DNA damage. 
• Both women and men can carry a mutation in the MSH2 gene.
• In the MSH2 gene, inherited mutations are associated with Lynch syndrome. Other names for Lynch syndrome are hereditary nonpolyposis colorectal cancer (HNPCC) and Muir Torre syndrome(a subtype of Lynch syndrome in people with an increased risk of developing rare skin tumors).
• People with an MSH2 mutation have an increased risk of most cancers, but particularly cancer of the large intestine (colon and rectum) and uterus (endometrium). There are screening and prevention guidelines for certain cancers in people with an MSH2 mutation.
• People who test positive for an MSH2 mutation can participate in clinical trials. People who carry an inherited MSH2 mutation and have been diagnosed with cancer may also receive certain treatments or participate in clinical trials.
• Children who inherit an MSH2 mutation from both their mother and father may have a very rare syndrome known as "constitutional mismatch repair deficiency", which may carry a high risk of various cancers during childhood and adolescence.

Which Cancer Risks Does an Inherited MSH2 Mutation Increase?

If you have tested positive for an inherited MSH2 mutation, you are advised to contact a multidisciplinary oncology team that can review your personal and family cancer history and help you choose the best plan to manage your cancer risk.

Table: Cancer risks for people with an MSH2 mutation. Source: NCCN: Genetic / Familiar High – Risk Assessment: Colorectal Version 1.2020

People with an inherited MSH2 mutation may also have an increased risk of other cancers. The exact risks for the following cancer types are unknown:

• Pancreatic cancer
• Sebaceous (oil cyst) skin growths
• Breast cancer in women

Studies are ongoing to understand how a mutation in the MSH2 gene affects cancer risk.

How Should Risk Be Managed in People with an Inherited MSH2 Mutation?

The National Comprehensive Cancer Network (NCCN) provides risk management guidelines for men and women with an MSH2 mutation. You are advised to contact a multidisciplinary oncology team that can review your personal and family cancer history and help you determine the best risk management plan.

NCCN risk management guidelines for people with an MSH2 mutation include information on the following cancers:

• Colorectal cancer
• Uterine cancer
• Ovarian cancer
• Pancreatic cancer
• Urinary tract cancer
• Brain cancer
• Stomach cancer
• Breast cancer

Colorectal cancer

• Have a colonoscopy between ages 20 -25 (or 2 -5 years before the youngest age of colon cancer in the family if the diagnosis was before age 25).
• Repeat colonoscopy every 1 – 2 years. Talk to your doctor about whether screening should be annual or every two years. Men, people over 40, and those with a history of colon cancer or colon polyps may benefit most from annual screening.
• Daily aspirin may reduce colorectal cancer risk. The best dose and timing for aspirin are unknown. Current research has found that taking 600 mg of aspirin daily reduces colorectal cancer risk in people with Lynch syndrome. Discuss the benefits and risks, optimal timing, and dose with your doctor.

Uterine cancer

• Symptom awareness and biopsy: Uterine cancer can often be detected early through symptoms followed by a biopsy. Experts therefore recommend that all women be aware of uterine cancer symptoms and promptly report anything persistent to their doctor.
  • Abnormal vaginal discharge
  • Pelvic or abdominal pain
  • Abdominal bloating
  • Difficulty eating
  • Frequent feeling of bladder fullness

• Screening: In the absence of symptoms, regular uterine cancer screening through transvaginal ultrasound and/or endometrial biopsies does not appear to yield better outcomes than symptom awareness followed by biopsy for any woman showing symptoms. Nevertheless, some women undergo regular screening with transvaginal ultrasound and endometrial biopsies. Transvaginal ultrasound is not recommended for premenopausal women. Women should discuss the benefits, risks, costs, and timing of transvaginal ultrasound and endometrial biopsies with their doctors to decide about screening.
• Surgery: Removing the uterus (hysterectomy) reduces uterine cancer risk in women with Lynch syndrome. However, hysterectomy has not been shown to reduce the risk of death from uterine cancer. Women should discuss the benefits and risks of hysterectomy with their doctors after completing childbearing. The best time for surgery may vary with the gene mutation and family cancer history.
• Drug treatment: Oral contraceptives (birth control drugs) may reduce uterine cancer risk in women with Lynch syndrome. Women should discuss the benefits, risks, and timing of contraceptives with their doctors.

Ovarian cancer

• Surgery: Removing the ovaries and fallopian tubes (salpingo-oophorectomy) may reduce ovarian cancer risk in women with Lynch syndrome. Women should discuss its benefits and risks with their doctors after completing childbearing. The best time for surgery varies with the gene mutation and family cancer history.
• Symptom awareness: Experts recommend that all women know the symptoms of ovarian cancer. Women should report any of the following symptoms lasting several weeks and any changes from normal to their doctors:
  • Pelvic or abdominal pain
  • Abdominal bloating
  • Difficulty eating
  • Feeling full early
  • Frequent feeling of bladder fullness

• Screening: Regular screening with transvaginal ultrasound and CA125 blood tests is performed in the absence of symptoms. However, ovarian cancer screening does not help detect ovarian cancer early. Women not planning surgery should discuss the benefits, risks, costs, and timing of transvaginal ultrasound and CA125 with their doctors.
• Drug treatment: Oral contraceptives (birth control drugs) may reduce uterine cancer risk in women with Lynch syndrome. Women should discuss the benefits, risks, and timing of contraceptives with their doctors.

Pancreatic Cancer Screening in People with a Family History

• People with an MSH2 mutation who have a first- or second-degree relative with pancreatic cancer should consider screening in their early 50s or 10 years before the relative's age at diagnosis.
• For people considering pancreatic cancer screening, US-NCCN recommends screening at an experienced facility, ideally in a research setting. Before screening, people should discuss its benefits, risks, costs, and limitations with their doctors.
• Consider annual screening with contrast-enhanced MRI-MRCP (magnetic resonance cholangiopancreatography) and/or EUS (endoscopic ultrasound).

Bladder, Kidney, and Ureter Cancer

• Consider beginning annual urinalysis between ages 30 – 35, particularly for men and people with a family history of urinary tract cancer.

Brain Cancer

• Consider beginning physical and neurological examinations between ages 25 – 30.

Stomach Cancer

• For people with a family history of stomach cancer and/or Asian ancestry:
• Consider stomach cancer screening at age 40 every 3 – 5 years using a procedure called EGD (esophagogastroduodenocopy – esophagogastroduodenoscopy).
• If stomach screening is performed, consider H. Pylori testing and treatment.

Breast Cancer

• Manage breast cancer risk based on family history. Risk-reducing mastectomy (surgical removal of the breasts) is generally not recommended.

Screening and Prevention of Other Cancers

The guidelines do not include information about screening and prevention of other cancers in people with an MSH2 mutation. However, clinical trials may be available.

Cancer Treatment for People with an MSH2 Mutation

Experts are conducting research studies to learn about the best treatments for people with an inherited MSH2 mutation.

Most cancers in people with an inherited MSH2 mutation will have a "MSI – high" or "MSI – H" (microsatellite instability) tumor biomarker. This biomarker is also known as "MMR – D" (mismatch repair deficiency). Tumor testing for MMR – D or MSI – high may be important because these tumors are more likely to respond to immunotherapy agents known as immune checkpoint inhibitors.

MSI – H Colorectal Cancer

• In people with stage 2 colorectal cancer, MSI – high cancers have a good prognosis (disease course) and may not benefit from adjuvant 5 – Fluorouracil therapy (immunotherapy used in colorectal cancer).
• Keytruda (pembrolizumab) is an immune checkpoint inhibitor used to treat metastatic or advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Opdivo (nivolumab) has been approved as an immune checkpoint inhibitor used alone or in combination with Yervoy (ipilimumab) for metastatic cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Immune Checkpoint Inhibitors for the Treatment of Any MSI – H Cancer

• Keytruda (pembrolizumab) was approved to treat any MSI – H solid (organ) tumor that has progressed after treatment and has no other treatment option.

Other Medical Concerns for People with an Inherited MSH2 Mutation

Some mutations in the MSH2 gene cause a subtype of Lynch syndrome sometimes called Muir – Torre syndrome. In addition to increased risks of Lynch syndrome cancers, people with Muir – Torre syndrome have an increased risk of developing uncommon skin tumors. These rare tumors include sebaceous adenomas and carcinomas, which occur in glands producing an oily substance called sebum (sebaceous glands). Multiple rapidly growing tumors called keratoacanthomas may also occur, particularly in sun-exposed areas of skin. Annual skin examinations by a dermatologist are recommended for everyone with an inherited MSH2 mutation, whether or not someone in their family has these skin tumors.

Children who inherit an MSH2 mutation from both their mother and father may have a very rare syndrome known as “constitutional mismatch repair deficiency (CMMRD).” CMMRD may carry a high risk of various cancers in childhood and adolescence. Children with CMMRD syndrome may have blood (hematological) and brain / central nervous system tumors, while colorectal and other cancers commonly seen in older patients with Lynch syndrome may also occur. Most, but not all, CMMRD patients resemble neurofibromatosis, a genetic disorder that causes tumors to form on nerve tissue, particularly showing harmless light-brown "café au lait" skin spots. For a child to have CMMRD syndrome, both the mother and father must have an MSH2 mutation. If one partner has a known mutation, the couple may wish to discuss testing the other partner with a genetic counselor before having children.

Parents seeking to select embryos without inherited MSH2 mutations have the option of using assisted reproductive technology and preimplantation genetic diagnosis.