What Is an MSH6 Mutation? Which Cancer Risks Does It Increase?

What is an inherited MSH6 mutation? General information for carriers

• MSH6 takes its name from "MutS homolog 6". The gene is located on chromosome 2, and the MSH6 gene protein's role in DNA damage repair is important.
• Both women and men can carry a mutation in the MSH6 gene.
• In the MSH6 gene, inherited mutations are associated with Lynch syndrome. Other names for Lynch syndrome include Hereditary Nonpolyposis Colorectal Cancer (HNPCC) and Muir Torre syndrome(a subtype of Lynch syndrome in people at greater risk of developing rare skin tumors).
• People carrying an MSH6 mutation have a greater risk of most cancers, particularly large bowel cancer (colon and rectum) and uterine (endometrial) cancer. There are screening and prevention guidelines for certain cancers in people with an MSH6 mutation.
• There are opportunities for people who test positive for an MSH6 mutation to join clinical trials. People carrying an inherited MSH6 mutation who have been diagnosed with cancer may also receive certain treatments or participate in clinical trials.
• Children who inherit an MSH6 mutation from both parents may have a very rare syndrome known as "constitutional mismatch repair deficiency" , which may confer a high risk of various cancers during childhood and adolescence.

Which cancer risks does an inherited MSH6 mutation increase?

If you test positive for an inherited MSH6 mutation, a team that can review your and your family's cancer history and help you choose the best plan for managing your cancer risk — specifically, a multidisciplinary oncology team — is recommended as a point of contact.

Table: Cancer risks for people carrying an MSH6 mutation. Source: NCCN: Genetic / Familiar High – Risk Assessment: Colorectal Version 1.2020

People carrying an inherited MSH6 mutation may also have an increased risk of other cancers. The exact risks for the following cancer types are unknown:

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

Studies are ongoing into how mutations in the MSH6 gene affect cancer risk.

How should risk be managed for people carrying an inherited MSH6 mutation?

The United States National Comprehensive Cancer Network (US-NCCN) provides risk management guidelines for men and women with an MSH6 mutation. It is recommended that you contact a multidisciplinary oncology team that can review your and your family's cancer history and help you decide on the best risk management plan.

The NCCN risk management guidelines for people carrying an MSH6 mutation include information on the following cancers:

• Colorectal cancer
• Uterine cancer
• Ovarian (female ovary) cancer
• Pancreatic cancer
• Urinary tract cancer
• Brain cancer
• Stomach cancer

Colorectal cancer

• Have a colonoscopy between the ages of 30-35 (or 2 – 5 years before the earliest age of colon cancer in the family, if it was diagnosed before age 25).
• Repeat colonoscopy every 1 – 2 years. Talk to your doctor about whether your screening should be annual or every two years. Men, people over 40, and people 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. Recent research found that taking 600 mg of aspirin daily reduced colorectal cancer risk in people with Lynch syndrome (see related scientific research). Talk to your doctor about the benefits and risks, and the best timing and dose.

Uterine cancer

• Symptom awareness and biopsy: Uterine cancer can often be detected early based on symptoms followed by a biopsy. For this reason, experts recommend that all women be aware of uterine cancer symptoms and report anything persistent to their doctor immediately.
• Abnormal vaginal discharge
• Pain in the pelvis or abdomen
• Abdominal bloating
• Difficulty eating
• A frequent sensation of a full bladder
• Screening: In the absence of symptoms, regular uterine cancer screening with transvaginal ultrasound and / or endometrial biopsies does not appear to produce better outcomes than symptom awareness followed by a biopsy for any woman with symptoms. Nevertheless, some women undergo regular screening with transvaginal ultrasound and endometrial biopsies. Transvaginal ultrasound is not recommended for premenopausal women. Women should talk to their doctors about the benefits, risks, costs, and timing of transvaginal ultrasound and endometrial biopsies to make a decision about screening.
• Surgery: Removal of 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 talk to their doctors about the benefits and risks of hysterectomy after completing child-rearing. The best time for surgery may vary according to the gene mutation and the family's cancer history.
• Medication: Oral contraceptive medicines (birth control medicines) may reduce uterine cancer risk in women with Lynch syndrome. Women should talk to their doctors about the benefits, risks, and timing of contraceptive medicines.

Ovarian cancer

• Surgery: According to experts, there are insufficient records to recommend removal of the ovaries and fallopian tubes (salpingo – oophorectomy) for all women carrying an MSH6 mutation. Women should talk to their doctors about the benefits and risks of salpingo – oophorectomy after completing child-rearing. The best time for surgery varies according to the gene mutation and the family's cancer history.
• Symptom awareness: Experts recommend that all women know the symptoms of ovarian cancer. Women should report any of the following symptoms that last for several weeks, and anything different from normal, to their doctor:
  • Pain in the pelvis or abdomen
  • Abdominal bloating
  • Difficulty eating
  • Early satiety; a frequent sensation of a full bladder

• Screening: In the absence of symptoms, regular screening with transvaginal ultrasound and CA125 blood tests is performed. However, ovarian cancer screening does not help detect ovarian cancer early. Women who are not planning surgery should talk to their doctors about the benefits, risks, costs, and timing of transvaginal ultrasound and CA125.
• Medication: Oral contraceptive medicines (birth control medicines) may reduce uterine cancer risk in women with Lynch syndrome. Women should talk to their doctors about the benefits, risks, and timing of contraceptive medicines.

Pancreatic cancer screening for people with a family history

• People carrying an MSH6 mutation who have a first- or second-degree relative with pancreatic cancer should consider screening in their early 50s or 10 years before their relative's age at diagnosis.
• For people considering pancreatic cancer screening, NCCN recommends screening at an experienced facility, ideally in a research setting. Before being screened, people should talk to their doctors about the benefits, risks, costs, and limitations of screening.
• Consider annual screening with contrast-enhanced MRI-MRCP (magnetic resonance cholangiopancreatography) and / or EUS (endoscopic ultrasound).

Bladder, kidney, and ureter cancer

• People with a family history of urinary tract cancer should consider starting annual urinalysis between the ages of 30 – 35

Brain cancer

• Consider starting physical and neurological examinations between the ages of 25 – 30.

Stomach cancer

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

Breast cancer

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

Screening and prevention of other cancers

The guidelines do not include information about screening and prevention of other cancers for people with an MSH6 mutation. However, there may be clinical trials.

Cancer treatment for people with an MSH6 mutation

Experts are conducting research studies to learn about the best treatments for people carrying an inherited MSH6 mutation.

Most cancers in people carrying an inherited MSH6 mutation will have a tumor biomarker known as “MSI – high” or “MSI – H” (microsatellite instability). 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 5 – Fluorourasil adjuvant therapy (immunotherapy used in colorectal cancer).
• Keytrude (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) is 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 treating any MSI–H cancer

• Keytrude (pembrolizumab) was approved to treat any solid tumor that tests MSI – H, has progressed after treatment, and has no other treatment options.

Other medical concerns for people carrying an inherited MSH6 mutation

Some mutations in the MSH6 gene cause a subtype of Lynch syndrome sometimes called Muir – Torre syndrome. In addition to the increased risk of Lynch syndrome cancers, people with Muir – Torre syndrome have a greater risk of developing uncommon skin tumors. These rare skin 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, especially in sun-exposed areas of the skin. An annual skin examination by a dermatologist is recommended for all individuals carrying an inherited MSH6 mutation, whether or not someone in their family has these skin tumors.

Children who inherit an MSH6 mutation from both parents may have “constitutional mismatch repair deficiency (CMMRD)”, a very rare syndrome. CMMRD may confer a high risk of various cancers during childhood and adolescence. Children with CMMRD syndrome may have blood (hematological) and brain / central nervous system tumors, and patients with Lynch syndrome at an older age commonly develop colorectal and other cancers. 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” patches on the skin. Both the mother and father must have an MSH6 mutation for a child to have CMMRD syndrome. If one partner has a known mutation, couples may wish to speak with a genetic counselor about testing the other partner before having children.

For parents seeking to select embryos without inherited MSH6 mutations, assisted reproductive technology and preimplantation genetic diagnosis are available options.