What Is an MLH1 Mutation? Which Cancer Risks Does It Increase?

What Is an Inherited MLH1 Mutation? Important Information for Carriers

• The name MLH1 comes from “MutL homolog 1”. The MLH1 gene protein is located on chromosome 3 and plays a role in repairing DNA damage.
• Both women and men can have an MLH1 gene mutation.
• In the MLH1 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 a higher risk of developing rare skin tumors.
• People carrying an MLH1 mutation have higher risks of many cancers, particularly cancers of the large intestine (colon and rectum) and uterus (endometrium). There are screening and prevention guidelines for certain cancers in people with an MLH1 mutation.
• People who test positive for an MLH1 mutation can participate in clinical trials. People carrying an inherited MLH1 mutation who have been diagnosed with cancer may also receive certain treatments or participate in clinical trials.
• Children who inherit an MLH1 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 in childhood and adolescence.

Which Cancer Risks Increase with an Inherited MLH1 Mutation?

If you test positive for an inherited MLH1 mutation, it is recommended that you speak with a specialist geneticist who can review your personal and family cancer history and help select the best plan for managing your cancer risk.

MLH cancer risks:

Table: Cancer risks for people carrying an MLH1 mutation. Source: NCCN: Genetic / Familiar High – Risk Assessment: Colorectal Version 1.2020

People carrying an inherited MLH1 mutation may also have higher risks of other cancers. The exact risks for the following cancer types are unknown:

• Sebaceous (oil cyst) skin growths
• Prostate cancer 
• Breast cancer

Studies of how mutations in the MLH1 gene affect cancer risk are ongoing.

Risk Management for People Carrying an Inherited MLH1 Mutation

The National Comprehensive Cancer Network (NCCN) provides risk management guidelines for men and women with MLH1 mutations. It is recommended that you consult a specialist geneticist who can review your personal and family cancer history and help determine the best risk management plan.

NCCN risk management guidelines for people carrying an MLH1 mutation include information about 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 earliest age of colon cancer in the family if the diagnosis was before age 25).
• Repeat colonoscopy every 1–2 years. Talk with your doctor about whether screening should be annual or every other year. 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 of aspirin are unknown. Current research has found that taking 600 mg of aspirin daily reduces colorectal cancer risk in people with Lynch syndrome. Talk with your doctor about 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 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 with transvaginal ultrasound and / or endometrial biopsies does not appear to achieve better outcomes than symptom awareness followed by a biopsy in 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 discuss the benefits, risks, costs, and timing of transvaginal ultrasound and endometrial biopsies with their doctor 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 doctor after completing child-rearing. The best timing for surgery may vary according to the gene mutation and family cancer history.
• Medication: Oral contraceptives (birth control medications) may reduce uterine cancer risk in women with Lynch syndrome. Women should discuss the benefits, risks, and timing of contraceptive medications with their doctor.

Ovarian Cancer

• Surgery: Removing the ovaries and fallopian tubes (salpingo-oophorectomy) may reduce ovarian cancer risk in women with Lynch syndrome. Women should discuss the benefits and risks of salpingo-oophorectomy with their doctor after completing child-rearing. The best timing for surgery depends on 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 that persist for several weeks, and any changes from normal, to their doctor:
  • Pelvic or abdominal pain
  • Abdominal bloating
  • Difficulty eating
  • Feeling full early
  • Frequent feeling of bladder fullness
• Screening: In the absence of symptoms, regular screening is performed with transvaginal ultrasound and CA125 blood tests. However, ovarian cancer screening does not help detect ovarian cancer early. Women who do not plan surgery should discuss the benefits, risks, costs, and timing of transvaginal ultrasound and CA125 with their doctor.
• Medication: Oral contraceptives (birth control medications) may reduce uterine cancer risk in women with Lynch syndrome. Women should discuss the benefits, risks, and timing of contraceptive medications with their doctor.

Pancreatic Cancer Screening in People with a Family History

• People carrying an MLH1 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 and ideally in a research setting. Before screening, people should discuss its benefits, risks, costs, and limitations with their doctor.
• 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 people of Asian ancestry:
  • 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 testing and treatment for H. Pylori.

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 for people with MLH1 mutations. However, clinical trials may be available.

Cancer Treatment for People with an MLH1 Mutation

Experts are conducting research studies to identify the best treatments for people carrying an inherited MLH1 mutation.

Most cancers in people carrying an inherited MLH1 mutation will have “MSI – high” or “MSI – H” (microsatellite instability) as a 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 5 – fluorouracil 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) 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

• Keytrude (pembrolizumab) was approved for the treatment of any solid tumor testing as MSI – H that has progressed after treatment and has no other treatment options.

Other Medical Concerns for People Carrying an Inherited MLH1 Mutation

Some mutations in the MLH1 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 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, particularly in sun-exposed skin. Annual skin examinations by a dermatologist are recommended for all individuals carrying an inherited MLH1 mutation, whether or not someone in their family has had these skin tumors.

Children who inherit an MLH1 mutation from both their mother and father may have “constitutional mismatch repair deficiency (CMMRD)”, a very rare syndrome. CMMRD may carry high risks of various cancers during childhood and adolescence. Children with CMMRD syndrome may have blood (hematological) and brain / central nervous system tumors, while colorectal and other cancers are generally seen in patients with Lynch syndrome at an older age. Many, though not all, patients with CMMRD resemble neurofibromatosis, a genetic disorder causing tumors to form on nerve tissue, particularly showing harmless, light-brown “café au lait” skin spots. For a child to have CMMRD syndrome, both their mother and father must have an MLH1 mutation. If one member of a couple has a known mutation, the couple may wish to talk with a genetic counselor about testing the other person before having children.

To select embryos without inherited MLH1 mutations, parents can use assisted reproductive technology and preimplantation genetic diagnosis as options.