MMR genes encode MMR proteins that repair DNA defects during replication; alterations in the genes result in neoplasm formation. Deficient mismatch repair (dMMR) is associated with high levels of microsatellite instability (MSI-H) and suggests potential responsiveness to anti-programmed cell death 1 (PD-1)–based immune checkpoint inhibitor immunotherapy, which makes it a predictive biomarker.

Cancer Risks

MMR genes are susceptibility biomarkers because germline detection of a pathogenic variant in one of the genes may indicate potential risks for the patient and potentially other family members. Malignancy risk varies with the gene (see sidebar), but an estimated annual 4,300 colorectal and 1,800 endometrial cancer diagnoses are attributed to HNPCC.

According to the National Comprehensive Cancer Network’s (NCCN’s) Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal (version 2.2023), risk for female breast cancer may also be increased but the magnitude is unclear. Individuals with HNPCC are also at risk for nonmalignant skin conditions, including sebaceous adenocarcinomas, sebaceous adenomas, and keratoacanthomas.

Indications for Germline Testing

Per the NCCN guidelines, individuals with any of the following should be referred for genetic counseling:

• Tumor with MSI-H or loss of expression in one of the MMR genes
• Known pathogenic or likely pathogenic variant in the family
• Colon or endometrial cancer diagnosis and at least one of the following:
  • Younger than 50 years
  • One first- or second-degree relative with an HNPCC cancer diagnosis before age 50
  • More than two relatives with an HNPCC cancer

• Family history of:
  • One or more first-degree relatives with a colon or endometrial cancer diagnosis before age 50
  • One first-degree relative with two or more HNPCC cancers
  • Three or more relatives with HNPCC cancer

Management and Recommendations for Care

Individuals with a known pathogenic variant associated with HNPCC need lifelong cancer screening, but the recommendations are complex and constantly evolving. Regularly reviewing their screening plan with a genetics professional ensures they are current and appropriate. Testing is typically offered around age 20–25 so that intensive screening can begin in that timeframe.

The NCCN guidelines and other recommendations for care factor the specific gene with the pathogenic variant and its associated risks, as well as the individual’s personal and family history, and may include:

• Colonoscopy with removal of polyps every one to two years should begin at age 20–25 for individuals with pathogenic MLH1, MSH2, or EPCAM variants or five years before the youngest diagnosis of colorectal cancer in the family, whichever is earliest. Colonoscopy is initiated at age 30 for individuals with MSH6 and PMS2 variants or five years before the youngest diagnosis of colorectal cancer in the family, whichever is earliest.
• Conduct an upper endoscopy every two to four years beginning at age 30–35. Evaluate biopsies for H. pylori infections and treat as indicated.
• Consider risk-reducing hysterectomy with oophorectomy, based on each individual’s childbearing plans, risk associated with the specific gene, and family history. Instruct patients with a uterus to report any unexplained vaginal spotting, bleeding, or discharge. Consider endometrial biopsy every one to two years starting at age 30–35.
• Begin annual urine analysis at age 30–35 in patients with MLH1 and MSH2 pathogenic variants.
• Annual physical exam, including neurologic evaluation, should begin at age 25–30.
• NCCN’s Breast Cancer Risk Reduction clinical practice guidelines (version 2.2024) recommend risk assessment–based screening using a model that considers personal and family history (e.g., Gail Model, Tyrer-Cuzick Risk Assessment Calculator). Patients at increased risk should have more intensive screening that begins at a younger age.
• Conduct an annual full-body skin examination for sebaceous adenoma, sebaceous adenocarcinoma, or keratoacanthoma. Educate patients about decreasing ultraviolet exposure, consistently using sunscreen with an SPF of 30, and wearing protective clothing, including hats and sunglasses.
• Consider pancreatic cancer screening for individuals who have a pathogenic variant in MLH1, MSH2, or MSH6 and at least one first-degree relative with pancreatic cancer at age 50 or 10 years before the youngest pancreatic cancer diagnosis in the family. Screening should be performed in centers capable of high-volume screening with magnetic resonance cholangiopancreatography or endoscopic ultrasound.
• Begin annual prostate screening, including digital rectal examination and prostate-specific antigen testing, at age 40 or earlier depending on family history and a shared decision-making discussion.

Nursing Implications

Patients and families with HNPCC need ongoing support and education to ensure that the extensive screening guidelines are followed. As children in these families approach the age of 20–25, they should be offered the option of testing to clarify risk and whether they would benefit from more intensive screening. Supportive educational messages should reiterate that early detection of cancers is possible with appropriate screening and that risk-reducing measures will help in cancer prevention, ultimately decreasing the morbidity and mortality associated with an HNPCC diagnosis.