Lynch syndrome

Overview

Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that significantly increases a person’s risk of developing colorectal cancer and several other types of cancer, often at a younger age than the general population. Unlike familial adenomatous polyposis (FAP), Lynch syndrome does not typically involve hundreds of polyps in the colon. Instead, it predisposes individuals to cancers of the colon, endometrium (uterus), ovary, stomach, small intestine, liver, and more. Early detection through screening is essential for effective management.

Causes

Lynch syndrome is caused by inherited mutations in one of several mismatch repair (MMR) genes that help correct errors during DNA replication. The most commonly affected genes include:

• MLH1

• MSH2

• MSH6

• PMS2

• EPCAM – deletions in this gene can silence the nearby MSH2 gene

These mutations result in microsatellite instability (MSI), a hallmark feature of tumors in Lynch syndrome. The condition is inherited in an autosomal dominant pattern, meaning a single mutated gene from either parent can cause the syndrome.

Symptoms

Lynch syndrome itself does not cause symptoms, but it increases the risk of developing various cancers. The most common and significant symptoms arise from the cancers associated with the syndrome:

• Colorectal cancer – symptoms may include changes in bowel habits, blood in stool, abdominal pain, or unexplained weight loss

• Endometrial cancer – abnormal uterine bleeding, especially after menopause

• Ovarian cancer – bloating, pelvic pain, or changes in menstruation

• Other possible cancers – including cancers of the stomach, small bowel, urinary tract, liver, brain, and skin

Family history often reveals multiple relatives with Lynch-associated cancers, particularly at younger ages.

Diagnosis

Diagnosis of Lynch syndrome involves a combination of personal and family history analysis, tumor testing, and genetic testing. Key diagnostic steps include:

• Family history evaluation – using criteria such as the Amsterdam or Bethesda guidelines

• Microsatellite instability (MSI) testing – performed on tumor tissue to detect genetic instability

• Immunohistochemistry (IHC) – used to assess the presence of MMR proteins in tumor tissue

• Germline genetic testing – confirmation of mutations in MMR genes through blood or saliva samples

Early identification is critical, as it allows for targeted cancer screening and risk-reduction strategies in both patients and their family members.

Treatment

Treatment of cancers in individuals with Lynch syndrome follows standard cancer protocols but may also include additional considerations due to the inherited nature of the disease. Management strategies include:

• Surgical treatment – such as colectomy for colon cancer or hysterectomy for endometrial cancer

• Chemotherapy and immunotherapy – especially checkpoint inhibitors for MSI-high tumors

• Regular cancer surveillance – including:

  • Colonoscopy every 1–2 years starting in early adulthood

  • Annual endometrial and ovarian cancer screening in women

  • Periodic screening for other associated cancers depending on family history

• Risk-reducing surgeries – such as prophylactic hysterectomy and oophorectomy in women after childbearing is complete

• Genetic counseling – for patients and at-risk family members

Prognosis

The prognosis for individuals with Lynch syndrome varies depending on the type and stage of cancer at diagnosis. With early and regular screening, cancers can often be detected at treatable stages, significantly improving outcomes. Preventive strategies and early interventions can reduce cancer risk and mortality. However, without appropriate surveillance, the lifetime risk of colorectal cancer can exceed 80%, and the risk of endometrial cancer in women can be as high as 60%. Lifelong follow-up and risk-reduction planning are essential for optimal outcomes.