Hereditary nonpolyposis colorectal cancer

Overview

Hereditary Nonpolyposis Colorectal Cancer (HNPCC), more commonly known as Lynch syndrome, is an inherited condition that significantly increases the risk of colorectal cancer and various other cancers, particularly endometrial (uterine) cancer. Unlike other hereditary colorectal cancer syndromes, such as familial adenomatous polyposis (FAP), Lynch syndrome is not associated with the development of numerous colon polyps. It is one of the most common inherited cancer syndromes and is caused by mutations in genes responsible for DNA mismatch repair.

Causes

Lynch syndrome is caused by inherited mutations in one of several DNA mismatch repair (MMR) genes, including:

• MLH1

• MSH2

• MSH6

• PMS2

• EPCAM (which indirectly affects MSH2 expression)

These genes are responsible for correcting DNA replication errors. When one of these genes is mutated, DNA errors accumulate, leading to increased cancer risk. The condition follows an autosomal dominant inheritance pattern, meaning a person only needs one mutated copy of the gene to be at risk.

Symptoms

Lynch syndrome itself does not cause symptoms but predisposes individuals to early-onset cancers. The most commonly associated cancers and features include:

• Colorectal cancer: Often occurs before age 50, typically on the right side of the colon, and may develop rapidly without many polyps

• Endometrial cancer: Common in women with Lynch syndrome, often presenting before menopause

• Other associated cancers:

  • Ovarian cancer

  • Stomach cancer

  • Small intestine cancer

  • Hepatobiliary tract cancer

  • Urinary tract cancer (ureter and renal pelvis)

  • Pancreatic and brain cancers

  • Sebaceous gland tumors (in Muir–Torre variant)

A family history of early-onset colorectal or endometrial cancer is a common indicator of Lynch syndrome.

Diagnosis

Diagnosis of Lynch syndrome involves a combination of clinical criteria, tumor testing, and genetic analysis. Key diagnostic steps include:

• Family history evaluation: Using Amsterdam or revised Bethesda criteria

• Microsatellite instability (MSI) testing: Assesses the DNA instability often present in Lynch-associated tumors

• Immunohistochemistry (IHC): Determines the presence or absence of MMR proteins in tumor tissue

• Germline genetic testing: Confirms mutations in MMR genes or EPCAM

Genetic counseling is recommended for individuals undergoing testing and for family members of those diagnosed with Lynch syndrome.

Treatment

Treatment for Lynch syndrome-related cancers is generally the same as for sporadic cancers, but management includes special considerations for cancer risk reduction. Strategies include:

• Colorectal cancer: Surgery, chemotherapy, and regular surveillance for recurrence

• Risk-reducing surgery: Prophylactic hysterectomy and oophorectomy may be recommended for women who have completed childbearing

• Surveillance:

  • Colonoscopy every 1–2 years starting in the early 20s

  • Annual endometrial and ovarian cancer screening for women

  • Periodic screening for other associated cancers based on family history

• Aspirin therapy: May reduce colorectal cancer risk, as shown in some studies

A multidisciplinary care approach involving oncologists, gastroenterologists, genetic counselors, and gynecologists is essential for comprehensive management.

Prognosis

The prognosis for individuals with Lynch syndrome depends on early detection and timely treatment. Regular surveillance greatly improves outcomes by enabling early cancer diagnosis, when treatment is most effective. Colorectal cancers associated with Lynch syndrome tend to respond well to treatment when caught early. However, the lifelong risk of multiple cancers remains elevated, making continuous follow-up crucial. With proper screening and management, many individuals with Lynch syndrome can lead long, healthy lives.