- Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common inherited colorectal cancer syndrome and a significant contributor to early-onset malignancies.
- It is an autosomal dominant genetic disorder caused by germline mutations in DNA mismatch repair (MMR) genes, which normally correct errors during DNA replication. The most frequently affected genes are MLH1, MSH2, MSH6, and PMS2, along with EPCAM, whose deletions can silence MSH2 through epigenetic mechanisms. When these genes are defective, the result is microsatellite instability (MSI), a condition in which repetitive DNA sequences become highly prone to mutations, driving tumorigenesis.
- Individuals with Lynch syndrome face a substantially increased risk of developing colorectal cancer, often at a younger age than the general population, with cancers typically arising in the proximal (right-sided) colon. Unlike familial adenomatous polyposis (FAP), Lynch syndrome does not produce hundreds of polyps; instead, it is characterized by the development of few adenomas that progress rapidly to carcinoma due to defective DNA repair. This accelerated adenoma–carcinoma sequence highlights the importance of vigilant surveillance in affected individuals.
- Beyond colorectal cancer, Lynch syndrome confers a broad spectrum of cancer risks. Women with the syndrome have a particularly high lifetime risk of endometrial cancer, often equal to or greater than their risk of colorectal cancer. Other associated malignancies include cancers of the ovary, stomach, small intestine, hepatobiliary tract, urinary tract (ureter and renal pelvis), pancreas, and brain (particularly glioblastomas, as seen in Turcot syndrome, a variant of Lynch). The diversity of affected tissues reflects the systemic impact of defective mismatch repair on genomic stability.
- Clinically, suspicion of Lynch syndrome arises from family history and cancer patterns, often guided by the Amsterdam criteria (three relatives with Lynch-associated cancers, across two generations, with one diagnosed before age 50) or the broader revised Bethesda guidelines. Molecular testing of tumors for microsatellite instability (MSI) or loss of MMR protein expression by immunohistochemistry (IHC) serves as an important screening step. Confirmatory diagnosis requires germline genetic testing. Identification of carriers has major implications not only for patients but also for at-risk family members.
- Management of Lynch syndrome focuses on early detection, prevention, and risk reduction. Intensive colorectal surveillance with colonoscopy every 1–2 years beginning between ages 20–25 (or 2–5 years earlier than the youngest colorectal cancer diagnosis in the family) is the standard of care, given the rapid progression of adenomas. For women, annual endometrial sampling and transvaginal ultrasound may be offered, though many experts recommend prophylactic hysterectomy and bilateral salpingo-oophorectomy after childbearing to reduce gynecologic cancer risk. Lifestyle modifications, including diets high in fiber and regular physical activity, may offer additional benefit.
- Therapeutically, the recognition of Lynch syndrome has reshaped treatment approaches. Tumors with high microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) often show resistance to conventional chemotherapy such as 5-fluorouracil but respond exceptionally well to immune checkpoint inhibitors (e.g., pembrolizumab, nivolumab), as these tumors accumulate a high mutational burden that enhances immunogenicity. This makes Lynch syndrome–associated cancers a prime example of how germline genetics and tumor biology guide precision oncology.
- In summary, Lynch syndrome is an inherited cancer predisposition syndrome caused by defects in DNA mismatch repair genes, leading to microsatellite instability and increased risk of colorectal and multiple extracolonic cancers. It differs from other hereditary colorectal cancer syndromes in that it does not cause polyposis but instead accelerates adenoma progression to carcinoma. Early recognition, genetic testing, and surveillance are essential to reducing morbidity and mortality. Advances in molecular diagnostics and immunotherapy have not only improved outcomes for affected patients but also transformed Lynch syndrome into a paradigm of hereditary cancer risk management and precision medicine.
