Lynch syndrome

Lynch syndrome
Name	Lynch syndrome
Synonyms	Hereditary nonpolyposis colorectal cancer (HNPCC)
Field	Oncology, Medical genetics
Causes	Germline mutations in DNA mismatch repair genes
Diagnosis	Amsterdam criteria, Bethesda guidelines, Immunohistochemistry, Microsatellite instability testing
Treatment	Colectomy, Hysterectomy, Salpingo-oophorectomy, Aspirin
Frequency	1 in 279 to 1 in 440 individuals

Lynch syndrome is an autosomal dominant inherited disorder caused by germline mutations in DNA mismatch repair genes, significantly increasing the risk for several cancers, most notably colorectal cancer and endometrial cancer. It is the most common hereditary cause of colorectal cancer, accounting for approximately 3% of all cases. The condition was historically termed Hereditary nonpolyposis colorectal cancer (HNPCC) before being renamed in recognition of the pioneering work of Dr. Henry T. Lynch.

Overview

Lynch syndrome is characterized by a markedly elevated lifetime risk of developing malignancies, with the highest risks associated with the colon and the endometrium. Individuals with this condition also face increased risks for cancers of the ovary, stomach, small intestine, hepatobiliary tract, urinary tract, brain, and sebaceous glands. The underlying genetic defect impairs the DNA mismatch repair system, leading to the accumulation of mutations and a phenotype known as microsatellite instability, which is a hallmark of tumors arising in this syndrome. Management centers on intensive cancer surveillance and consideration of risk-reducing surgery.

Causes and genetics

The syndrome is caused by pathogenic variants in one of several DNA mismatch repair genes: MLH1, MSH2, MSH6, and PMS2. A subset of cases is caused by deletions in the EPCAM gene, which lead to silencing of the adjacent MSH2 gene. These genes are responsible for correcting errors that occur during DNA replication; their inactivation results in a hypermutable state. Inheritance follows an autosomal dominant pattern, meaning a child of an affected parent has a 50% chance of inheriting the mutation. The Knudson two-hit hypothesis explains tumorigenesis, where the inherited germline mutation constitutes the first "hit" and a subsequent somatic mutation inactivates the remaining functional allele.

Diagnosis

Diagnostic evaluation often begins with assessment of personal and family history using established criteria such as the Amsterdam criteria and the revised Bethesda guidelines. Tumor testing is a cornerstone, typically involving immunohistochemistry to assess loss of mismatch repair protein expression or PCR-based analysis for microsatellite instability. Confirmatory genetic testing for a germline mutation in the implicated genes is the definitive diagnostic step. The diagnosis can have profound implications for family members, leading to recommendations for genetic counseling and predictive testing for at-risk relatives.

Management and treatment

Clinical management is multidisciplinary, involving gastroenterology, gynecology, oncology, and genetic counseling. For colorectal cancer risk, intensive surveillance with colonoscopy is recommended, typically every 1-2 years starting between ages 20-25. For women, surveillance for endometrial cancer may include transvaginal ultrasound and endometrial biopsy, though risk-reducing hysterectomy with bilateral salpingo-oophorectomy is often considered after childbearing. Chemoprevention with aspirin has shown promise in reducing colorectal cancer incidence. When cancer develops, surgical treatment, such as subtotal colectomy for colon cancer, is often more extensive due to the high risk of metachronous cancer.

Epidemiology

Lynch syndrome is estimated to affect between 1 in 279 to 1 in 440 individuals in the general population, though many remain undiagnosed. It accounts for about 2-4% of all colorectal cancer cases and a significant proportion of endometrial cancer cases. The prevalence of specific gene mutations varies geographically and among different ethnic groups; for instance, certain founder mutations have been identified in populations such as Finns and Ashkenazi Jews. The penetrance of cancer is high but variable, depending on the specific mutated gene, with MLH1 and MSH2 mutations conferring the highest risks.

History

The condition was first described in the medical literature by Dr. Aldred Scott Warthin in 1913, based on his observations of a family with a striking history of gastric cancer and endometrial cancer. However, it was Dr. Henry T. Lynch and his colleagues who, in the 1960s and 1970s, systematically characterized the cancer family syndrome, initially naming it Cancer Family Syndrome and later Hereditary Nonpolyposis Colorectal Cancer. The genetic basis began to unravel in 1993 with the discovery of linkage to chromosome 2p and the subsequent identification of MSH2 and MLH1 as the causative genes. The term "Lynch syndrome" was formally adopted to honor Dr. Lynch's seminal contributions.

Category:Genetic disorders Category:Oncology Category:Syndromes