Lynch Syndrome

In 1913 Warthin described a family in Michigan with a propensity to develop gastrointestinal and gynecologic cancers without colorectal polyps. In 1966, Lynch et al. published data on two other Midwestern families with a clustering of similar types of cancer. This syndrome, Lynch syndrome (formerly known as hereditary nonpolyposis colorectal cancer), is the most common hereditary cancer syndrome and is inherited in an autosomal dominant fashion. Typically, Lynch syndrome is the result of germline mutations in the mismatch repair (MMR) genes MSH2, MSH6, PMS2, or MLH1 with subsequent heterozygous loss of function [1-5]. While Lynch syndrome accounts for approximately 1-7% of all colorectal carcinomas, there is also an elevated risk of extracolonic malignancies including carcinomas of the small bowel, upper genitourinary tract, stomach, pancreas, ovary, and endometrium. In women, endometrial cancer and colon cancer are equally likely to be the sentinel tumor event. The MMR proteins are responsible for the repair of DNA basepair errors or “mismatches” that develop during DNA replication. When these errors occur, they are most commonly in long, repetitive DNA sequences commonly seen in microsatellites. Microsatellites are short mono, di, or trinucleotide repeats in noncoding regions throughout the human genome.

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Last date updated on April, 2024