Lynch syndrome (ORPHA:144)
A rare form of hereditary nonpolyposis colon cancer (HNPCC) characterized by predisposition to a wide variety of cancers, including neoplasms of the digestive tract, urinary tract, endometrium, ovary, brain, and prostate, as well as sebaceous skin tumors. LS-associated tumors are typically characterized by the presence of microsatellite instability (MSI) and loss of expression of MMR proteins in tumor tissue.
Epidemiology
The population prevalence of germline pathogenic variants in the MMR genes has been estimated at 1:279. Cancer type incidences vary with the affected gene, sex, and population. LS accounts for approximately 3% of colorectal (CRC) and endometrial cancers (EC).
Clinical description
LS-associated cancer usually occurs in adulthood, at earlier ages compared to the general population. CRC is the predominant LS-associated cancer; it has an increased risk of being synchronous or metachronous and is typically located in the proximal colon; symptoms include abdominal pain, iron deficiency or signs of colonic obstruction. EC is the most prevalent LS-associated cancer in women and manifests with pelvic pain and menorrhea. Other cancers include ovarian, stomach, hepatobiliary tract, pancreas, breast, small intestine, urinary tract, prostate, brain (mainly glioblastoma) and skin cancers (sebaceous adenomas/carcinomas/epitheliomas and keratoacanthomas). Muir-Torre and Turcot syndromes were terms used to describe patients with skin neoplasia, or with tumors of the colon and central nervous system, respectively.
Etiology
LS is caused by heterozygous pathogenic germline variants affecting DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2). Other variants involve C-terminal deletions of EPCAM leading to methylation of the adjacent MSH2 promoter in epithelial tissue. Rarely, LS is due to constitutional inactivation of MLH1 by epimutation.
Diagnostic methods
Amsterdam/revised Bethesda criteria fail to identify up to 50% of LS patients. MSI analysis and/or immunohistochemical analysis of MMR protein expression in CRC and EC is recommended for all patients. Universal or age-dependent somatic and/or germline genetic testing of these patients is undergoing evaluation. Cascade testing should follow the identification of an individual with a MMR pathogenic mutation.
Differential diagnosis
Differential diagnosis includes several forms of attenuated polyposis, particularly recessive tumor syndromes associated with germline biallelic pathogenic variants in MUTYH, NTHL1, MBD4, or MSH3, polymerase proofreading-related adenomatous polyposis, constitutional MMR deficiency, and other cancer predisposition syndromes such as PTEN hamartoma tumor or Li-Fraumeni syndrome. Unexplained cases might be classified as Lynch-like syndrome or familial CRC type X, depending on the status of the MMR system in the tumors.
Antenatal diagnosis
Prenatal and preimplantation genetic diagnoses are possible if a pathogenic variant has been identified in a parent.
Genetic counseling
LS follows an autosomal dominant mode of inheritance with incomplete penetrance. The inheritance pattern of MLH1 epimutations is variable, presumably reflecting their mechanistic basis. Genetic counseling should be offered to affected individuals and their relatives to inform them of the increased risk of cancer. Each child of an individual with LS has a 50% chance of inheriting the variant.
Management and treatment
Due to the high risk of synchronous or metachronous tumors, patients should be included in surveillance programs consisting of colonoscopy with removal of precancerous polyps, and transvaginal ultrasound examination and endometrial biopsy (with yearly education on EC and ovarian cancer) for women, every 1-2 years starting at the age of 20-25 years. Full colectomy should be considered in LS-CRC patients. Screening may start at an earlier age depending on family history. Aspirin decreases the risk of CRC. Prophylactic hysterectomy and bilateral salpingo-oophorectomy can be proposed to women after childbearing age. Treatments supporting anti-tumoral immune response show great success against MSI-high tumors.
Prognosis
Early diagnosis and surveillance significantly reduce morbidity and mortality. LS-associated tumors tend to have a better prognosis at similar stage compared with microsatellite stable tumors.

                            Last update: 
                            September 2023


                            - Expert reviewer(s): 
                            Pr Stefan ARETZ | ERN GENTURIS* - Dr Marta PINEDA RÍU | ERN GENTURIS* - Dr Laura VALLE | ERN GENTURIS*


                                * European Reference Network