Lynch syndrome

Lynch syndrome (LS) is a familial cancer syndrome that is primarily associated with an increased risk of colorectal cancer (CRC) and endometrial cancer, and may predispose to the development of other tumors.

LS is the most common cause of hereditary nonpolyposis CRC. The second most frequent type of cancer among LS patients is endometrial cancer in women, followed by ovarian and urinary tract cancers.

LS is caused by pathogenic germline mutations in DNA mismatch repair genes known as "mismatch repair" or MMR genes. Depending on which gene is mutated, there is an increased risk for a specific type of cancer. For example, mutations in MLH1 and MSH2 increase the predisposition to nonpolyposis colorectal cancer, whereas the incidence of colorectal cancer in carriers of PMS2 variants is lower and the disease is usually less severe.

Symptoms

Lynch syndrome increases predisposition to CRC and other tumors such as ovarian, stomach, small intestine, urinary tract, biliary tract, brain, sebaceous skin tumors, pancreas and prostate. Not all people carrying Lynch syndrome-related mutations develop cancer, although they are at increased risk, which usually increases with age and may be influenced by other factors.

Disease management

Periodic colonoscopies, approximately every 1-2 years, are usually recommended in individuals diagnosed with LS.

Hysterectomy and prophylactic salpingo-oophorectomy, in women affected by the syndrome, can sometimes be used to prevent endometrial and ovarian cancer. Individualized counseling should be provided on the need for surgery, the risk involved, and the optimal timing of surgery.

There are several pharmacological treatments that can be used to try to reduce the risk of CRC and other LS-related tumors such as high-dose aspirin and estrogen therapy. Additionally, supplementation with vitamin complexes may be recommended.

Risk factors that may influence the development of CRC and other neoplasms should also be controlled, such as reducing overweight, avoiding smoking, minimizing or eliminating alcohol consumption, preventing type 2 diabetes, and controlling cholesterol and triglyceride levels.

Genes analyzed

MLH1 MSH2 MSH6 PMS2

Bibliography

Abu-Ghazaleh N, Kaushik V, Gorelik A,et al. Worldwide prevalence of Lynch syndrome in patients with colorectal cancer: Systematic review and meta-analysis. Genet Med. 2022 May;24(5):971-985.

Biller LH, Syngal S, Yurgelun M.Recent advances in Lynch syndrome. Fam Cancer. 2019 Apr;18(2):211-219.

Borràs E, Pineda M, Blanco I,et al. MLH1 founder mutations with moderate penetrance in Spanish Lynch syndrome families. Cancer Res. 2010 Oct 1;70(19):7379-91.

Cerretelli G, Ager A, Arends MJ,et al. Molecular pathology of Lynch syndrome. J Pathol. 2020 Apr;250(5):518-531.

Cohen SA, Pritchard CC, Jarvik G.Lynch Syndrome: From Screening to Diagnosis to Treatment in the Era of Modern Molecular Oncology. Annu Rev Genomics Hum Genet. 2019 Aug 31;20:293-307.

Idos G, Valle .Lynch Syndrome. 2004 Feb 5 [updated 2021 Feb 4]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021.

Lastella P, Patruno M, Forte G,et al. Identification and surveillance of 19 Lynch syndrome families in southern Italy: report of six novel germline mutations and a common founder mutation. Fam Cancer. 2011 Jun;10(2):285-95.

Ponti G, Castellsagué E, Ruini C,et al. Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. Clin Genet. 2015 Jun;87(6):507-16.

Taeubner J, Wieczorek D, Yasin L,et al. Penetrance and Expressivity in Inherited Cancer Predisposing Syndromes. Trends Cancer. 2018 Nov;4(11):718-728.

van Riel E, Ausems MG, Hogervorst FB,et al. A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome. Hered Cancer Clin Pract. 2010 Aug 12;8(1):7.

von Salomé J, Liu T, Keihäs M,et al. Haplotype analysis suggest that the MLH1 c.2059C?>?T mutation is a Swedish founder mutation. Fam Cancer. 2018 Oct;17(4):531-537.

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