Genetics, diagnosis and treatment of Lynch syndrome: Old lessons and current challenges (Review)

Abstract

Lynch syndrome (LS) is an autosomal dominant genetic disorder associated with germline mutations in DNA mismatch repair (MMR) genes. The carriers of pathogenic mutations in these genes have an increased risk of developing a colorectal cancer and/or LS-associated cancer. The LS-associated cancer types include carcinomas of the endometrium, small intestine, stomach, pancreas and biliary tract, ovary, brain, upper urinary tract and skin. The criteria for the clinical diagnosis of LS and the procedures of the genetic testing for identification of pathogenetic mutations carriers in MMR genes have long been known. A crucial point in the mutation detection analysis is the correct definition of the pathogenecity associated with MMR genetic variants, especially in order to include the mutation carriers in the endoscopy surveillance programs more suited to them. Therefore, this may help to improve the LS-associated cancer prevention programs. In the present review, we also report the recent discoveries in molecular genetics of LS, such as the new roles of MMR protein and immune response of MMR repair deficiency in colorectal cancer. Finally, we discuss the main therapeutic approaches, including immunotherapy, which represent a valid alternative to traditional therapeutic methods and extend the life expectancy of patients that have already developed LS-associated colorectal cancer.

MSH2 Overexpression Due to an Unclassified Variant in 3’-Untranslated Region in a Patient with Colon Cancer

“…A defective MMR system mainly results from mutations in the same MMR genes and is the basis of Lynch syndrome (LS). LS is an autosomal dominant condition caused by a defect in one of the MMR genes and is characterized by a high lifetime risk of tumor development, especially colorectal cancer (20-70%), endometrial cancer (15-70%), and other extracolonic tumors (15%) [7]. The molecular characterization of LS patients relies on the identification of point mutations and large rearrangements in the coding regions of the MMR genes, MLH1, MSH2, PMS2, and MSH6 [8][9][10][11][12][13].…”

Primary malignant pericardial tumour in Lynch syndrome

“…In fact, the extraordinary rarity of the case together with the personal history of cancer raised the suspicion of DNA germline predisposition which ultimately led to genome profiling in order to identify molecular alterations potentially beneficial for diagnosis, treatment and follow-up. MSH2 inactivation leads to MMR defects, MSI, and a high mutational burden, which may have an important implication in predicting response to immunotherapies like pembrolizumab and nivolumab [13,14] . In case of non-operable disease recurrence or new non-operable cancer, in addition to conventional chemotherapies, the patient could have been a candidate to receive immunotherapy, currently widely used and effective in other solid neoplasms such as melanoma, non-small cell lung cancer and renal cell carcinoma [15].…”

Promising Colorectal Cancer Biomarkers for Precision Prevention and Therapy

“…With the advent of immunotherapy, CRCs are also classified based on mismatch-repair-deficiency or proficiency and the level of microsatellite instability, (dMMR-MSI-H; pMMR-MSI-L). It is now known that dMMR-MSI-H CRC is associated with a high tumor mutation burden and immune cell infiltration [45,46].…”