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

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.

Keywords: Lynch syndrome; correlation genotype-phenotype; highly immunogenic frame-shift neo-peptides; immunotherapy; mismatch repair genes; unclassified genetic variants.

Figure 1.

Mismatch repair-deficient cells accumulate an abundance of mutations at coding microsatellites that may give rise to a loss of function of the respective proteins; however, may additionally trigger the translation of highly immunogenic FSPs or -antigens. FSP, frameshift neo-peptide.

Figure 2.

In tumoral cells, the ligation of T-cell PD-1 results in the downregulation of T-cell (CD8+ and CD4+) effector functions that may destroy tumor tissue; this downregulation of T-cell may favor the neoplastic expansion. PD-1, programmed cell death-1; FSP, frameshift neo-peptide.

Figure 3.

Management of patients with Lynch syndrome.