Synergistic Effects of Low-Risk Variant Alleles in Cancer Predisposition

Novel Implications in Molecular Diagnosis of Lynch Syndrome

“…In light of literature data indicated that “minor” MMR proteins have other functions besides the postreplicative repair that could be highly relevant in carcinogenesis; in our laboratories, we have also analyzed the minor MMR genes, MSH6, PMS2, MLH3, and MSH3 for germline variants detected in patients negative for germline mutations in the major MMR genes. Many of the subjects analyzed in our series [ 50 , 51 , 64 , 85 ] showed coinheritance of different genetic alterations in the minor MMR genes ( Table 3 ) we speculate a likely additive role of low penetrance alleles in the disease development, in favor of a putative polygenic inheritance for Lynch syndrome, according to recent literature data [ 87 – 89 ].…”

“…In our experience, we have identified several patients carrying genetic VUS (missense, intronic, and silent variants) not only in main genes, MLH1 and MSH2 [ 80 ], but also in other MMR genes. According to international recommendations (Colon cancer Family Registry 2009, InSiGHT Variant Interpretation Committee 2011) we used a multifactorial likelihood model in an attempt to define a pathogenetic role for numerous VUS identified in MMR genes [ 50 , 51 , 64 , 85 ]. The segregation analysis, population studies (to exclude the polymorphic nature of the variant), assessment of MSI in tumor tissues, detection of loss of protein expression in tumor tissues by immunohistochemical analysis (IHC), in silico analysis by a variety of bioinformatics tools, and gene expression studies are strategies that have to be used to assess an exhaustive evaluation of the pathogenicity of uncertain variants [ 85 ].…”

“…In these cases high-throughput sequencing procedures play an important role to identify new constitutive and somatic mutations in putative genes associated with hereditary predisposition to cancer [ 64 ].…”

“…In some cases, VUSs make a more substantial overall contribution to cancer risk than the well-assessed severe Mendelian variants. It is also possible that the simultaneous presence of some polymorphisms and VUSs in cancer predisposition genes that behave as low risk alleles might contribute in a cooperative manner to increase the risk of hereditary cancer [ 12 , 64 ]. Therefore, current literature data suggest a significant proportion of the inherited susceptibility to relatively common human diseases may be due to the addition of the effects of a series of low frequency variants of different genes, probably acting in a dominant and independent manner, with each of them conferring a moderate but even detectable increase in the relative cancer risk [ 50 , 51 , 75 , 81 – 83 ].…”