Association of low‐risk MSH3 and MSH2 variant alleles with Lynch syndrome: Probability of synergistic effects

Abstract

Mutations in the MLH1 and MSH2 genes account for a majority of cases of families with Lynch Syndrome. Germ-line mutations in MSH6, PMS2 and MLH3 are responsible for disease in a minority of cases, usually associated with milder and variable phenotypes. No germ-line mutations in MSH3 have so far been associated with Lynch Syndrome, although it is known that impaired MSH3 activity leads to a partial defect in mismatch repair (MMR), with low levels of microsatellite instability at the loci with dinucleotide repeats in colorectal cancer (CRC), thus suggesting a role for MSH3 in carcinogenesis. To determine a possible role of MSH3 as predisposing to CRC in Lynch syndrome, we screened MSH3 for germ-line mutations in 79 unrelated Lynch patients who were negative for pathogenetic mutations in MLH1, MSH2 and MSH6. We found 13 mutant alleles, including silent, missense and intronic variants. These variants were identified through denaturing high performance liquid chromatography and subsequent DNA sequencing. In one Lynch family, the index case with early-onset colon cancer was a carrier of a polymorphism in the MSH2 gene and two variants in the MSH3 gene. These variants were associated with the disease in the family, thus suggesting the involvement of MSH3 in colon tumour progression. We hypothesise a model in which variants of the MSH3 gene behave as low-risk alleles that contribute to the risk of colon cancer in Lynch families, mostly with other low-risk alleles of MMR genes.

Synergistic Effects of Low-Risk Variant Alleles in Cancer Predisposition

“…Moreover, The same situation could occur in other forms of hereditary cancer and it may explain the large number of cases remained unresolved as well as the phenotypic heterogeneity that characterizes all hereditary cancer syndromes. [53]. Symbols and abbreviations used are denoted as fellow: Arrows, analysed members of family; black symbol, colorectal cancer or cancer associate with HNPCC; gray symbols, adenomas or cancer not associated with HNPCC; CRC, colorectal cancer; Br, brain cancer; GU, gastric ulcer; BL, bladder cancer; Bre, breast cancer; TA, tubular adenoma.…”

“…The majority of research into mutations has focused on MLH1 and MSH2, however mutations in these two gene are not present in many patients. So far, 10% of mutations in MMR genes have been identified in the MSH6 gene and a total of 5% in MLH3 and PMS2 and very recently germ-line mutations in the MSH3 gene [53]. These genes are defined as "minor MMR genes" because they have redundant functions in mismatch repair in replication.…”

ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis)

“…In the somatic tumor tissue, mutations in the MMRs genes result in high levels of MSI. [29][30][31][32][33][34] …”

Incomplete Segregation of <em>MSH6</em> Frameshift Variants with Phenotype of Lynch Syndrome

“…The nine novel DNA variants were not detected in the 100 healthy controls (Table 2). To verify the pathogenicity of the novel variants, we used a combination of computational and segregation analyses, as described in our previous studies [7,21]. The results are shown in Table 2.…”

“…Approximately 10% of the mutations in MMR genes have been identified in MSH6 gene, and PMS2 and MLH3 mutations contribute to a combined 5% [5,6]. Only one study has investigated mutations in MSH3 [7]. These mutations manifest as high levels of microsatellite 2 of 12 instability (MSI), which occurs in >90% of all LS carcinomas [8,9].…”