Evaluation of Lynch syndrome modifier genes in 748 MMR mutation carriers

Abstract

Several studies have reported that, in Lynch syndrome resulting from mutations of the mismatch repair (MMR) genes, a CA repeat r17 within the IGF1 promoter, SNPs within the xenobiotic metabolizing enzyme gene CYP1A1 and SNPs on 8q23.3 and 11q23.1 modify colorectal cancer (CRC) risk in MMR mutation carriers. We analysed the impact of these polymorphisms on CRC risk in 748 French MMR mutation carriers derived from 359 families. We also analysed the effect of the Novel 1 SNP (18q21), which has recently been shown to increase CRC risk in the general population. We observed a significant difference in the CRC-free survival time between males and females, between MSH2 and MSH6 mutation carriers and between MLH1 and MSH6, indicating that this series is representative of Lynch syndrome. In contrast, the univariate log-rank test, as well as multivariate Cox model analysis controlling for familial aggregation and mutated MMR gene, year of birth and gender showed that the polymorphic alleles tested were not associated with a significant CRC risk increase, neither on the entire sample nor among males and females. This discrepancy with previous reports might be explained both by the genetic heterogeneity between the different populations analysed and the allelic heterogeneity of the MMR mutations. We conclude that genotyping of these polymorphisms is not useful to evaluate CRC risk in MMR mutation carriers and to optimize their clinical follow-up.

A Model to Determine Colorectal Cancer Risk Using Common Genetic Susceptibility Loci

“…Previous works have found the modifying effects of common SNPs in carriers of mismatch repair gene mutations; 36 however these results were not replicated in other studies. 37, 38 Using family history as a surrogate, we found that the genetic risk score of common loci remains to be significantly associated with increased risk of CRC in both men and women with a positive family history of CRC (results not shown), suggesting common genetic loci improve risk prediction in this group. Second, although our independent validation study includes approximately 1,800 subjects, we validated the models for men (~1,100) and women (~700) separately; therefore, the sample size is somewhat limited.…”

Genetic variant in the telomerase gene modifies cancer risk in Lynch syndrome

“…12 These results were partly confirmed in a cohort of Australian and Polish MMR mutation carriers, but were not replicated in a French cohort. 13,14 We selected the hTERT variant rs2075786 by somehow combining candidate gene and GWAS-based approaches. First, hTERT has an important role at very early stages of carcinogenesis, its expression has been linked to increased susceptibility to tumorigenesis, and rs2075786 has been associated with cancer risk.…”

“…11 In contrast, two genetic variants previously identified in CRC genome-wide association studies (GWAS), rs16892766 and rs3802842, might modify cancer risk in LS families. [12][13][14] Telomeres are located at the end of chromosomes and protect the chromosome ends from nucleolitic degradation, end-to-end fusions and irregular recombination, being thus critical for genome stability and integrity. Telomeres progressively shorten with each cell replication cycle.…”

Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers?

“…In the general population, the association was stronger for CRC diagnosed under age 60 years suggesting potential age modifying effects in MMR gene mutation carriers. This SNP has also been reported as a CRC risk modifier for MMR gene mutation carriers in three other studies(13–15); but not in one study(16). Talseth-Palmer et al(14) did not observe a significant effect of rs16892766 alone on CRC risk but observed a trend of an increased risk of CRC for the pair-wise combination of SNPs rs3802842 and rs16892766 in MLH1 mutation carriers.…”

“…If these SNPs also predicted CRC risk in MMR gene mutation carriers, there would be a potential to use them to more accurately predict individual risk estimates for Lynch syndrome. Three studies observed two variants, 8q23.3 (rs16892766) and 11q23.1 (rs3802842), to be associated with increased risk of CRC in Lynch syndrome especially for females only(13, 14) or MLH1 mutation carriers only(14, 15); however, another study(16) observe no associations. In this study of MMR gene mutation carriers, we have investigated associations of CRC with SNPs at 11 loci: 8q23.3 (rs16892766), 8q24.21 (rs6983267), 9p24 (rs719725), 10p14 (rs10795668), 11q23.1 (rs3802842), 14q22.2 (rs4444235), 15q13.3 (rs4779584), 16q22.1 (rs9929218), 18q21.1 (rs4939827), 19q13.1 (rs10411210) and 20p12.3 (rs961253).…”