Chromosome 8q23.3, 10p14 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome – a combined analysis of the Australian, Dutch and Polish Lynch syndrome cohorts

Background

For a decade researchers have been searching for modifier genes in individuals with a molecular diagnosis of Lynch syndrome but the task has proven difficult as discordant results seem to be the rule rather than the exception. Recently, two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome patients irrespective of which gene was mutated. In a combined study of CRC risk in Australian and Polish Lynch syndrome patients only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three datasets was performed to better define this association.

Methods

The three populations combined totalled 1359 individuals from 425 families with a molecular diagnosis of Lynch syndrome. To date, this represents the largest Lynch syndrome cohort examined for modifier genes. Seven SNPs, from 6 different CRC susceptibility loci, were genotyped by both research groups and the data analysed collectively.

Results

Individuals with MLH1 mutations harbouring the CC (variant) genotype of SNP rs3802842 are at increased risk of CRC (HR=2.77, p<0.001) and develop CRC on average 11 years earlier than individuals with the AA (wild type) genotype. All females (MLH1, MSH2 and MSH6 mutation carriers) carrying the CC genotype of SNP rs3802842 are at increased risk of CRC (HR=2.16, p=0.005), while female MLH1 mutation carriers are at highest risk (HR=3.88, p<0.001).

To investigate whether a cluster of risk alleles increases the risk of CRC, SNP rs3802842 was combined with the other six SNPs additively. MLH1 mutation carriers harbouring 3 risk alleles for SNP combination; rs3802842 (11q23.1) + rs16892766 (8q23.3) display an increased risk of CRC (HR=5.67, p=0.001) and an immense difference in the age of diagnosis of CRC of 28 years is observed compared to individuals with 0 risk alleles. While SNP combination; rs3802842 + rs10795668 (10p14) displays an increased risk of CRC for all females harbouring 4 risk alleles (HR=5.52, p=0.003).

Conclusion

These results confirm the role of modifier genes in HNPCC. We recommend that Lynch syndrome patients with MLH1 mutations and all Lynch syndrome females are genotyped for two SNPs in each group so that a personalised risk assessment and tailored surveillance program can be offered to patients at increased risk of CRC and therefore likely to develop their CRCs at much younger ages than the average age of disease onset.