Recently, Houlle et al1 reported results of two modifier SNPs in Lynch syndrome, rs16892766 on 8q23.3 and rs3802842 on 11q23.1 previously identified as low-susceptibility colorectal cancer (CRC) loci, challenging earlier reported findings.2, 3
In 2009 Wijnen et al2 demonstrated that two SNPs located on 8q23.3 (rs16892766) and 11q23.1 (rs3802842) were associated with an increased risk of developing CRC in Dutch Lynch syndrome patients. The study revealed that patients’ homozygote for SNP rs16892766 were associated with an elevated risk of CRC in a dose-dependent manner with a 2.16-fold increased risk of developing CRC, whereas the variant (CC) genotype of SNP rs3802842 was associated with an increased risk of CRC in female carriers only (HR=3.08).2 In a combined analysis of the two SNPs, the risk was significantly associated with the number of risk alleles and the effect was shown to be stronger in female carriers than in male carriers.
Recently, Talseth-Palmer et al3 confirmed the increased risk of CRC in Lynch syndrome patients in a combined Australian and Polish sample cohort but only in MLH1 mutation carriers. In this study the two Lynch syndrome populations (Australian and Polish) were analysed separately and together, as a larger sample size gives increased power and more reproducible results. SNP rs3802842 revealed a significant association on the risk of developing CRC in the combined sample population (Australian and Polish) with a HR of 2.67. When analysed separately, the Australian sample population displayed significant results whereas the Polish sample population displayed a trend, which demonstrates the increased power acquired when more samples are analysed together. SNP rs16892766 was only significantly associated with the increased risk of CRC in Australian MLH1 mutation carriers, but as this was the same SNP that displayed an association in the Dutch study2 we also analysed the additive effect of the two SNPs. We were able to show that MLH1 mutation carriers from Australia and Poland harbouring three risk alleles for the two SNPs developed CRC on average 24 years younger and were at 5.52-fold increased risk of CRC compared with individuals harbouring no risk alleles. The quote in the report by Houlle et al1 ‘During the submission of this study, Talseth-Palmer et al15 reported that in MLH1 carriers, but not in MSH2 carriers, the 11q23.1 CC and 8q23.3 AC genotypes were associated with an increased risk, but this significant association detected in 373 Australian mutation carriers was not found in 311 Polish mutation carriers analysed in the same study’ is incorrect, as we did see this association in our combined sample cohort.
A decreased risk of CRC (HR=0.267, P=0.0271) for the CC (variant) genotype for SNP rs16892766 is reported by Houlle et al.1 According to previously published results discussed above this result is contradictory. A decreased risk of CRC indicate a later age of onset of CRC in the two individuals who harboured the CC genotype for SNP rs16892766, but the age of onset of CRC of these two individuals was not reported and can therefore not be commented on. It is highlighted by the French authors that the small number of subjects harbouring this genotype could affect the reported results. We believe that the observed results could be due to the fact that either of these two individuals harbours the variant (CC) genotype for SNP rs3802842, which seems to be important for the increased risk of CRC as observed in the Australian/Polish sample cohort.
A meta-analysis of the French and Dutch data set was performed by Houlle et al1 indicating that SNP rs3802842 at 11q23.1 is not associated with increased risk of developing CRC, and the only association observed in this meta-analysis was a decreased risk of CRC for SNP rs16892766 in male mutation carriers, which contradicts previously reported results.2, 3 SNP rs16892766 (8q23.3) did not show an association with the CC (variant) genotype for the overall sample size as shown on the Forest plot (Figure 11), which is not surprising as positive and negative results combined will end up with a neutral result. But false positive results in the Dutch study2 and false negative results in the French study1 cannot be ruled out as a reason for the neutral results observed in the meta-analysis. Also, the heterogeneity of the population (ie, MMR gene) is not taken into account when a meta-analysis is performed and as shown by Talseth-Palmer et al3 this can drastically affect the observed results.
This work was supported by grants from the Hunter Medical Research Institute, Cancer Institute NSW, Glady's M. Brawn Memorial Fund through the University of Newcastle, National Health & Medical Research Council and the Dutch Cancer Society (KWF 2005-3247).