Combined analysis of three lynch syndrome cohorts confirms the modifying effects of 8q23.3 and 11q23.1 in MLH1 mutation carriers

Abstract

Two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome (LS) patients. Recently, in a combined study of Australian and Polish LS patients, only MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three data-sets was performed to better define this association. This cohort-study includes three sample populations combined totaling 1,352 individuals from 424 families with a molecular diagnosis of LS. Seven SNPs, from six different CRC susceptibility loci, were genotyped by both research groups and the data analyzed collectively. We identified associations at two of the six CRC susceptibility loci in MLH1 mutation carriers from the combined LS cohort: 11q23.1 (rs3802842, HR 5 2.68, p 0.0001) increasing risk of CRC, and rs3802842 in a pair-wise combination with 8q23.3 (rs16892766) affecting age of diagnosis of CRC (log-rank test; p 0.0001). A significant difference in the age of diagnosis of CRC of 28 years was observed in individuals carrying three risk alleles compared to those with 0 risk alleles for the pair-wise SNP combination. A trend (due to significance threshold of p 0.0010) was observed in MLH1 mutation carriers towards an increased risk of CRC for the pair-wise combination (p 5 0.002). This study confirms the role of modifier loci in LS. We consider that LS patients with MLH1 mutations would greatly benefit from additional genotyping of SNPs rs3802842 and rs16892766 for personalized risk assessment and a tailored surveillance program.

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

“…First, information on hereditary nonpolyposis colorectal cancer was not collected across studies, hence, we were not able to examine directly if added common genetic risk loci would improve risk prediction for subjects with rare-high-penetrance mutations. 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.…”

Microsatellite Instability as a Biomarker for PD-1 Blockade

“…Compared with patients with an MLH1 mutation, for example, those with an MSH2 mutation have a higher risk of a noncolorectal malignancy and those with an MSH6 mutation have a higher risk of endometrial cancer (35,36). Patients with an MLH1 mutation, in turn, are more likely to develop colorectal cancer at a young age in the presence of specific risk alleles (37).…”

Is the reported modifying effect of 8q23.3 and 11q23.1 on colorectal cancer risk for MLH1 mutation carriers valid?

“…In a recent study, Talseth-Palmer et al 6 conducted a pooled analysis by combing the studies by Wijnen et al 3 and Talseth-Palmer et al 4 to investigate the role of seven SNPs from six independent loci on CRC risk for MMR gene mutation carriers. They reported that carriers of the C-allele of rs16892766 (8q23.3) and the C-allele of rs3802842 (11q23.1) are at increased risk of CRC for MLH1 mutation carriers.…”

“…This is the design used by the study of Talseth-Palmer et al 6 While this retrospective design overcomes the limitations of case-control and prospective cohort studies described above, it introduces additional problems given MMR gene mutation carriers will not be random with respect to CRC status overall, and with respect to age. The sampling of MMR gene mutation carriers does not represent a true cohort, and standard analysis methods (such as Cox regression used by Talseth-Palmer et al…”

“…This weighted cohort analysis method has been used for studies investigating risk factors modifying cancer risks for carriers of rare high-risk genetic mutations. 3,[8][9][10] Of the two studies included in the pooled analysis by Talseth-Palmer et al, 6 Wijnen et al 3 did conduct a weighted Cox regression approach, 7 as we suggest above "to correct for this potential testing bias." However, in the current study, the authors did not use this approach therefore their observation of the modifying effect of 8q23.3 and 11q23.1 on CRC risk for MLH1 mutation carriers may not be valid.…”