Contribution of rare germline copy number variations and common susceptibility loci in Lynch syndrome patients negative for mutations in the mismatch repair genes

In colorectal carcinoma (CRC), 35% of cases are known to have a hereditary component, while a lower proportion (approximate to 5%) can be explained by known genetic factors. In this study, copy number variations (CNVs) were evaluated in 45 unrelated patients with clinical hypothesis of Lynch syndrome (Amsterdam or Bethesda criteria); negative for MLH1, MSH2, MSH6, PMS2, CHEK2*1100delC and TP53 pathogenic mutations; aiming to reveal new predisposing genes. Analyses with two different microarray platforms (Agilent 180K and Affymetrix CytoScan HD) revealed 35 rare CNVs covering 67 known genes in 22 patients. Gains (GALNT6 and GALNT11) and losses (SEMA3C) involving the same gene families related to CRC susceptibility were found among the rare CNVs. Segregation analysis performed on four relatives from one family suggested the involvement of GALNT11 and KMT2C in those at risk of developing CRC. Notably, in silico molecular analysis revealed that 61% (41/67) of the genes covered by rare CNVs were associated with cancer, mainly colorectal (17 genes). Ten common SNPs, previously associated with CRC, were genotyped in 39 index patients and 100 sporadic CRC cases. Although no significant, an increased number of risk alleles was detected in the index cases compared with the sporadic CRC patients. None of the SNPs were covered by CNVs, suggesting an independent effect of each alteration in cancer susceptibility. In conclusion, rare germline CNVs and common SNPs may contribute to an increased risk for hereditary CRC in patients with mismatch repair proficiency. What's new? Colon cancer can run in families, but only a very small percentage of these cancers have been traced to specific genetic mutations. These authors took a closer look at the genomes of individuals with inherited colon cancer who don't carry the most common genetic mutations that cause it. They looked for changes in copy number among these patients, and found 35 rare variations. Further investigation revealed that many of the genes affected by these copy number variations have previously been associated with colorectal cancer. Thus these copy number variations may bestow increased risk of colon cancer.