Identification of chromosomal copy number variations and novel candidate loci in hereditary nonpolyposis colorectal cancer with mismatch repair proficiency.

The pathogenesis of microsatellite stable hereditary non-polyposis colorectal cancers (MSS HNPCC) is unclear. To identify genomic regions that might be involved in MSS HNPCC pathogenesis, we selected 20 pairs of MSS HNPCC for a genome-wide study using copy number variation targeted (CNV-targeted) CytoScan HD Array. A remarkably increased frequency of 20q gain (70%) and high levels of copy-neutral loss of heterozygosity (40%) were observed. The most frequent tumor-specific CNVs included amplifications (7p21.3-15.1, 8q13.3-24.3, 13q14.1-33.3 and 20q12-13.33) and deletions (8p11.23-23.1, 15q11.2-26.1, 17p13.1-13.3 and 18q11.2-21.33). In addition, 10 novel CNVs were discovered and led to identification of WDR16 and RAPGEF5 as candidate genes involved in tumorigenesis, displaying a robust correlation between expression and genomic alterations. Moreover, WDR16 and RAPGEF5 exhibited altered protein expression levels as assessed by immunohistochemistry (IHC) in 41 other independent samples. Finally, high consistencies (68-84%) were observed between CNVs by Array and quantitative PCR. These findings are important for further elucidating MSS HNPCC pathogenesis.