Allele-specific imbalance mapping identifies HDAC9 as a candidate gene for cutaneous squamous cell carcinoma

More than 3.5 million nonmelanoma skin cancers were treated in 2006; of these 700,000 were cutaneous squamous cell carcinomas (cSCCs). Despite clear environmental causes for cSCC, studies also suggest genetic risk factors. A cSCC susceptibility locus, Skts5, was identified on mouse chromosome 12 by linkage analysis. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. These loci show copy number increases in approximate to 10% of cSCC tumors. Here, we show that an additional 15-22% of tumors exhibit copy-neutral loss of heterozygosity. Furthermore, our previous data identified microsatellite markers on 7p21 and 7q31 that demonstrate preferential allelic imbalance (PAI) in cSCC tumors. On the basis of these results, we hypothesized that the human orthologous locus to Skts5 would house a gene important in human cSCC development and that tumors would demonstrate allele-specific somatic alterations. To test this hypothesis, we performed quantitative genotyping of 108 single nucleotide polymorphisms (SNPs) mapping to candidate genes at human SKTS5 in paired normal and tumor DNAs. Nine SNPs in HDAC9 (rs801540, rs1178108, rs1178112, rs1726610, rs10243618, rs11764116, rs1178355, rs10269422 and rs12540872) showed PAI in tumors. These data suggest that HDAC9 variants may be selected for during cSCC tumorigenesis. What's new? While inherited risk factors have been suggested to play a role in cutaneous squamous cell carcinomas (cSCC) in addition to environmental causes, so far few well-validated genetic risk variants exist. Human 7p21 however shows evidence of preferential allelic imbalance (PAI) and copy neutral loss of heterozygosity in cSCCs. 7p21 is orthologous to a mouse skin cancer susceptibility locus, Skts5. Here, candidate genes at Skts5 identified from the mouse were assessed for evidence of PAI in human cSCCs. Multiple variants in HDAC9 were identified that show evidence of allele-specific gains in cSCC, suggesting that HDAC9 may be important in cSCC development.