title: Allele-specific imbalance mapping identifies HDAC9 as a candidate gene for cutaneous squamous cell carcinoma.
abstract: 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 ∼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.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH; The Ohio State University Comprehensive Cancer Center, Columbus, OH.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Fleming
authors.forename: Amy M
authors.initials: AM
authors.lastname: Dworkin
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Allain
authors.forename: Soledad
authors.initials: S
authors.lastname: Fernandez
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
authors.forename: Sara B
authors.initials: SB
authors.lastname: Peters
authors.forename: O Hans
authors.initials: OH
authors.lastname: Iwenofu
authors.forename: Katie
authors.initials: K
authors.lastname: Ridd
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.forename: Amanda Ewart
authors.initials: AE
authors.lastname: Toland
mesh_terms: D022981:Allelic Imbalance / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods; D005838:Genotype; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D012097:Repressor Proteins / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D012097:Repressor Proteins; C486544:HDAC9 protein, human; D006655:Histone Deacetylases
keywords: HDAC9; Skts5; allelic-specific imbalance; cutaneous squamous cell carcinoma