Abstract 4857: Allelic-specific imbalance mapping identifies HDAC9 as a candidate susceptibility gene for cutaneous squamous cell carcinoma
Authors: Fleming Jessica L. , Dworkin Amy M. , Zhang Mingfeng , Qureshi Abrar A. , Allain Dawn C. , Fernandez Soledad , Wei Lai , Peters Sara , Iwenofu O. Hans , Ridd Katie , Bastian Boris C. , Han Jiali , Toland Amanda E. 
Published: August 2012

Abstract
Non-melanoma skin cancer (NMSC) is the most common cancer in the world. More than 3.5 million NMSCs were treated in 2006; of those, 700,000 were cutaneous squamous cell carcinomas (cSCC). There are several predisposing factors to cSCC; however, little is known about the genetic risk factors. Identification of genetic factors contributing to cSCC will enable the identification of those at risk and will lead to improved therapeutic options. A cSCC susceptibility locus, Skts5, was identified on mouse chromosome 12 by linkage analysis of F1 backcrosses between resistant Mus Spretus (Spret/GS) and susceptible Mus Musculus (NIH/Ola) mice. Other susceptibility loci identified in these crosses show preferential allelic imbalance in skin tumors, indicating that allele-specific somatic genetic alterations in these regions may be markers for cancer susceptibility loci. Skts5 spans a 14 megabase region with 65 coding elements. Based on sequence variations and differential gene expression between Spret/GS and NIH/Ola we were able to identify 11 candidate genes. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. Previous studies conducted in our lab show gains on 7p and 7q31 in 10% of cSCC tumors. An additional 3% of cSCC tumors were found to have copy-neutral loss of heterozygosity. Further analysis revealed that microsatellite markers on 7p21 and 7q31 demonstrated preferential allelic imbalance in cSCC tumors. The question of this study is whether genetic variations at SKTS5 are playing a role in human cSCC susceptibility. We hypothesize that human cSCC tumors will show allele-specific somatic genetic changes at SKTS5 and that these alterations contribute to cSCC risk. In order to identify candidate genes at SKTS5, we performed genotyping of 70 single nucleotide polymorphisms (SNPs) encompassing our top mouse candidate genes using Sequenom MassARRAY. Three SNPs at SKTS5, two in HDAC9 (rs6959028 and rs12540872) and one in IFRD1 (rs2074796) showed statistically significant evidence of preferential allelic imbalance in cSCC tumors. Conversely, when SNPs were tested in two cSCC case/control collections no significant association for risk was seen. Because our study analyzed 40 SNPs in HDAC9 and two showed preferential allelic imbalance in tumors, we hypothesized that there might be HDAC9 haplotypes demonstrating preferential imbalance. We generated 4,5,6 and 7 marker haplotypes. Following multiple comparisons testing, significant haplotypes of each size containing rs6959028 and/or rs12540872 were identified with differential frequencies between normal blood and tumor DNA. From these studies our data identifies HDAC9 as a candidate gene for cSCC tumorigenesis. Risk with this locus needs to be further evaluated. Future studies will be needed to determine which HDAC9 SNPs are causal, as well as to identify the molecular mechanism(s) by which the variants contribute to cSCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4857. doi:1538-7445.AM2012-4857