Talk abstracts

Talk on Wednesday 03:45-04:00pm submitted by Jessica Fleming

Allelic-specific imbalance mapping identifies HDAC9 and IFRD1 as candidate susceptibility genes for cutaneous squamous cell carcinoma

Jessica L. Fleming (MVIMG, The Ohio State University), Amy M. Dworkin (National Human Genome Research Institute, National Institute of Health), Mingfeng Zhang (Dermatology, Harvard Medical School), Abrar A. Qureshi (Dermatology, Harvard Medical School), Dawn C. Allain (Internal Medicine, The Ohio State University), Soledad Fernandez (Biostatistics, The Ohio State University)

Abstract:
More than 3.5 million NMSCs were treated in 2006; of those, 700,000 were SCCs. There are several predisposing factors to SCC, but little is known about the genetic risk factors. Identification of genetic risk factors for SCC will facilitate detection of those at risk and will lead to improved therapeutic options. A SCC susceptibility locus, Skts5, was identified by linkage analysis of M. Spretus and M. Musculus mice. Other susceptibility loci identified in these crosses show allele-specific imbalance in skin tumors, indicating that allele-specific somatic genetic alterations may be markers for cancer susceptibility loci. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. Previously, our lab showed gains on 7p and 7q31 in 10% of SCC tumors. An additional 15% of tumors tested showed copy-neutral LOH. Further analysis revealed that microsatellite markers on 7p21 and 7q31 demonstrated allele-specific imbalance in SCCs.The question of this study is whether genetic variations at SKTS5 are playing a role in human SCC susceptibility. We hypothesized that human SCC tumors will show allele-specific somatic genetic changes at SKTS5 and that these alterations contribute to SCC risk. To test this, we genotyped 70 SNPs from our top mouse candidate genes. Three SNPs at SKTS5, two in HDAC9 (rs6959028 and rs12540872) and one in IFRD1 (rs2074796) showed significant evidence of allele-specific imbalance in SCC tumors. Because our study analyzed 35 SNPs in HDAC9 and two showed allele-specific imbalance in tumors, we hypothesized that there may be HDAC9 haplotypes demonstrating preferential imbalance. Haplotypes containing rs6959028 and/or rs12540872 were found to have significantly different frequencies between normal blood and tumor DNA. When these SNPs were genotyped in SCC case/control collections a protective effect was seen in heterozygous individuals for rs2074796. From these studies our data identifies HDAC9 and IFRD1 as candidate genes for SCC tumorigenesis.

Keywords: Skin cancer, HDAC9, IFRD1