Talk abstracts

Talk on Monday 04:15-04:30pm submitted by Jessica Fleming

Identification of Genetic Risk Factors for Cutaneous Squamous Cell Carcinoma Susceptibility on Chromosome 7

Jessica L. Fleming (MVIMG; The Ohio State University), Amy M. Dworkin (National Institute of Health), Boris C. Bastian (Pathology; Sloan-Kettering Cancer Center), Allan Balmain (Surgery; University of California, San Francisco), Amanda E. Toland (MVIMG; The Ohio State University)

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 (SCC).There are several predisposing factors to SCC; however little is known about the genetic risk factors. If we are able to identify genetic risk factors, we can target people at risk. A SCC susceptibility locus, Skts5, had been identified on mouse chromosome 12 by linkage analysis on F1 backcrosses between resistant Mus Spretus and susceptible Mus Musculus 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 contribute to cancer. The orthologous locus to Skts5 in humans maps to 7p21 and 7q31. The question of this study is whether genetic variations at SKTS5 are playing a role in human SCC susceptibility. We hypothesize that human SCC tumors will show allele-specific somatic genetic changes at SKTS5 and that these alterations contribute to SCC risk. Low-resolution genotyping was performed in tumor and matched normal DNA using ABI genotyping of microsatellite markers. Markers mapping to 7p21 and 7q31 showed preferential allelic imbalance with p-values of 0.047 and 0.016 respectively. In order to identify candidate genes at SKTS5, we performed high-resolution genotyping using Sequenom MassARRAY. Normal and tumor DNA were analyzed across 70 single-nucleotide polymorphisms (SNPs) at SKTS5. 7 SNPs at SKTS5, 4 in HDAC9, 2 in ETV1, and 1 in IFRD1 show statistically significant evidence of preferential allelic imbalance in SCC tumors. We conclude that one or more of these SNPs is driving SCC susceptibility. Future studies will focus on the functionality of variants as well as case/control studies. The identification of functional germline variants that contribute to SCC susceptibility provides an initial step in developing genetic screening for this disease.

References:
1. Rogers HW, Weinstock MA, Harris AR, Hinckley MR, Feldman SR, et al. Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 146: 283-287.
2. Nagase H, Mao JH, Balmain A (1999) A subset of skin tumor modifier loci determines survival time of tumor-bearing mice. Proc Natl Acad Sci U S A 96: 15032-15037.
3. Nagase H, Mao JH, Balmain A (2003) Allele-specific Hras mutations and genetic alterations at tumor susceptibility loci in skin carcinomas from interspecific hybrid mice. Cancer Res 63: 4849-4853

Keywords: skin cancer, HDAC9, genetic susceptibility