Abstract 2007: Concurrent gene promoter hypermethylation and allele loss occurs infrequently in head and neck squamous cell carcinomas

Abstract

Abstract Malignancies arise as a result of environmental insults that cause an accumulation of molecular changes in the genomes and epigenomes of the affected somatic cells. Numerous models have been described that outline the set of consequential alterations for different tumor types throughout carcinogenesis. The implication of Knudson's two-hit hypothesis for inactivation of tumor suppressor genes, with regards to the emerging field of integrative genomics, is that this gene silencing can be achieved through deletion of one allele and hypermethylation of the other. We aimed to characterize this process in the upper airway epithelium through an array-based molecular investigation of 19 head and neck squamous cell carcinomas (HNSCCs). We utilized a genome-wide integrated approach, combining data from DNA methylation arrays (>1400 loci) with SNP-based resequencing (>500K loci) copy number data, and a novel analytical approach involving model-based clustering methods. We found that while methylation and gene copy number were well-correlated for a number of loci, few tumor suppressors exhibited concomitant silencing alterations. In fact, of the commonly altered genes in this disease only CDKN2A possessed both hypermethylation and allele loss, and only at one locus for a minority of tumors (3/18). Three tumors also lacked one copy of the maintenance methyltransferase gene, DNMT1, and these samples had a lower average methylation across all loci measured than those with a normal copy number (P<0.0001) at this site. Our results suggest that coordination of molecular mechanisms rarely occurs at single genes; however they may be linked through global regulatory processes affecting the patterns of coordinated alterations in order to control carcinogenic gene pathways. A thorough understanding of these alteration patterns and integration of such molecular processes are critical for the identification of cellular targets/biomarkers in HNSCC and for rational therapeutic administration. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2007.