The dysregulation of gene expression, indispensible for cellular transformation, is controlled by a range of underlying molecular mechanisms, including allelic imbalance, copy number variation (CNV) and epigenetic alterations. In fact, CNV and epigenetic alterations (such as aberrant DNA methylation) are often commonplace in human tumors due to their associated selective survival and proliferation advantages. However, the relationship between CNV and DNA methylation alteration in cancer remains poorly studied. In order to directly compare these forms of somatic alterations, we first performed genome-wide analyses in a case series of head and neck squamous cell carcinomas (HNSCCs) using the Affymetrix GeneChip® Human Mapping 500K gene array to investigate CNV in 19 matched tumor-blood samples. Next, we examined DNA methylation alterations using the Illumina GoldenGate cancer methylation panel of CpG dinucleotide loci on 68 HNSCCs, including the 19 samples assayed for CNV. Unsupervised clustering of the methylation data using a recursively-partitioned mixture model yielded six distinct methylation profile classes. Strikingly, the overall amount of copy number variation was found to vary significantly according to modeled methylation class, with tumors showing substantial, large-scale copy number variation segregating into separate classes. Specifically, all tumors that possessed chromosome 8p loss and 8q reduplication (n=7) were members of one methylation class. Plotting CNV profiles in a methylation-class-specific manner for chromosome 8, we were able to explore the locus-specific relationships between methylation alterations and CNV. Although some chromosome 8 genes had increased methylation in the amplified 8q arm, in general, chromosome 8 genes tended not to have differential methylation associated with CNV. Our results demonstrate that there is a significant relationship between methylation profiles of cancer-related genes and CNV in HNSCC, although the timing of these transformational events is less clear. Additional investigations in HNSCC and other cancers using integrative genomics approaches are necessary, and hold promise for significantly advancing our understanding of tumor biology and thereby, the potential to reveal key targets for novel, directed therapeutic approaches.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1428.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO