Abstract 346: Integrative genomic analysis of sporadic clear cell renal cell carcinoma

Abstract

Abstract Sporadic clear cell Renal Cell Carcinoma (ccRCC) is the most common type of adult kidney cancer. Using high-density copy-number profiling and gene expression profiles, we performed an integrated genomic analysis of 54 sporadic tumor samples. We took a two pronged approach, focusing on 1) all samples and 2) comparing ccRCCs that express both HIF1α and HIF2α (H1H2) and those that express only HIF2α (H2), sub-types of ccRCC that we previously described. For all samples at a frequency over 10%, we identified regions of amplification on 1q, 5q, 7q, 8q, 12p, and 20q, and regions of deletion on 1p, 3p, 6q, 8p, 9p, and 14q, as previously described. We used our integrative analysis to identify target genes that had consistent copy-number and gene expression changes (e.g. amplified and upregulated or deleted and downregulated) within regions on chromosomes 5 and 7. Combining our data with an independent dataset (Beroukhim et al., 2009) and including a literature based analysis, we were able to narrow down to three target genes, which we subsequently validated using a renal cancer cell line. We then compared genomic changes in H1H2 and H2 ccRCCs. Prior data suggested that H2 ccRCCs have increased expression of genes involved in double strand break repair, thus potentially greater genomic stability. Using high-density copy-number data, we have confirmed that H2 tumors have significantly fewer genomic aberrations compared to H1H2 tumors (for amplifications p=0.032 and for deletions p=0.003). In addition, using GISTIC, we found that deletion of chromosome 6 is significantly more common in H1H2 tumors (p<0.001), whereas deletion of chromosome 9 is significantly more common in H2 tumors (p<0.001). Of note, deletion of chromosome 9 previously has been associated with poor prognosis. Thus, correlations between the copy-number data and gene expression profiles indicate that the H1H2 and H2 classes of ccRCC tumors may each have a distinct set of drivers of tumorigenesis; target gene validation for these groups is underway. These experiments provide novel insights into the biology of clear cell Renal Cell Carcinoma (ccRCC). Beroukhim et al. Patterns of Gene Expression and Copy-Number Alternations in von-Hippel Lindau Disease-Associated and Sporadic Clear Cell Carcinoma of the Kidney. Can Res 2009; 69: (11):4674-81. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 346. doi:10.1158/1538-7445.AM2011-346