Abstract 2989: Identification of a potential tumor suppressor function for SNX9 by mining public genomic data

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Members of the sorting nexin (SNX) family of proteins are involved in intracellular trafficking and endocytosis processes, with functions essential to regulation of cell surface receptor levels and subsequent signaling by receptor-mediated endocytosis. Detrimental mutations and altered expression of SNX genes have been found in several cancers and tumor cell lines. A recent publication (Mao et al. AJCR 2011) identified a chromosomal translocation that created a SNX9:UNC5C fusion gene in prostate cancer cells. UNC5C is a known tumor suppressor gene. Although SNX9 is known to regulate degradation of EGFR, a well-established prognostic marker for lung cancer, no tumorigenic role has been identified for SNX9. We investigated associations of SNX9 to cancer phenotypes by mining curated public genomic data available in NextBio. Integration of diverse datatypes such as gene/miRNA expression, methylation, and copy-number variation in NextBio allowed us to uncover several lines of evidence which indicated that SNX9 activity is altered in many types of cancer. i) Loss of the SNX9 gene was observed in many different cancers including multiple myeloma, leukemia, lymphoma, melanoma, glioblastoma, renal clear cell carcinoma, and breast cancer. ii) Hypermethylation of SNX9, indicative of overall gene silencing, occurred in colorectal cancer, breast cancer and glioblastoma. iii) The miRNA predicted to target SNX9, miR-493-5p, was up-regulated in prostate, testicular, liver, and lung cancers. iv) SNX9 gene expression was down regulated relative to normal tissues in multiple myeloma, leukemia, lymphoma, cancers of the skin, breast, prostate and more. Correlations within the data suggest an association between the loss of SNX9 and more aggressive or recurrent disease; SNX9 is reduced in higher grade, metastatic clear cell carcinoma relative to lower grade, non-metastatic clear cell carcinoma. In myeloma and leukemia patients, lower SNX9 expression in primary tumors correlated with earlier relapsing disease. SNX9 expression was also lower when comparing recurring with primary acute myeloid leukemia. Querying our PharmacoAtlas application revealed that SNX9 gene expression was altered by a number of anti-neoplastic therapies. For example, paclitaxel, bortezomib, and letrozole treatments were each found to increase SNX9 gene expression in breast cancer cells whereas doxorubicin treatment resulted in decreased SNX9 expression. The integrative analysis of curated public genomic data drawn from thousands of studies strongly supports a hypothesis that SNX9 is a putative tumor suppressor and biomarker for more aggressive forms of cancer. As genomic technologies are applied to patient evaluation and therapeutic guidance, integrating multiple lines of evidence from research and clinical data to identify biomarkers such as SNX9 will increasingly inform clinical decision making. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2989. doi:1538-7445.AM2012-2989