Abstract 4300: Solute carrier family group of membrane transporter gene alteration in collecting duct renal cell carcinoma
Authors: Chintala Sreenivasulu , Wang Jianmin , Wei Lei , Liu Biao , Ciamporcero Eric , Miles Kiersten Marie , Elbanna May , Adelaiye Remi , Shen Li , Orillion Ashley , Ku Sheng Yu , Papanicolau-Sengos Antonios , Morrison Carl D. , Pili Roberto 
Published: August 2015

Abstract
Collecting duct renal cell carcinoma (CDC) is a rare (∼1-3%) type of kidney cancer, aggressive in nature, associated with poor prognosis and limited response to treatments such as cisplatin/gemcitabine and tyrosine kinase inhibitors. Accordingly, there is an unmet need for understanding the molecular alterations associated with CDC and the development of novel effective therapeutic agents for this disease. Since cisplatin based therapy is widely used to manage CDC and the response is often very limited, we investigated the possible molecular alteration(s) associated with cisplatin resistance in CDC. RNA sequence analysis was performed on 5 CDC cases to evaluate gene expression profiles. Immunohistochemical analysis was performed on 6 cases of CDC tumor samples (2 cases included in sequencing) and their matched normal kidneys arranged in a tissue microarray to assess the representative overexpressed genes. Clinical annotation was evaluated to determine the association of gene expression with cisplatin based therapy response and survival. RNA sequencing analysis data revealed the upregulation of 2879 genes and the downregulation of 1951 genes in CDC tumors, as compared to matched normals. Among the altered genes, many of them were transporters. Since transporters play a significant role in drug resistance mechanism(s), particularly in cisplatin resistance, we investigated the Solute Carrier (SLC) family group of membrane transporter genes and found 41 genes upregulated (log2 fold change of 6.4 to 1.0) and 95 genes downregulated (log2 fold change of -8.4 to -0.8). The number of altered SLC family genes was 136 (41 upregulated and 95 downregulated), which is 3.8 percent (136 out of 4830) of the total gene alterations and 45.3% (136 out of 300) of the SLC group of family members, indicating their significance in CDC. The critical analysis of individual amino acid transporters of SLC family genes from the upregulated group led us to investigate three transporters: SLC7A11 (xCT, cystine transporter), SLC1A3 (GLAST, glutamate and aspartate transporter), and SLC6A7 (PROT, proline transporter), which are known to be drug resistance markers. RNA sequence data showed the upregulation of SLC7A11 and SLC1A3 mRNA in 75% of the cases (3 out of 4), with SLC6A7 upregulated in 100% of the cases (4 out of 4). Immunohistochemical analysis of 6 CDC tumors revealed the overexpression of xCT, a known marker for cisplatin resistance in 66% (4 out of 6) of the cases. Kaplan Meyer survival analysis revealed the worst survival for CDC patients with xCT overexpression. Our results demonstrate for the first time that overexpression of xCT, a known cisplatin resistance marker, is associated with CDC. These results suggest that xCT targeted combination therapies may be beneficial to CDC patients.
Citation Format: Sreenivasulu Chintala, Jianmin Wang, Lei Wei, Biao Liu, Eric Ciamporcero, Kiersten Marie Miles, May Elbanna, Remi Adelaiye, Li Shen, Ashley Orillion, Sheng Yu Ku, Antonios Papanicolau-Sengos, Carl D. Morrison, Roberto Pili. Solute carrier family group of membrane transporter gene alteration in collecting duct renal cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4300. doi:10.1158/1538-7445.AM2015-4300