Abstract 730: Genomic characterization of hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a rare and aggressive kidney cancer
Authors: Vats Pankaj , Zhang Yuping , Dhanashekaran Sarvana Mohan , Pandi Narayanan Sathiya , Cao Xuhong , Su Fengyun , Shukla Sudhanshu , Wang Rui , Cieslik Marcin , Pan Jincheng , Ricketts Christopher J. , Kumpati Prem Kumar , Alva Ajjai , Linehan Marston W. , Mehra Rohit , Chinnaiyan Arul M. 
Published: August 2019

Background

Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a rare autosomal-dominant syndromic disorder associated with germline FH mutations. Affected individuals have a predisposition to cutaneous and uterine leiomyoma’s, and are at increased risk of developing a renal cell carcinoma (HLRCC- associated RCC) with aggressive clinical outcome. However, aside from FH bi-allelic loss, additional genomic features of HLRCC are currently poorly understood.

Method

Five cases of HLRCC-associated RCC were characterized using integrated next generation sequencing (NGS) technology. This included an index case where multiple tumor sites (kidney, lung, liver, lymph node, skin, and uterine) from a single patient were characterized. For integrative analysis, in-house data were combined with five RCC cases with FH bi-allelic loss from The Cancer Genome Atlas Study. Single cell sequencing was carried out on normal human kidney to study the cell of origin for HLRCC- associated RCC.

Results: Integrative NGS profiling and analysis of HLRCC-associated RCC tumors (n=10) revealed several important observations such as 1) a high frequency loss of whole chromosomes, which is reminiscent of tumors arising from the distal nephron, 2) low mutational burden similar to that observed in other kidney tumors and, 3) a HLRCC specific gene expression signature and discovery of a novel therapeutic candidate (HLRCC-TC1). Importantly, among renal tumors, HLRCC-TC1 was specifically expressed in HLRCC and other RCCs with poor clinical outcome. Application of siRNAs and neutralizing antibodies to HLRCC-TC1 reduced cell proliferation of the HLRCC cell line UOK262, but did not for that of control cell lines.

Conclusion: The observed FH bi-allelic mutation along with recurrent chromosome-wide losses and integrative analysis with human kidney single cell sequencing data support a distal nephron origin for HLRCC- associated RCC. In addition, our study provides evidence for nominating HLRCC-TC1 as a novel cancer-specific therapeutic target. Further studies are needed to conduct an in-depth characterization of HLRCC-TC1.

Citation Format: Pankaj Vats, Yuping Zhang, Sarvana Mohan Dhanashekaran, Narayanan Sathiya Pandi, Xuhong Cao, Fengyun Su, Sudhanshu Shukla, Rui Wang, Marcin Cieslik, Jincheng Pan, Christopher J. Ricketts, Prem Kumar Kumpati, Ajjai Alva, Marston W. Linehan, Rohit Mehra, Arul M. Chinnaiyan. Genomic characterization of hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a rare and aggressive kidney cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 730.