Abstract 1244: BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of mutations in chromatin remodeling genes
Authors: Jikuya Ryosuke , Furuya Mitsuko , Baba Masaya , Aburatani Hiroyuki , Metwalli Adam R. , Schmidt Laura S. , Linehan W. Marston , Yao Masahiro , Hasumi Hisashi 
Published: August 2018

Abstract
Background
Birt-Hogg-Dubé (BHD) syndrome is a hereditary kidney cancer syndrome, which predisposes patients to develop cutaneous fibrofolliculomas, pulmonary cysts and renal tumors with various types of histology including chromophobe renal cell carcinoma (chRCC), hybrid oncocytic/chromophobe tumor (HOCT), clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC) and oncocytoma. The responsible gene FLCN is a tumor suppressor for kidney cancer which plays an important role in energy homeostasis through the regulation of mitochondrial oxidative metabolism. In previous studies, we demonstrated that kidney-targeted Flcn knockout mice develops hyperproliferative polycystic kidney; however, this mouse model dies at three weeks of age before developing kidney cancer, suggesting that mutations in addition to FLCN are necessary for the development of renal neoplasms. To understand the molecular mechanisms by which alterations in metabolism under FLCN-deficiency lead to kidney cancer development, we conducted whole-exome sequencing analysis as well as metabolite analysis of BHD-associated kidney cancer.
Results
Whole-exome sequencing analysis of BHD-associated kidney cancer revealed that copy number variations (CNV) of BHD-associated kidney cancer are considerably different from those already reported in sporadic cases. We observed less CNV in chRCC, HOCT and oncocytoma compared to ccRCC and pRCC, which might reflect the indolent nature of chRCC, HOCT and oncocytoma. Somatic mutation analysis revealed that very few genes are commonly mutated in BHD-associated kidney cancer; however, chromatin remodeling genes were frequently mutated in BHD-associated kidney cancer (17/29 tumors, 59%), suggesting that alterations in epigenome regulation might drive kidney cancer development in cooperation with FLCN mutations. Metabolite analysis of BHD-associated kidney cancer revealed the metabolic reprogramming towards mitochondrial oxidative metabolism and upregulated lipolysis, which may fuel FLCN-deficient tumor cells to acquire a growth advantage driving tumor progression. Redox regulations including pentose phosphate pathway and glutathione synthetic pathway were upregulated in BHD-associated kidney cancer, which may protect FLCN-deficient tumor cell from reactive oxygen species produced from abundant mitochondria with increased respiratory capacity.
Conclusions
BHD-associated kidney cancer displays unique molecular characteristics which are completely different from sporadic kidney cancer. These data provides mechanistic insight into tumorigenesis under FLCN deficiency as well as a foundation for the development of novel therapeutics for kidney cancer.
Funded in part under NCI,NIH contract HHSN261200800001.
Citation Format: Ryosuke Jikuya, Mitsuko Furuya, Masaya Baba, Hiroyuki Aburatani, Adam R. Metwalli, Laura S. Schmidt, W. Marston Linehan, Masahiro Yao, Hisashi Hasumi. BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of mutations in chromatin remodeling genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1244.