BHD-associated Kidney Cancer Exhibits Unique Molecular Characteristics and a Wide Variety of Variants in Chromatin Remodeling Genes

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2018 May 17

PMID 29767721

Citations 6

Authors

Hisashi Hasumi

Mitsuko Furuya

Kenji Tatsuno

Shogo Yamamoto

Masaya Baba

Yukiko Hasumi

Yasuhiro Isono

Kae Suzuki

Ryosuke Jikuya

Shinji Otake

Kentaro Muraoka

Kimito Osaka

Narihiko Hayashi

Kazuhide Makiyama

Yasuhide Miyoshi

Keiichi Kondo

Noboru Nakaigawa

Takashi Kawahara

Koji Izumi

Junichi Teranishi

Yasushi Yumura

Hiroji Uemura

Yoji Nagashima

Adam R Metwalli

Laura S Schmidt

Hiroyuki Aburatani

W Marston Linehan

Masahiro Yao

Affiliations

Soon will be listed here.

Abstract

Birt-Hogg-Dubé (BHD) syndrome is a hereditary kidney cancer syndrome, which predisposes patients to develop kidney cancer, cutaneous fibrofolliculomas and pulmonary cysts. 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. However, the process by which FLCN-deficiency leads to renal tumorigenesis is unclear. In order to clarify molecular pathogenesis of BHD-associated kidney cancer, we conducted whole-exome sequencing analysis using next-generation sequencing technology as well as metabolite analysis using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry. Whole-exome sequencing analysis of BHD-associated kidney cancer revealed that copy number variations of BHD-associated kidney cancer are considerably different from those already reported in sporadic cases. In somatic variant analysis, very few variants were commonly observed in BHD-associated kidney cancer; however, variants in chromatin remodeling genes were frequently observed in BHD-associated kidney cancer (17/29 tumors, 59%). Metabolite analysis of BHD-associated kidney cancer revealed metabolic reprogramming toward upregulated redox regulation which may neutralize reactive oxygen species potentially produced from mitochondria with increased respiratory capacity under FLCN-deficiency. BHD-associated kidney cancer displays unique molecular characteristics that are completely different from sporadic kidney cancer, providing mechanistic insight into tumorigenesis under FLCN-deficiency as well as a foundation for development of novel therapeutics for kidney cancer.

Citing Articles

Metabolic alterations in hereditary and sporadic renal cell carcinoma.

Coffey N, Simon M Nat Rev Nephrol. 2024; 20(4):233-250.

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Single-cell transcriptomes underscore genetically distinct tumor characteristics and microenvironment for hereditary kidney cancers.

Jikuya R, Murakami K, Nishiyama A, Kato I, Furuya M, Nakabayashi J iScience. 2022; 25(6):104463.

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Genetic Alterations in Renal Cancers: Identification of The Mechanisms Underlying Cancer Initiation and Progression and of Therapeutic Targets.

Testa U, Pelosi E, Castelli G Medicines (Basel). 2020; 7(8).

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FLCN alteration drives metabolic reprogramming towards nucleotide synthesis and cyst formation in salivary gland.

Isono Y, Furuya M, Kuwahara T, Sano D, Suzuki K, Jikuya R Biochem Biophys Res Commun. 2019; 522(4):931-938.

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