Comparative Analyses Define Differences Between Bhd-Associated Renal Tumour and Sporadic Chromophobe Renal Cell Carcinoma

Authors

Ryosuke Jikuya
Todd A Johnson
Kazuhiro Maejima
Jisong An
Young-Seok Ju
Hwajin Lee
Kyungsik Ha
WooJeung Song
Youngwook Kim
Yuki Okawa
Shota Sasagawa
Yuki Kanazashi
Masashi Fujita
Seiya Imoto
Taku Mitome
Shinji Ohtake
Go Noguchi
Sachi Kawaura
Yasuhiro Iribe
Kota Aomori
Tomoyuki Tatenuma
Mitsuru Komeya
Hiroki Ito
Yusuke Ito
Kentaro Muraoka
Mitsuko Furuya
Ikuma Kato
Satoshi Fujii
Haruka Hamanoue
Tomohiko Tamura
Masaya Baba
Toshio Suda
Tatsuhiko Kodama
Kazuhide Makiyama
Masahiro Yao
Brian M Shuch
Christopher J Ricketts
Laura S Schmidt
W Marston Linehan
Hidewaki Nakagawa
Hisashi Hasumi

Publication Date

6-1-2023

Journal

eBioMedicine

Abstract

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome, caused by germline alteration of folliculin (FLCN) gene, develops hybrid oncocytic/chromophobe tumour (HOCT) and chromophobe renal cell carcinoma (ChRCC), whereas sporadic ChRCC does not harbor FLCN alteration. To date, molecular characteristics of these similar histological types of tumours have been incompletely elucidated.

METHODS: To elucidate renal tumourigenesis of BHD-associated renal tumours and sporadic renal tumours, we conducted whole genome sequencing (WGS) and RNA-sequencing (RNA-seq) of sixteen BHD-associated renal tumours from nine unrelated BHD patients, twenty-one sporadic ChRCCs and seven sporadic oncocytomas. We then compared somatic mutation profiles with FLCN variants and RNA expression profiles between BHD-associated renal tumours and sporadic renal tumours.

FINDINGS: RNA-seq analysis revealed that BHD-associated renal tumours and sporadic renal tumours have totally different expression profiles. Sporadic ChRCCs were clustered into two distinct clusters characterized by L1CAM and FOXI1 expressions, molecular markers for renal tubule subclasses. Increased mitochondrial DNA (mtDNA) copy number with fewer variants was observed in BHD-associated renal tumours compared to sporadic ChRCCs. Cell-of-origin analysis using WGS data demonstrated that BHD-associated renal tumours and sporadic ChRCCs may arise from different cells of origin and second hit FLCN alterations may occur in early third decade of life in BHD patients.

INTERPRETATION: These data further our understanding of renal tumourigenesis of these two different types of renal tumours with similar histology.

FUNDING: This study was supported by JSPS KAKENHI Grants, RIKEN internal grant, and the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research.

Keywords

Birt-Hogg-Dubé (BHD) syndrome, Chromophobe renal cell carcinoma (ChRCC), Folliculin (FLCN), Renal tumour predisposition syndrome

Comments

Supplementary Materials

PMID: 37182269