University of Oulu

Giannareas, N., Zhang, Q., Yang, X. et al. Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG. Nat Commun 13, 7320 (2022).

Extensive germline-somatic interplay contributes to prostate cancer progression through HNF1B co-option of TMPRSS2-ERG

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Author: Giannareas, Nikolaos1; Zhang, Qin1; Yang, Xiayun1;
Organizations: 1Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland
2Division of Urology, Department of Surgery, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong, China
3Department of Tumour Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
4Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
5Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
6Fudan University Shanghai Cancer Center & MOE Key Laboratory of Metabolism and Molecular Medicine and Department of Biochemistry and Molecular Biology of School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4.4 MB)
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Language: English
Published: Springer Nature, 2022
Publish Date: 2023-06-19


Genome-wide association studies have identified 270 loci conferring risk for prostate cancer (PCa), yet the underlying biology and clinical impact remain to be investigated. Here we observe an enrichment of transcription factor genes including HNF1B within PCa risk-associated regions. While focused on the 17q12/HNF1B locus, we find a strong eQTL for HNF1B and multiple potential causal variants involved in the regulation of HNF1B expression in PCa. An unbiased genome-wide co-expression analysis reveals PCa-specific somatic TMPRSS2-ERG fusion as a transcriptional mediator of this locus and the HNF1B eQTL signal is ERG fusion status dependent. We investigate the role of HNF1B and find its involvement in several pathways related to cell cycle progression and PCa severity. Furthermore, HNF1B interacts with TMPRSS2-ERG to co-occupy large proportion of genomic regions with a remarkable enrichment of additional PCa risk alleles. We finally show that HNF1B co-opts ERG fusion to mediate mechanistic and biological effects of the PCa risk-associated locus 17p13.3/VPS53/FAM57A/GEMIN4. Taken together, we report an extensive germline-somatic interaction between TMPRSS2-ERG fusion and genetic variations underpinning PCa risk association and progression.

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Series: Nature communications
ISSN: 2041-1723
ISSN-E: 2041-1723
ISSN-L: 2041-1723
Volume: 13
Issue: 1
DOI: 10.1038/s41467-022-34994-z
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This work was supported by the grants from the National Natural Science Foundation of China (82073082), the Jane and Aatos Erkko Foundation, the Finnish Cancer Foundation, the Sigrid Juseliuksen Saatio, and the Fudan University Recruit Funding. The work was also supported by a grant from National Institute of Health (1R01CA250018) to L.W.
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