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

Nikolaos Giannareas, Qin Zhang, Xiayun Yang, Rong Na, Yijun Tian, Yuehong Yang, Xiaohao Ruan, Da Huang, Xiaoqun Yang, Chaofu Wang, Peng Zhang, Aki Manninen, Liang Wang and Gong-Hong Wei ()
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Nikolaos Giannareas: University of Oulu
Qin Zhang: University of Oulu
Xiayun Yang: University of Oulu
Rong Na: the University of Hong Kong
Yijun Tian: H. Lee Moffitt Cancer Center and Research Institute
Yuehong Yang: University of Oulu
Xiaohao Ruan: Shanghai Jiaotong University School of Medicine
Da Huang: Shanghai Jiaotong University School of Medicine
Xiaoqun Yang: Shanghai Jiaotong University School of Medicine
Chaofu Wang: Shanghai Jiaotong University School of Medicine
Peng Zhang: Shanghai Medical College of Fudan University
Aki Manninen: University of Oulu
Liang Wang: H. Lee Moffitt Cancer Center and Research Institute
Gong-Hong Wei: University of Oulu

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34994-z

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