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A novel germline EGFR variant p.R831H causes predisposition to familial CDK12-mutant prostate cancer with tandem duplicator phenotype

Oncogene volume 39, pages 6871–6878 (2020)Cite this article

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Abstract

5–10% of total prostate cancer (PCa) cases are hereditary. Particularly, immune checkpoint inhibitor-sensitive tandem duplicator phenotype (TDP) accounts for 6.9% of PCa cases, whereas genetic susceptibility genes remain completely unknown. We identified a Chinese family with two PCa patients, in which the PCa phenotype co-segregated with a rare germline variant EGFRR831H. Patient-derived conditionally reprogrammed cells (CRC) exhibited increased EGFR and AKT phosphorylation, and a sensitivity to EGFR antagonist Afatinib in migration assays, suggesting the EGFR allele was constitutively active. Both EGFRR831H-mutant tumours contained biallelic CDK12 inactivation, together with prominent tandem duplication across the genome. These somatic mutations could be detected in urine before surgery. Analysis of public databases showed a significant correlation between the mutation status of EGFR and CDK12. Taken together, our genetic and functional analyses identified a previously undescribed link between EGFR and PCa.

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Fig. 1: EGFRR831H allele co-segregates with PCa members of the pedigree.
Fig. 2: CRCs carrying EGFR p.R831H showed enhanced EGFR signaling as well as upregulation of CDK12.
Fig. 3: Biallelic CDK12-loss correlates with prominent tandem duplication across the genome.
Fig. 4: Non-invasive detection of CDK12D877A-mutation in urine supernatant.

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Acknowledgements

We thank the patients and their family members for participating in our study. We gratefully acknowledge excellent technical assistance provided by Ms. Yuan Zhu, Ms. Shanshan Zhang, and Ms. Yayun Fang from Zhongnan Hospital of Wuhan University. We would like to acknowledge the TCGA and COSMIC databases for providing use of data free of charge. We also thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

Funding

This study was supported in part by grants from the Health commission of Hubei Province scientific research project (WJ2019H080), Chinese Central Special Fund for Local Science and Technology Development of Hubei Province (2018ZYYD023), Science and Technology Department of Hubei Province Key Project (2018ACA159), and Wuhan Science and Technology Bureau Key Project (2018061005132294). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Kaiyu Qian, Gang Wang, Lingao Ju

Authors and Affiliations

  1. Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China

    Kaiyu Qian, Yongwen Luo, Yejinpeng Wang, Tianchen Peng, Yu Xiao & Xinghuan Wang

  2. Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China

    Kaiyu Qian, Gang Wang, Lingao Ju & Yu Xiao

  3. Human Genetic Resources Preservation Center of Hubei Province, Wuhan, China

    Kaiyu Qian, Gang Wang, Lingao Ju & Yu Xiao

  4. Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China

    Gang Wang, Lingao Ju & Yu Xiao

  5. Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China

    Jiyan Liu

  6. Center of Life Sciences, Peking University, Beijing, China

    Fangjin Chen & Yi Zhang

  7. Euler Technology, Beijing, China

    Yi Zhang

  8. Medical Research Institute, Wuhan University, Wuhan, China

    Xinghuan Wang

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  1. Kaiyu Qian
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Corresponding authors

Correspondence to Yi Zhang or Xinghuan Wang.

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Statement of patient consent

All PCa patients, family members of the PCa pedigree, and additional cancer patients, provided written informed consent. All study procedures were performed in accordance with the ethical standards of the Institutional Ethics Review Committee.

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Qian, K., Wang, G., Ju, L. et al. A novel germline EGFR variant p.R831H causes predisposition to familial CDK12-mutant prostate cancer with tandem duplicator phenotype. Oncogene 39, 6871–6878 (2020). https://doi.org/10.1038/s41388-020-01476-9

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