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

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.

Oncogene. 2020 Sep 25 [Epub ahead of print]

Kaiyu Qian, Gang Wang, Lingao Ju, Jiyan Liu, Yongwen Luo, Yejinpeng Wang, Tianchen Peng, Fangjin Chen, Yi Zhang, Yu Xiao, Xinghuan Wang

Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China., Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China., Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China., Center of Life Sciences, Peking University, Beijing, China., Center of Life Sciences, Peking University, Beijing, China. ., Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China. .