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

By Kaiyu Qian, Gang Wang, Lingao Ju, Jiyan Liu, Hang Zheng, Yingao Zhang, Liang Chen, Yaoyi Xiong, Yongwen Luo, Yejinpeng Wang, Tianchen Peng, Fangjin Chen, Dongmei Liu, Xuefeng Liu, Yi Zhang, Yu Xiao, Xinghuan Wang

Posted 25 Feb 2020
medRxiv DOI: 10.1101/2020.02.23.20027045

5-10% of total prostate cancer (PCa) cases are hereditary. Particularly, immunocheckpoint inhibitor-sensitive tandem duplicator phenotype (TDP) accounts for 6.9% 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 tumors 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 mutation status of EGFR and CDK12. Taken together, our genetic and functional analyses identified a previously undescribed link between EGFR and prostate cancer.

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