A novel germline EGFR variant p.R831H causes predisposition to familial CDK12-mutant prostate cancer with tandem duplicator phenotype
- 25 September 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 39 (44), 6871-6878
- https://doi.org/10.1038/s41388-020-01476-9
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.This publication has 18 references indexed in Scilit:
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