Journal
ONCOGENE
Volume 39, Issue 44, Pages 6871-6878Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-020-01476-9
Keywords
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Funding
- 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]
- Wuhan Science and Technology Bureau Key Project [2018061005132294]
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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 EGFR(R831H). 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 EGFR(R831H)-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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