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DNA damage repair alterations are frequent in prostatic adenocarcinomas with focal pleomorphic giant‐cell features
Author(s) -
Lotan Tamara L,
Kaur Harsimar B,
Alharbi Abdullah M,
Pritchard Colin C,
Epstein Jonathan I
Publication year - 2019
Publication title -
histopathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.626
H-Index - 124
eISSN - 1365-2559
pISSN - 0309-0167
DOI - 10.1111/his.13806
Subject(s) - msh2 , prostate cancer , biology , prostate , dna repair , dna mismatch repair , mlh1 , cancer research , pathology , microsatellite instability , cancer , medicine , gene , allele , genetics , microsatellite
Aims Prostatic adenocarcinomas with focal pleomorphic giant‐cell features constitute a rare tumour subtype with abysmal clinical outcomes. More than one‐third of patients with this histology die within a year of the initial diagnosis of prostate cancer. We aimed to perform molecular profiling of these tumors to identify potential therapeutic targets. Methods and results Here, we performed next‐generation sequencing with a highly validated targeted panel ( UW ‐OncoPlex) on somatic tumour DNA extracted from eight cases of prostatic adenocarcinoma with focal pleomorphic giant‐cell features, including cases with and without prior treatment for prostate cancer. We found that DNA damage repair mutations are common in this rare subset of prostate tumours, with two of eight having bi‐allelic pathogenic mutations in homologous DNA repair genes (including BRCA 2 and NBN ) and two of eight having bi‐allelic pathogenic mutations in mismatch repair genes (including MSH 2 and MLH 1 ). Conclusion These data are consistent with emerging data showing that DNA repair alterations are enriched among castration‐resistant prostate cancer and aggressive subsets of primary tumours. Given that these patients are potential candidates for poly( ADP ‐ribose) polymerase inhibitor and/or immune checkpoint blockade, and have a poor prognosis with standard therapy, we recommend that tumour and germline DNA sequencing with or without mismatch repair protein immunohistochemistry be considered for all prostatic adenocarcinomas with focal pleomorphic giant‐cell features.