DNA Damage Repair Alterations are Frequent in Prostatic Adenocarcinomas with Focal Pleomorphic Giant Cell Features

Abstract

Aims

Prostatic adenocarcinomas with focal pleomorphic giant cell features are a rare tumour subtype with abysmal clinical outcomes. More than one third of cases with this histology die within a year of the initial diagnosis of prostate cancer. Potential targeted therapies are desperately needed, however the molecular features of these tumours remain unknown.

Materials and Methods

Here, we performed next generation sequencing using a highly validated targeted panel (UW‐Oncoplex) on somatic tumour DNA extracted from 8 cases of prostatic adenocarcinomas with focal pleomorphic giant cell features, including cases with and without prior treatment for prostate cancer.

Results

We find that DNA damage repair mutations are common in this rare subset of prostate tumours, with 2 of 8 having bi‐allelic pathogenic mutations in homologous DNA repair genes (including BRCA2 and NBN) and 2 of 8 having bi‐allelic pathogenic mutations in mismatch repair genes (including MSH2 and MLH1).

Conclusion

These data are consistent with emerging data 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 PARP inhibitor and/or immune checkpoint blockade and have poor prognosis with standard therapy, we recommend tumour and germline DNA sequencing with or without mismatch repair protein immunohistochemistry be considered for all prostatic adenocarcinomas with focal pleomorphic giant cell features.

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