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 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 BRCA2 and NBN) and two of eight having bi-allelic pathogenic mutations in mismatch repair genes (including MSH2 and MLH1). 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.

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

“…Prostate adenocarcinomas with focal pleomorphic giant cell features are rare prostate cancer subtype with dismal clinical prognosis. A recent study reported the genetic analysis of 8 cases of prostatic adenocarcinomas with focal pleomorphic giant cell features, showing that DNA damage repair mutations are common, with two out of eight having biallelic pathogenic mutations in homologous DNA repair genes and two out of eight having biallelic pathogenic mutations in mismatch repair genes ( MSH2 and MLH1 ) [156].…”

Gene fusion characterisation of rare aggressive prostate cancer variants—adenosquamous carcinoma, pleomorphic giant‐cell carcinoma, and sarcomatoid carcinoma: an analysis of 19 cases

“…5 Recently, Lotan et al studied eight prostatic adenocarcinomas with pleomorphic giant-cell features, and found DNA damage repair mutations but not ERG fusions. 7 ADT, androgen deprivation therapy; IHC, immunohistochemistry. *A low-grade prostatic adenocarcinoma had a positive ERG fluorescence in-situ hybridisation result, but the sarcomatoid component was negative; this was interpreted as two unrelated tumour clones.…”

“…To our knowledge, only a few studies assessing a handful of cases have examined the molecular characteristics of these rare variants. [4][5][6][7] A better understanding of the molecular features of these tumour variants could shed light on the clinical and biological diversity of prostate cancer, and potentially have therapeutic significance. We studied a cohort of rare prostatic carcinoma variants, including adenosquamous carcinoma, sarcomatoid carcinoma, and pleomorphic giant-cell carcinoma, for their molecular profiles, using fluorescence in-situ hybridisation (FISH) and next-generation sequencing (NGS).…”

“…However, our understanding of the molecular characteristics of these rare variants is currently limited. To our knowledge, only a few studies assessing a handful of cases have examined the molecular characteristics of these rare variants 4–7 . A better understanding of the molecular features of these tumour variants could shed light on the clinical and biological diversity of prostate cancer, and potentially have therapeutic significance.…”

Molecular pathology of prostate cancer: a practical approach

“…57 Presence of HRD is associated with aggressive histological features including Gleason pattern 5 and intraductal/ductal prostate carcinoma. [58][59][60][61][62] In one of the first trials, olaparib demonstrated greatest efficacy in mCRPC patients harbouring genetic alterations in genes directly or indirectly involved in HRD. 63 Recently published data from the phase 3 PROfound trial provide further evidence for olaparib activity in mCRPC with HRD, especially in patients with BRCA1, BRCA2, or ATM alterations.…”