Biallelic tumour suppressor loss and DNA repair defects in de novo small‐cell prostate carcinoma

• DOI: 10.1002/path.5137
• Publication Date: 2018-07-17T11:55:33Z
• Authors: Edmund CP Chedgy; Gillian Vandekerk...; Cameron Herberts; Matti Annala; Adam J Donoghue; Michael Sigouros; Elie Ritch; Werner Struss; Saki Konomura; Janet Liew; Sunil Parimi; Joanna Vergidis; Antonio Hurtado‐Coll; Andrea Sboner; Ladan Fazli; Himisha Beltran; Kim N Chi; Alexander W Wyatt
• Keywords: MSH2

Abstract Small‐cell prostate carcinoma (SCPC) is an aggressive malignancy that managed similarly to small‐cell lung cancer. SCPC can evolve from adenocarcinoma in response androgen deprivation therapy, but, rare cases, present at initial cancer diagnosis. The molecular aetiology of de novo incompletely understood, owing the scarcity tumour tissue and short life‐expectancy patients. Through a retrospective search our regional oncology pharmacy database, we identified 18 patients diagnosed with between 2004 2017. Ten had pure pathology, remainder some admixed foci, but all were treated first‐line platinum‐based chemotherapy. median overall survival was 28 months. We performed targeted DNA sequencing, whole exome sequencing mRNA profiling on formalin‐fixed paraffin‐embedded archival tissue. observed frequent biallelic deletion and/or mutation suppressor genes TP53 , RB1 PTEN what found treatment‐related SCPC. Indeed, RNA level, closely resembled However, five loss repair genes, including BRCA1 BRCA2 ATM MSH2 / 6 potentially underlying high genomic instability this disease variant. Two harboured ETS gene rearrangements involving androgen‐driven promoters, consistent evolution ancestor. Overall, results reveal highly landscape underlies unusual pathological variant, suggest opportunities for therapy strategies few treatment options. Copyright © 2018 Pathological Society Great Britain Ireland. Published by John Wiley & Sons, Ltd.