Niraparib Before Surgery in Treating Patients With High Risk Localized Prostate Cancer and DNA Damage Response Defects

AbstractDNA-Damage Response (DDR) proteins are crucial for maintaining the integrity of the genome by identifying and repairing errors in DNA. Variants affecting their function can have severe consequences since failure to repair damaged DNA can result in cells turning cancerous. Here, we compare germline and somatic variants in DDR genes, specifically looking at their locations in the corresponding three-dimensional (3D) structures, Pfam domains, and protein–protein interaction interfaces. We show that somatic variants in metastatic cases are more likely to be found in Pfam domains and protein interaction interfaces than are pathogenic germline variants or variants of unknown significance (VUS). We also show that there are hotspots in the structures of ATM and BRCA2 proteins where pathogenic germline, and recurrent somatic variants from primary and metastatic tumours, cluster together in 3D. Moreover, in the ATM, BRCA1 and BRCA2 genes from prostate cancer patients, the distributions of germline benign, pathogenic, VUS, and recurrent somatic variants differ across Pfam domains. Together, these results provide a better characterisation of the most recurrent affected regions in DDRs and could help in the understanding of individual susceptibility to tumour development.

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Re: Hung-Ming Lam, Holly M. Nguyen, Mark P. Labrecque, et al. Durable Response of Enzalutamide-resistant Prostate Cancer to Supraphysiological Testosterone Is Associated with a Multifaceted Growth Suppression and Impaired DNA Damage Response Transcriptomic Program in Patient-derived Xenografts. Eur Urol 2020;77:144–55

European Urology ◽

10.1016/j.eururo.2020.05.022 ◽

2020 ◽

Vol 78 (3) ◽

pp. e137-e138

Author(s):

Giovanni Lavorgna ◽

Francesco Montorsi ◽

Andrea Salonia

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

Growth Suppression ◽

Durable Response ◽

Damage Response

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Abstract 1312: ATM transcriptional regulation mediated by BRCA1/E2F1 axis controls DNA damage response in prostate cancer

10.1158/1538-7445.am2012-1312 ◽

2012 ◽

Author(s):

Cristian P. Moiola ◽

Paola De Luca ◽

Florencia Zalazar ◽

Javier Cotignola ◽

Kevin Gardner ◽

...

Keyword(s):

Prostate Cancer ◽

Dna Damage ◽

Transcriptional Regulation ◽

Dna Damage Response ◽

Damage Response

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Effect of DNA damage response mutations on prostate cancer prognosis: a systematic review

Future Oncology ◽

10.2217/fon-2019-0298 ◽

2019 ◽

Vol 15 (28) ◽

pp. 3283-3303 ◽

Cited By ~ 2

Author(s):

Stephanie L Swift ◽

Shona H Lang ◽

Heath White ◽

Kate Misso ◽

Jos Kleijnen ◽

...

Keyword(s):

Prostate Cancer ◽

Systematic Review ◽

Dna Damage ◽

Clinical Outcomes ◽

Dna Damage Response ◽

Parp Inhibitor ◽

Cancer Prognosis ◽

Castration Resistant ◽

Damage Response ◽

Brca1 Brca2

The prognosis of men with prostate cancer (PC) with mutations in DNA damage response ( DDR) genes undergoing different treatments is unclear. This systematic review compared clinical outcomes in PC patients with DDR mutations ( DDR+) versus no mutations ( DDR-). 14 resources plus gray literature were searched for studies in PC and subgroups (castration-resistant PC, metastatic PC and metastatic castration-resistant PC) by DDR gene ( ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C) mutation status. From 11,648 records, 26 studies were included. For mCRPC, six studies reported comparative efficacy for key outcomes. Improvements in several clinical outcomes were observed for DDR+ (vs DDR-) after PARP inhibitor therapy or immunotherapy. DDR+ PC patients may have improved outcomes depending on the treatment they undergo.

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