Genomic attributes of homology-directed DNA repair deficiency in metastatic prostate cancer. JCI Insight 2021 Dec 08;6(23)
Date
12/09/2021Pubmed ID
34877933Pubmed Central ID
PMC8675196DOI
10.1172/jci.insight.152789Scopus ID
2-s2.0-85120888453 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
Cancers with homology-directed DNA repair (HRR) deficiency exhibit high response rates to poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy. Though mutations disrupting BRCA1 and BRCA2 associate with HRR deficiency (HRRd), patterns of genomic aberrations and mutation signatures may be more sensitive and specific indicators of compromised repair. Here, we evaluated whole-exome sequences from 418 metastatic prostate cancers (mPCs) and determined that one-fifth exhibited genomic characteristics of HRRd that included Catalogue Of Somatic Mutations In Cancer mutation signature 3. Notably, a substantial fraction of tumors with genomic features of HRRd lacked biallelic loss of a core HRR-associated gene, such as BRCA2. In this subset, HRRd associated with loss of chromodomain helicase DNA binding protein 1 but not with mutations in serine-protein kinase ATM, cyclin dependent kinase 12, or checkpoint kinase 2. HRRd genomic status was strongly correlated with responses to PARPi and platinum chemotherapy, a finding that supports evaluating biomarkers reflecting functional HRRd for treatment allocation.
Author List
De Sarkar N, Dasgupta S, Chatterjee P, Coleman I, Ha G, Ang LS, Kohlbrenner EA, Frank SB, Nunez TA, Salipante SJ, Corey E, Morrissey C, Van Allen E, Schweizer MT, Haffner MC, Patel R, Hanratty B, Lucas JM, Dumpit RF, Pritchard CC, Montgomery RB, Nelson PSAuthor
Navonil De Sarkar PhD Assistant Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDNA Repair-Deficiency Disorders
Disease Models, Animal
Genomics
Humans
Male
Mice
Neoplasm Metastasis
Prostatic Neoplasms
