Abstract
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.
Highlights
Prostate cancer (PC) is a common age-associated malignancy that is recognized to comprise distinct phenotypic and genomic subtypes [1,2,3]
Deep molecular profiling of metastatic PC has identified several subtypes categorized by defects in DNA repair processes, most commonly mutations in genes such as BRCA2 involved in homology-directed DNA repair (HRR; refs. 1, 4)
We identified signatures associated with 5 mutational processes present in at least 5% of tumors (Figure 1A): signature 1 (CSig1), attributed to spontaneous deamination of 5-mC and associated with aging, present in 99% of tumors; signature 3 (CSig3), attributed to HRR deficiency (HRRd), present in 19.6% of tumors; unassigned signature 8 (CSig8), present in 7% of tumors (~2% of tumors had both CSig3 and CSig8); and signatures 6, 15, and 26, attributed to DNA mismatch repair (MMR) defects, present in 1.4%, 10.6%, and 1.9% of tumors, respectively
Summary
Prostate cancer (PC) is a common age-associated malignancy that is recognized to comprise distinct phenotypic and genomic subtypes [1,2,3]. Deep molecular profiling of metastatic PC (mPC) has identified several subtypes categorized by defects in DNA repair processes, most commonly mutations in genes such as BRCA2 involved in homology-directed DNA repair Somatic alterations in DNA repair genes occur in approximately 20% of mPCs [6, 7]. Preclinical studies of other genes recurrently mutated in mPC, such as chromodomain helicase DNA binding protein 1 (CHD1) and speckle type BTB/POZ protein (SPOP), indicate they may mediate HRR deficiency MPCs with HRRd are associated with exceptional responses to platinum chemotherapy and to inhibitors of poly(ADP-ribose) polymerase (PARP) 1 [11,12,13]. Identifying tumor features that accurately predict HRRd and consequent vulnerability to genotoxic drugs would enhance clinical care by improving treatment allocations
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