Abstract 424: Defining prostate cancer subtypes by genomic features associated with defects in DNA repair processes
Authors: Sarkar Navonil De , Kohlbrenner Emily , Coleman Ilsa , Nelson Peter S. 
Published: August 2018

Introduction: Prostate cancer (PC) exhibits a spectrum of genomic aberrations, a subset of which associate with responses to specific therapeutics. In particular, mutations in genes involved in DNA repair processes expose therapeutic vulnerabilities that include PARP inhibitors and DNA-damaging chemotherapy for homology-directed repair(HR) defects and immune checkpoint blockade for mismatch repair (MMR) defects. Deploying appropriate therapy is dependent on accurate tumor classification.

Experimental Procedures: We evaluated whole-exome sequences derived from localized (n = 465) and metastatic (n = 208) PCs to identify mutations and structural aberrations predicted to disrupt or alter the function of genes involved in DNA repair processes. We annotated all tumors for trinucleotide (COSMIC) mutation signatures by comparing somatic alterations in tumor versus paired normal exomes. We compared the type and frequency of presumed pathogenic mutations, tumor ploidy, copy number aberrations, and mutational signatures between primary and metastatic tumors and evaluated associations between specific DNA repair gene aberrations and mutation signatures.

Results: Overall, 54% of localized PCs and 24.5% of metastatic PCs had a component of their somatic mutation burden associated with a mutation signature indicative of a DNA repair defect. Metastatic PCs had significantly higher numbers of somatic mutations (n=223) compared to primary PCs (n=93) (p&lt;0.008). Aneuploid and hypermutated tumors are also more common in metastatic PCs compared to primary PCs. Tumors with high LOH (&gt;0.1) scores were enriched for pathogenic mutations in BRCA1/2 and lowest LOH scores were observed in tumors with mutation/loss of CDK12, which were near-diploid. In addition to relatively frequent aberrations in BRCA2, BRCA1 and ATM, we found CDK12 mutations in ~1% of primary PCs and 5.3% of metastatic PCs. Tumors with BRCA1/2 loss or ATM and RecQ-Helicase pathway aberration exhibited larger amplifications and loss events, whereas PCs with CDK12 aberrations demonstrated a high number (n&gt;73 to 261) of focal (500b-1mb range) amplifications with rare focal losses.

Conclusions: 102 individual metastatic cases with some fraction of HR-defect signature and 41 (~40%) of them are without any bona fide HR pathway mutations. DNA repair gene (DRG) aberrations are common in metastatic PC and associate with distinct mutational signatures and structural aberrations that partition PCs into distinct subtypes. Epigenetic processes may contribute to HR signatures in tumors where DRG mutations were not identified. Preclinical and clinical studies are required to determine if mutation signatures are accurate predictors of responses to therapeutics. Thus, with these signatures, we have proposed a few molecular subcategories of prostate tumors and such information can be harnessed for future precision cancer therapies.

Citation Format: Navonil De Sarkar, Emily Kohlbrenner, Ilsa Coleman, Peter S. Nelson. Defining prostate cancer subtypes by genomic features associated with defects in DNA repair processes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 424.