225 Background: Metastatic, castration-resistant prostate cancer (mCRPC) is commonly the deadly form of PC. Among these, a subset of tumors are androgen-indifferent with the most aggressive often manifesting variant histology, including neuroendocrine or small cell changes. Neuroendocrine PC can be de novo (NEPC) or develop in response to therapy as treatment emergent (CRPC-NE). Currently effective durable treatments for NEPC are lacking. Hence, we sought to identify additional targets in CRPC/NEPC using an integrative platform of whole genome (WGS) and transcriptome sequencing (RNAseq). Methods: WGS was performed on55 tumor/normal pairs (CRPC-Ad, n= 32; CRPC-NE, n=13; de novo NEPC, n=7; metastatic hormone naïve, PC n=3) from 48 patients. RNAseq data was available in a subset of 21 samples. We employed the Isabl GxT analytic platform and manually curated single base substitution (SBS, COSMIC v3) molecular signatures and structural variants (SV) that involved tumor suppressor genes and oncogenes. Results: We observed 184 events in cancer-associated genes and targets in 38 cases. Non-canonical ETS fusions were identified in 2 CRPC-Ad patients ( MSMB-ERG and YWHAE-ETV4). Other rare events included SVs affecting ALK ( SLC45A3-ALK) and FGFR1 amplification in 1 patient each. Pathogenic germline alterations in 15% of patients with equal frequency in each clinicopathological state. These variants included genes such as BRCA1, BRCA2, and ATM, and other genes of uncertain relevance for prostate cancer ( e.g., PPM1D and MUTYH). SBS genomic signatures associated with homologous recombination deficiency (HRD) were observed in 15% of the patients (7 cases): 3 harbored germline BRCA1/2mutations, 2 with somatic BRCA2 mutations, and 2 without alteration in BRCA1/2 (1 of these CRPC-Ad had a complex SV disrupting RAD51B) without apparent enrichment for any histology, and a majority of both histologies were enriched in Mismatch repair (MMR)-associated SBS. One subject CRPC-NE and amphicrine character, which displayed a complete response to immune checkpoint blockade, harbored driver mutations in AR and CTNNB1, and homozygous loss of MSH2/6. Further, molecular signatures of potential clinical relevance were detected at varying contributions and included CDK12-type genomic instability (CRPC-Ad, n=2) (4%) and MMR deficiency with POLD1 proofreading (CRPC-Ad) who also experienced a durable response to pembrolizumab. Conclusions: WGS/RNAseq in CRPC and NEPC elucidates genomic signatures associated with HRD and MMR, complex SVs in oncogenes, and non-canonical ETS fusions. Expansion of our analysis is underway with enhanced integration of clinical metadata and RNAseq for rational trial design for aggressive variant CRPC and NEPC.
Homologous recombination deficiency (HRd) is a DNA repair defect prevalent in but not exclusive to breast and ovarian cancer most commonly associated with BRCA1 or BRCA2 alterations. HRd results in accumulation of small and large scale genetic alterations across the genome, including allele specific copy number alterations (aCNAs), small nucleotide variants (SNVs), deletions, and structural variants (SVs). Detection of HRd in tumors predicts response to genotoxic drugs such as PARP inhibitors and platinum. Genome wide aCNAs such as large state transitions (LST), loss of heterozygosity (LOH), and telomeric allelic imbalances (TAI) in conjunction with BRCA1/2 mutation detection have been implemented in routine diagnostic testing to identify HRd in tumors. However, these features represent a subset of the genetic signatures predictive of HRd, and we hypothesize that a significant portion of tumors with HRd are missed using these existing assays. Whole genome sequencing (WGS) enables the detection of the full spectrum of genetic lesions that arise in an HRd tumor in a single assay. To demonstrate the added value of WGS to identify HRd, we trained and validated a pan-cancer classifier of HRd. A tumor/normal matched cohort of 321 cancer patients sequenced by WGS was assembled and analyzed as part of a retrospective study, representing 62 tumor types. An unbiased analysis of HRd associated SV signatures revealed the top quartile of samples harboring tandem duplications (Dups) and deletions (Dels) in the size range of 1-10kbp were enriched with BRCA1, BRCA2, and RAD51C/D alterations. Through curating Dels, Dups, HRd SNV/InDel signatures, and alteration of HRd associated genes, 37 unique patients were found to have high confidence HRd, out of which 13% had no alterations in BRCA1, BRCA2, or other HRd genes. We then trained a random forest classifier to identify HRd tumors. The most important predictive features were WGS-specific, namely small deletions with microhomology, SV Dels, and SV Dups. The HRd classifier was validated using an independent cohort of 556 samples from the Pan-Cancer Analysis of Whole Genomes (PCAWG) study. Of 46 samples with biallelic BRCA1/2 alterations, the classifier achieved high areas under receiver-operator characteristic (AUROC, 0.99) and precision recall curves (AUPRC, 0.96). The aCNA score, the number of segments harboring LST, LOH, and TAI, had similar AUROC (0.96) but lower AUPRC (0.87). There were 11 BRCA1/2 non-altered cases predicted to be HRd with the classifier which were not identified by CNA scores, in which 10 had at least 1 alteration in an HRd gene, including RAD51C, CHEK2 biallelic alterations and SVs in PALB2, Fanconi pathway genes, and ATM/ATR. We conclude that a classifier incorporating the additional mutational features which can only be detected using WGS can achieve superior precision in identifying HRd tumors and, in the future, uncover additional patients for therapeutic options. Citation Format: Kevin Hadi, Gunes Gundem, Max F. Levine, Aditya Deshpande, Minal Patel, Stan Skzrypczak, Majd Al Assaad, Juan Miguel Mosquera, Olivier Elemento, Andrew L. Kung, Juan S. Medina-Martínez, Elli Papaemmanuil. A whole genome sequencing classifier of homologous recombination deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2149.
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