Abstract 1757: Pan-cancer analysis identifies signatures of HRD-positivity in germline BRCA1/2 mutated non-BRCA associated cancers
Authors: Muldoon Daniel M. , Mehine Miika , Tischfield Samuel , Brannon A. Rose , Ladanyi Marc , Stadler Zsofia K. , Solit David B. , Drilon Alexander , Berger Michael F. , Murciano-Goroff Yonina , Bandlamudi Chaitanya 
Published: March 2024

Abstract
Introduction: BRCA-associated cancers (breast, ovarian, pancreas, and prostate) with germline pathogenic mutations in BRCA1/2 (gBRCA1/2) are associated with homologous recombination deficiency (HRD) and benefit from platinum/PARPi. However, the role of gBRCA1/2 in non-BRCA assoc. cancers is poorly understood. HRD tumors present with ‘genomic scars’ that can be quantified in tumor profiling (“HRD-sum” score). We reasoned that the HRD-sum score together with germline mutation status (including loss of wild-type) is a strong correlate of HRD-positivity. Leveraging 42,448 prospectively sequenced patients across 63 cancer types, we sought to characterize the prevalence of the HRD-positivity in non-BRCA-assoc. cancers.
Methods: Allele-specific copy number data was inferred using FACETS. HRD-sum was calculated as a sum of the numbers of telomeric imbalances, large-scale transitions and genome-wide losses of heterozygosity. Calculating each score was iteratively optimized to improve detection of the scars using MSK-IMPACT targeted sequencing data using patient-matched WES data from 1841 tumors as reference. Germline mutations were identified by a clinically validated pipeline and annotated for pathogenicity using ClinVar. After excluding low quality tumors, 27,375 patients were retained for analysis. “HRD-positive” tumors are those with gBRCA1/2 mutations, loss of wild type, and an HRD-sum score &gt;=42.
Results: Expectedly, gBRCA1/2 mutations were more frequent in BRCA-assoc. cancers (7.2%, 558 of 7,737 patients) compared to non-BRCA-assoc. cancers (2.6%, 500 of 19,638) (p=5e-60). Among non-BRCA-assoc. cancers, gBRCA1/2 were most common in esophagogastric (3.9%), lung (3%), hepatobiliary (2.9%), and bladder (2.8%) cancers. Although biallelic loss in gBRCA1/2 patients was sig. higher in BRCA-assoc. cancers (80% vs. 37% in non-BRCA-assoc.), several cancer types showed high rates of loss of wild-type including gBRCA1 tumors in hepatobiliary (5/5) and endometrial (10/11) cancers. HRD-sum scores in all gBRCA1/2 biallelic tumors were sig. higher (median 58) compared to monoallelic (26) or wild-type (25) tumors. Notably, the non-BRCA assoc. cancers with biallelic gBRCA1/2 harbored higher HRD-sum scores compared to monoallelic (median 51 vs. 22, p&lt;0.0001). These include cancer types such as endometrial (64 vs. 37, p= 0.0014) and esophagogastric (62 vs. 45, p=0.0017). In all, 68% of gBRCA1/2 patients in BRCA-assoc. cancers showed HRD-positivity. Interestingly, 18% (91/500) of gBRCA1/2 patients in non-BRCA-assoc. cancers also showed HRD-positivity. These included 52% of esophagogastric, 28% of lung, and 22% of bladder cancer patients with gBRCA1/2.
Conclusion: Using a robust measure to detect HRD scars from MSK-IMPACT panel data, we demonstrate evidence for BRCA-mediated tumorigenesis in an expanded spectrum of cancers with potential therapeutic relevance.
Citation Format: Daniel M. Muldoon, Miika Mehine, Samuel Tischfield, A. Rose Brannon, Marc Ladanyi, Zsofia K. Stadler, David B. Solit, Alexander Drilon, Michael F. Berger, Yonina Murciano-Goroff, Chaitanya Bandlamudi. Pan-cancer analysis identifies signatures of HRD-positivity in germline BRCA1/2 mutated non-BRCA associated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1757.