Abstract P002: Timing onset of homologous recombination deficiency before cancer diagnosis in BRCA1/2 mutation carriers
Authors: Glodzik Dominik , Gulhan Doga , Park Peter J. 
Published: January 2023

Abstract
Introduction: Identification of individuals at risk of developing cancer is key to prevention, particularly among carriers of germline BRCA1/2 mutations. Cancers that develop in this population display loss of the wildtype copy BRCA1/2 and a reproducible pattern of somatic passenger mutations manifesting homologous recombination deficiency (HRD) (Davies et al. 2017). It is not known how much time elapses between the bi-allelic loss of genes responsible for homologous recombination deficiency and the development of cancer. A better understanding of this process and estimating the time between cancer initiation to diagnosis in patients with germline BRCA1/2 mutations would inform early detection strategies in the high-risk group. Methods: Passenger mutations in the cancer genome capture the life history of each cancer. We analyzed patterns of somatic mutations in whole genomes of 27 cancers from patients with germline BRCA1/2 mutations who developed cancers of different tissues with whole genome duplications (WGD). We conducted a meta-analysis of data from the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium (n=14) and the SCANB breast cancer biobank (n=13) (Staaf et al. 2019). Whole genome duplications in tumors allow for approximate timing of onset of HRD. The “molecular clock” mutations in characteristic CpG context accumulate with age and are used to time genomic events. Following bi-allelic BRCA1/2 loss, additional types of somatic mutations accumulate, notably the single point mutation signature SBS3 and HRD-associated indel and rearrangement signatures. Somatic mutations are assigned to the most likely signature which generated them. In tumors that carry it, whole genome duplication enables relative timing of other genomic events. Mutations that occur before and after the duplication are distinguished using allele frequencies (Gerstung et al. 2020). Results: Using this methodology, we observe that HRD-associated SBS3 accounts for as much as 40-60% of the duplicated mutations, suggesting that HRD developed prior to WGD. We use the “molecular clock” to time the intervals before and after WGD, and we estimate that WGD occurs six to thirteen years (interquartile range) prior to the most recent common ancestor of diagnosed tumor. Next, using the relative proportions of SBS3 and clock signatures deduced from post-WGD mutations, we infer how long before WGD SBS3 started to accumulate, providing an even closer bound for HRD development time point than the WGD timing alone. Conclusions: We establish a lower bound on the dormancy period of homologous recombination deficiency prior to cancer diagnosis which would inform early detection strategies in the high-risk group of BRCA1/2 carriers.
Citation Format: Dominik Glodzik, Doga Gulhan, Peter J. Park. Timing onset of homologous recombination deficiency before cancer diagnosis in BRCA1/2 mutation carriers. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P002.