Abstract 5692: Tissue specificity of chromosome aneuploidy correlates with BRCA-associated cancer risk

Abstract

Abstract Pathogenic germline variants of BRCA1 and BRCA2 disproportionally elevated the risk of specific cancer types (ex. breast [BRCA] and ovarian [OV] cancer) compared to tumors arising from other tissues. The reason underlying the strong tissue-specificity for BRCA-associated cancer risk remains largely unknown. Under the two-hit hypothesis, BRCA-mediated oncogenesis is thought to originate from a cell where the germline BRCA1/2 variant underwent loss of heterozygosity (LOH) of the wildtype BRCA allele, resulting in homologous recombination DNA repair deficiencies. Notably, tumor aneuploidy and loss of chromosome arms also show strong tissue specificity across cancer types. The apparent tissue specificities of BRCA-associated cancer risk and chromosome aneuploidy, together with deletion-induced LOH underlying the two-hit hypothesis, pose an intriguing possibility that they may be linked. Using genomic data from the TCGA PanCanAtlas and ICGC PCAWG projects, we calculated the frequencies of deletions of the chromosomal arms where the BRCA1/2 genes are located (17q for BRCA1; 13q for BRCA2) across different cancer types in tumors with no whole-genome doublings (WGD). Among TCGA cases, OV and BRCA showed significantly higher frequencies of 17q deletion (32.75% and 8.05%, respectively) than other cancer types (ranked 2/30 and 5/30, permutation p-value = 0.030 and 0.024), and relatively higher frequencies of 13q deletion (32.75% and 21.92%, respectively) compared to other cancers (ranked 5/32 and 8/32, p-value = 0.101 and 0.078). As expected, cancer types showing high fractions of BRCA1/2 deletions overlap with those showing 17q/13q deletions and often include BRCA and OV. Subsequently, we determined how often BRCA1/2 deletion co-occurred and thus may be caused by the corresponding 17q/13q deletions, showing that BRCA1 deletion carriers who also had chr17q deletion accounted for 40.76% in OV and 25.93% in BRCA patients, compared to 33.33% in all other cancer types while BRCA2 deletion carriers who also had chr13q deletion accounted for OV (53.97%) and BRCA (58.60%) patients, compared to 49.83% in all other cancer types. In addition, we validated our findings in non-overlapping cases of the ICGC PCAWG projects. Consistent with TCGA results, OV and BRCA showed higher frequencies of 17q and 13q deletion compared to other cancer types. To conclude, we identified a correlation between cross-cancer difference in arm-level and focal chromosome aneuploidy affecting BRCA1/2 and BRCA-associated cancer risk, and how chromosome aneuploid may give rise to tissue-specific risks of cancer remain to be investigated. Citation Format: Xinfeng Wang, Tomi Jun, Nan Sun, Jie He, Kuan-lin Huang. Tissue specificity of chromosome aneuploidy correlates with BRCA-associated cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5692.