Abstract P1-05-06: Establishment of novel BRCA1ness score to quantify BRCAness in breast cancer

Abstract

Abstract Germline mutations in the loci of BRCA1 or BRCA2 genes with loss of heterozygosity or additional somatic truncation at the WT allele in breast cancer result in characteristic clinicopathological features of homologous recombination deficiency, also known as “BRCAness.”. Although clinical genetic testing for mutations of BRCA1 and BRCA2 has increased the chances of identifying pathogenic variants, we speculated that there may be a difference in cancer biology by the degree of BRCAness. To address this question, we sought to develop a means to estimate the amount of BRCAness using a score consists of BRCA1-mutation-related genes. Thirty-four BRCA1-mutation related genes were selected by high area under the curve (AUC) levels in receiver operating characteristic (ROC) curve between BRCA1 mutation and non-mutation breast cancer, consistently in two large breast cancer cohorts, TCGA and METABRIC. The score was established by using gene set variation analysis (GSVA) algorithm on 34 genes. We found that the BRCA1ness score was the highest in triple negative breast cancer (TNBC) among subtypes consistently in both cohorts (both p < 0.001). Although BRCA1ness score did not correlate with mRNA expression of BRCA1 nor BRCA2 at all (spearman’s rank correlation coefficient (r) = 0.191 and 0.093, respectively), high BRCA1ness score was significantly associated with high rate of BRCA1 mutation (AUC = 0.735 and 0.709, respectively) in both cohorts. This level of AUC for BRCA1ness mutation score was highest compared to other factors, including BRCA1 expression (AUC = 0.323), DNA repair gene set score (AUC = 0.553 and 0.543), nor homologous recombination deficient (HRD) (AUC = 0.659), which are known as the characteristics of BRCAness. Furthermore, the score was significantly correlated with DNA repair gene set score (r = 0.593 and 0.323, both p < 0.01) as well as MKI67 expression (r = 0.655 and 0.626, both p < 0.01) in both cohorts. HRD score was also strongly correlated with BRCA1ness score in the TCGA cohort (r = 0.633). Interestingly, high BRCA1ness was significantly associated with worse disease-free survival (DFS) (p = 0.037 and p < 0.001, respectively) and disease-specific survival (DSS) (p = 0.012 and p < 0.001, respectively) in both cohorts. In conclusion, we established novel BRCA1ness score using mRNA expression of BRCA1-mutation-related genes, and found that it associate with DNA repair and worse survival. Citation Format: Masanori Oshi, Rongrong Wu, Akimitsu Yamada, Li Yan, Takashi Ishikawa, Itaru Endo, Kazuaki Takabe. Establishment of novel BRCA1ness score to quantify BRCAness in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-05-06.