Abstract P2-03-11: Genomic pattern of breast carcinomas carrying mutations of non-BRCA homologous recombination genes

Abstract

Abstract Background BRCA1 and BRCA2 are involved in the homologous recombination (HR) double-strand DNA break repair and genomic patterns of breast tumors with defective BRCA are characterized by increased genomic instability. The pre-clinical and clinical studies show that tumors with defective BRCA or other HR genes can response to platinum and PARP inhibitors. However, the genomic pattern of tumors carrying mutations of non-BRCA HR genes are not investigated. Methods Genomic patterns of breast carcinomas were performed by comparative genomic hybridization (CGH) array containing 60000 probes covering the whole genome with an average spacing of 40kb. The frequency of gains and losses for each regions detected by probes was calculated by ratio thresholds of 0.25 and -0.25, respectively. Large-scale genomic structural aberration was defined as the region of gains and losses of at least 10Mb. We analyzed the difference of large-scale aberration, including numbers, length and specific regions, between tumors with BRCA mutation (mtBRCA), non-BRCA HR mutation (mtHR) and wild type. Results We examined 41 breast carcinomas, including 15 cases with BRCA mutations, 14 with non-BRCA HR gene mutations and 12 without mutations (control). The 14 non-BRCA HR gene were 1 ATM, 1 BRIP1, 1 BARD1, 1 FANCA, 2 FANCB, 1 FANCI, 1 PALB2, 2 RAD50, 2 RAD51C and 2 RAD51D. The number and length of large-scale genomic structural aberration of mtBRCA tumors were significantly higher than wild type tumors (number p=0.005; length p=0.005), indicating CGH can distinguish the mtBRCA from control tumors. We then checked the mtHR tumors, which also revealed significantly increased number and longer length of structural aberrations compared to wild type tumors (number p=0.035; length p=0.022), but were not different from mtBRCA tumors (number p=0.204; length p=0.425). Among the specific regions on chromosomes, mtBRCA and mtHR tumors contained similar genomic aberration regions but different from wild type tumors. The most frequent aberration regions of mtBRCA and mtHR tumors are chromosome 6p22.1-p25, 6q21-q27, 8q11.1-q24, 11p11.2-p14.1, 11q, 12p and 19p, which are less revealed in the wild type (all p value <0.05). Conclusions Our study demonstrated a direct evidence that increased genomic instability were the common characteristics of mtBRCA and non-BRCA mtHR tumors. In addition, we identify the specific genomic patterns of mtBRCA and mtHR tumors, which can be a biomarker indicating HR deficiency and response to platinum and PARP inhibitors. Citation Format: Lin P-H, Kuo W-H, Wang M-Y, Lo C, Lin C-H, Lu Y-S, Chiu C-F, Huang C-S. Genomic pattern of breast carcinomas carrying mutations of non-BRCA homologous recombination genes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-11.