Abstract A25: Intragroup genomic, transcriptional, and epigenomic variability is higher in sporadic than in BRCA1-associated hereditary triple-negative breast tumors

Abstract

Abstract Intra-tumor genetic heterogeneity is a possible cause of therapy resistance and has consequences in the disease progression and patient survival. Triple-negative breast cancer (TNBC) is associated with rapid growth, early metastasis, and worse prognosis than other breast cancer subtypes. Close association has been identified between TNBC and germline loss-of-function mutations in BRCA1 gene which trigger the tumorigenic process in hereditary TNBC. Although at genomic level, TNBC was previously characterized as more heterogeneous than other breast cancer subtypes, the difference in genomic, epigenomic, and transcriptional variability between two groups of TNBC—sporadic (BRCA1-proficent) and hereditary (BRCA1-associated)—remains unclear. Here, we investigated both sporadic and hereditary TNBC, by using data from copy-number alterations (CNAs) array, methylation array, and RNA-Seq. A total of 80 samples, 40 TNBC BRCA1-proficient (classified as sporadic), 18 TNBC with BRCA1 germline mutation (classifed as hereditary) and 22 normal breast tissues used as controls, were used. Data from methylation and CNA arrays were analyzed with the RnBeads and snapCGH softwares, respectively. RNA-seq data was analyzed mainly with the STAR aligner, Bioconductor-GenomicFeatures and DESeq2 softwares. To assess the intragroup genomic, transcriptional, and epigenomic variability we used the inter-quantile difference between patients of the same group. Our results clearly demonstrated that the TNBC BRCA1-proficient group has a higher intragroup heterogeneity than the BRCA1-mutated group regarding (i) global pattern of gene expression, (ii) number and intensity of CNAs (copy number alterations), and (iii) level of promoter methylation. Moreover, normal breast samples showed the lowest intra-group heterogeneity for the last two features. Then, our results show higher genomic, transcriptional, and epigenomic variability in sporadic than hereditary TNBC and motivates further molecular subtyping of the sporadic TNBCs, which may reveal new targets to improve TNBC treatment. Citation Format: Kivvi Duarte de Mello Nakamura, Rodrigo Fernandes Ramalho, Rafael Canfield Brianese, Ana Krepischi, Bruna D. F. Barros, Dirce Maria Carraro. Intragroup genomic, transcriptional, and epigenomic variability is higher in sporadic than in BRCA1-associated hereditary triple-negative breast tumors [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr A25.