Genomic Correlates of DNA Damage in Breast Cancer Subtypes.

Esther Cabañas Morafraile,Eva M Galán-Moya,Jesús Fuentes-Antrás,Javier Pérez-Peña,Atanasio Pandiella,Aránzazu Manzano,Alberto Ocaña,Pedro Pérez-Segura

doi:10.3390/cancers13092117

Abstract

Simple SummaryBreast cancer (BC) is the most common invasive tumor in women and the second leading cause of cancer-related death. Therefore, identification of druggable targets to improve current therapies and overcome resistance is a major goal. In this work, we performed an in silico analysis of transcriptomic datasets in breast cancer, and focused on those involved in DNA damage, as were clearly upregulated using gene set enrichment analyses (GSEA), particular the following pathways: ATM/ATR, BARD1 and Fanconi Anemia. BHLHE40, RFWD2, BRIP1, PRKDC, NBN, RNF8, FANCD2, RAD1, BLM, DCLRE1C, UBE2T, CSTF1, MCM7, RFC4, YWHAB, YWHAZ, CDC6, CCNE1, and FANCI genes were amplified/overexpressed in BC, and correlated with detrimental prognosis. Finally, we selected the best transcriptomic signature of genes within this function that associated with clinical outcome to identify functional genomic correlates of outcome.Among the described druggable vulnerabilities, acting on the DNA repair mechanism has gained momentum, with the approval of PARP inhibitors in several indications, including breast cancer. However, beyond the mere presence of BRCA1/BRCA2 mutations, the identification of additional biomarkers that would help to select tumors with an extreme dependence on DNA repair machinery would help to stratify therapeutic decisions. Gene set enrichment analyses (GSEA) using public datasets evaluating expression values between normal breast tissue and breast cancer identified a set of upregulated genes. Genes included in different pathways, such as ATM/ATR, BARD1, and Fanconi Anemia, which are involved in the DNA damage response, were selected and confirmed using molecular alterations data contained at cBioportal. Nineteen genes from these gene sets were identified to be amplified and upregulated in breast cancer but only five of them NBN, PRKDC, RFWD2, UBE2T, and YWHAZ meet criteria in all breast cancer molecular subtypes. Correlation of the selected genes with prognosis (relapse free survival, RFS, and overall survival, OS) was performed using the KM Plotter Online Tool. In last place, we selected the best signature of genes within this process whose upregulation can be indicative of a more aggressive phenotype and linked with worse outcome. In summary, we identify genomic correlates within DNA damage pathway associated with prognosis in breast cancer.

Highlights

Cancer is characterized by a wide range of genomic alterations, with some of them involved in the oncogenic process [1]
We focused on those related with DNA damage response (DDR) pathways, including those classified by gene ontology as ATR, Fanconi Anemia, ATM, and BARD1 pathways, where a strong enrichment score (ES) and a low false discovery rate (FDR) was observed (ATR pathway; NES: 1,93; FDR: 0.002; Fanconi Anemia pathway; NES: 1.869; FDR: 0.004; BARD1 pathway; NES: 1.78; FDR: 0.013 ATM pathway; NES: 1.746; FDR: 0.015 ) (Figure 1B)
The expression of these four DNA damage gene sets was analyzed in the four described breast cancer subtypes, namely basal-like, HER2 enriched, luminal A and luminal B, as defined in material and methods

Summary

Introduction

Cancer is characterized by a wide range of genomic alterations, with some of them involved in the oncogenic process [1]. Among the different deregulated functions described as involved in cancer, regulation of DNA repair mechanisms has been reported as one with great potential for pharmacological intervention [4,5]. Genes involved in the process of DNA repair have been described as functionally dysregulated in several tumors, contributing substantially to the high grade of genomic instability observed in some cancers [6,7]. Germline mutations at BRCA1 and BRCA2 have been described in several solid tumors, such as breast, prostate or pancreatic cancer; and agents acting on the protein PARP have shown activity in this specific population [6,7,8,9]. Targeting components of the NHEJ (e.g., the protein PARP) induce a synthetic lethality approach in cells with germline inactivating mutations at BRCA1 and BRCA2 [6]

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Conclusion