Genomic Correlates of DNA Damage in Breast Cancer Subtypes

• Main Authors: Esther Cabañas Morafraile, Javier Pérez-Peña, Jesús Fuentes-Antrás, Aránzazu Manzano, Pedro Pérez-Segura, Atanasio Pandiella, Eva M. Galán-Moya, Alberto Ocaña
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Cancers
• Subjects: breast cancer; DNA damage response (DDR); <i>ATR</i>; <i>Fanconi Anemia</i>; <i>ATM</i>; <i>BARD1</i>
• Online Access: https://www.mdpi.com/2072-6694/13/9/2117

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 <i>BRCA1/BRCA2</i> 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 <i>ATM/ATR, BARD1,</i> and <i>Fanconi Anemia</i>, 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 <i>NBN</i>, <i>PRKDC, RFWD2, UBE2T,</i> and <i>YWHAZ</i> 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.