Abstract P6-01-40: Integrative transcriptomic analysis and cohort validation identify key genes in chemotherapy treatment response in Latino breast cancer patients
Authors: Guevara-Nieto Hedda Michelle , Parra-Medina Rafael , Mejia-Henao Juan C. , López-Correa Patricia , Diaz Sandra , Garai Jone , Zabaleta Jovanny , López-Kleine Liliana , Combita Alba L. 
Published: March 2023

Abstract
Purpose: Breast cancer (BC) is one of the most frequent invasive cancers and one of the main causes of cancer mortality in women. Effective treatment interventions for BC are urgently required to improve survival rate and quality of life. Chemotherapy has been widely applied in BC treatment; however, therapeutic resistance remains an unresolved issue. Currently, only a minority of patients benefit from chemotherapy, emphasizing the need to identify more effective hub genes associated with therapy response. The overarching goal of this study is to assess hub genes correlated with BC chemotherapy treatment response via multiple databases and validate the workflow in an independent cohort of Hispanic/Latino (Colombian) women diagnosed with invasive Luminal B BC candidates for neoadjuvant chemotherapy. Design: Screening and multistep filtering of common genes correlated with chemotherapeutic response was performed by integrating differentially expressed genes between responders and non-responders in publicly available datasets. For each database, the differentially expressed genes (DEGs) between non-responders and responders were identified using GEO2R and LIMMA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted for the identified common genes using Metascape and DAVID. Functional enrichment analysis and protein-protein interaction (PPI) network for DEGs were constructed using (STRING) database. Hub genes were identified from PPI network by Cytoscape software analysis. The mRNA expression of hub genes in BC and normal tissues was subsequently explored by UALCAN. Evaluation of the effect of hub genes on survival was performed using Kaplan-Meier plotter. Hub genes were imported into the DGIdb to obtain the potential for BC chemotherapy-associated treatment drugs. The previous workflow was then applied/validated to an Illumina high-throughput RNA sequencing of 50 Luminal B cases (HER2+ and HER2-) of Hispanic/Latino patients. Results: 490 DEGs were obtained from the intersection of five public databases. Pathway enrichment analysis revealed DEGs were associated with cell cycle, estrogen response, adaptive immune response, and regulation of kinase activity, among others. Thirty-two hub genes were identified from PPI network analysis with high degree nodes and betweennesscentrality. Significant differential expression of hub genes between BC tissue and normal tissues was observed in UALCAN. These genes were significantly associated with survival probability. Fifteen potential targeted therapeutic drugs were identified through DGIdb database. Validation workflow in independent Luminal B cohort showed 238 DEGs, 90 hub genes with high degree and enrichment in the regulation of hormone levels, cellular response to EGFR, signaling by ERBB2 and MAPK. GATA3 was the hub gene found in both databases and the validation set. Both databases and validation set show hub genes, enriched pathways, and drugs that indicate their close association with tumorigenesis and would contribute to acting an important role in therapy response prediction. Conclusions: This workflow was created using public databases and applied to a patient’s cohort of different ancestries. This methodology can successfully provide potential biomarkers that correlate with therapy response. Genes were selected from PPI network. Most of them were independent biomarkers of BC treatment response, including that in underrepresented patients. Moreover, these genes may exert critical function in non-response and progression.
Citation Format: Hedda Michelle Guevara-Nieto, Rafael Parra-Medina, Juan C. Mejia-Henao, Patricia López-Correa, Sandra Diaz, Jone Garai, Jovanny Zabaleta, Liliana López-Kleine, Alba L. Combita. Integrative transcriptomic analysis and cohort validation identify key genes in chemotherapy treatment response in Latino breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-40.