Abstract PR015: Evaluation of genetic ancestry as a covariable in gene expression analysis for chemotherapy response in Colombian breast cancer women
Authors: Guevara-Nieto Hedda Michelle , Parra-Medina Rafael Santiago , Henao Juan Carlos Mejia , Garai Jone , Zabaleta Jovanny , Lopez-Kleine Liliana , Combita Alba Lucia 
Published: December 2023

Breast cancer (BC) is a public health concern in Colombia that presents admixture of indigenous American (IA), European and African American (AA) ancestries. These differences could be affecting prognosis and neoadjuvant chemotherapy (NAC) response. This study aims to identify gene expression profiles associated with non-response to NAC in Colombian women diagnosed with invasive BC, including genetic ancestry as a covariable. An integrative transcriptome analysis was conducted on 87 samples of BC female patients belonging to Colombian NCI population and candidates for NAC. Patients either responded or did not respond to NAC. To estimate genetic ancestry, genotyping of 106 ancestry informative markers was performed from non-tumoral DNA. Molecular intrinsic subtypes were classified into four groups: All luminal, LuminalBHer2+/-, LuminalBHer2+ & HER2 enriched, and TNBC+Her2-enriched. Two analyses were performed: differential gene expression comparing RNA-Seq data from different molecular subtype grouping, and enrichment analysis comparing baseline vs follow-up samples from non-responders, as well as baseline samples from non-responders vs responders. All analyses were performed comparing ancestry as a covariable in differential expression model. Responders and nonresponders showed distinct gene signatures in all categories. Sample distribution shown 8% AA, 59% IA and 32% European ancestry. Subtype grouping with ancestry as a covariable found 4 differential expressed genes (DEG) across nonresponders and baseline analyses for all samples (CPNE9, GTSF1, NORAD, PPP1R35) associated with cell differentiation pathways. 1 luminal DEG (CGB3), 20 DEG for LuminalBHer2+/-, 202 DEGs for LuminalBHer2+ & HER2 enriched, and 7 DEGs for TNBC+Her2-enriched (AKR1E2, CEACAM6, IRS4,LIGO, MICU2, NPAS2 and STATH). Among these groups, enrichment pathways included positive regulation of cell migration, cell-cell adhesion, cellular response to hormone stimulus. We found a notable increase in differential gene expression as the proportion of IA genetic ancestry becomes greater. Genetic ancestry effect might indicate a connection between heterozygosity and genetic variance. We contrasted our results to other studies performed in other Latin American cohorts. Overall, our findings reveal a significant gene signature between responders and non-responders across subtype grouping. Our previous findings identified different sets of genes among this subtype grouping suggesting that genetic ancestry affects the gene signatures and as it's already reported, treatment response. Our results emphasizes the significance of assessing gene expression in heterogeneous populations with diverse ancestral backgrounds like Colombia, as a means to facilitate novel findings and alleviate disparities. Overexpression of these genes provides a potential to predict therapy response, alerting clinicians about patients who may not benefit from NAC.

Citation Format: Hedda Michelle Guevara-Nieto, Rafael Santiago Parra-Medina, Juan Carlos Mejia Henao, Jone Garai, Jovanny Zabaleta, Liliana Lopez-Kleine, Alba Lucia Combita. Evaluation of genetic ancestry as a covariable in gene expression analysis for chemotherapy response in Colombian breast cancer women [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr PR015.