血统驱动的乳腺癌基因转录调控:哥伦比亚人群中通过顺式和反式eQTL的调控

Introduction: Significant disparities in breast cancer phenotypes have been observed across population groups. Latina women show a higher prevalence of aggressive tumor subtypes and increased mortality compared to non-Hispanic White women. Genetic ancestry differences have been proposed as a potential mechanism influencing baseline tissue biology and tumor behavior. Specifically, ancestry-specific expression quantitative trait loci (eQTLs) may mediate these effects. This study aimed to identify ancestry-specific eQTLs associated with clinically relevant breast cancer genes. Methods: RNA-seq data from tumor and adjacent non-tumoral breast tissue of 183 patients from the NCI of Colombia were analyzed to obtain genotypes using a GATK4 variant-calling pipeline and the TOPMed imputation server. Normalized gene expression matrices were generated with STAR and DESeq2, and eQTLs were identified using MatrixEQTL in R. Local ancestry was inferred with RFMix to filter eQTLs within regions enriched for specific ancestries. Results: In non-tumor breast tissue, 234 Indigenous ancestry-specific cis-eQTLs associated with 18 eGenes were identified, with MACC1 being the only COSMIC-listed gene. Additionally, 1,371 Indigenous ancestry-specific trans-eQTLs were linked to 1,001 eGenes. After prioritization, 164 significant associations were identified, involving 31 COSMIC eGenes regulated by 76 trans-eQTLs. These included oncogenes such as ERBB2, CDK6, FGFR4, LASP1, and MDM2, and tumor suppressor genes like BRCA2, RB1, CDH1, and ATM. Conversely, 26 European ancestry-specific cis-eQTLs associated with four proximal eGenes (ST7L, SLC35E2A, PRPF38A, and ODR4) were identified. Moreover, 160 European ancestry-specific trans-eQTLs were linked to 194 eGenes showing enrichment in membrane-related processes, including oncogenes such as PRKCB and JAK3, and tumor suppressors like ATM and RB1. Due to low African ancestry representation among Colombian patients, this component was not analyzed. For Indigenous ancestry-specific eQTLs, trans associations between 12 variants located in 5q13.3 and tumor-relevant genes in 19q13.1, 11p15.5, and 1p34.2 were validated in cancer tissue, including MUC6, MED29, and PDCD5. Conclusion: These findings suggest that in non-tumoral breast tissue, transcriptional regulation can be mediated by Indigenous and European ancestry-specific variants influencing the expression of genes with key roles in tumor-related pathways. Validation analyses in tumor tissue indicated that only a subset of Indigenous ancestry-specific eQTLs may retain trans-regulatory effects and contribute to breast cancer biology.