Abstract B080: Assessment of the molecular mechanisms of a protective variant for breast cancer in Latinas
Authors: Zavala Valentina A. , Vidaurre Tatiana , Marker Katie , Casavilca Sandro , Tamayo Lizeth , Castañeda Carlos , Vásquez Jeannie , Valencia Fernando , Morante Zaida , Calderon M. , Abugattas J. , Gomez H. , Fuentes H. , Monge-Pimentel C. , Neciosup Silvia , Zabaleta Jovanny , Fejerman Laura 
Published: September 2020

Abstract
The incidence of breast cancer is lower in women of Latin American origin in the U.S. compared to European American and African American women. Among Latinas, the rs140068132A&gt;G variant, which is common in women with IAA, has been associated to a lower risk of breast cancer. The frequency of the G allele is 0% for non-Latinos while 12% in Latinos, being highest in the Peruvian population (23%). This variant is located on chromosome 6 near the Estrogen Receptor 1 gene (ESR1) and even though experimental evidence suggests that this variant might be functional, the molecular mechanisms that explain its protective effect are unknown. We hypothesize that the rs140068132-G variant decreases ESR1 expression, which affects the expression or function of genes involved in associated pathways. We aim to test the association of the rs140068132 variant and gene expression in breast cancer tumors from patients with high IAA. We collected 47 breast tumors and blood samples from the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru. These patients were genotyped for IAA estimation and determination of the rs140068132 genotype. Total RNA was extracted from tumor samples and used for a paired-end sequencing (2 × 75bp paired-end,100 million reads per sample) in the Illumina NextSeq500. Differential gene expression between genotypes was performed by DEseq2 R package and statistical significance was determined using FDR&lt;0.05 for samples with at least log2 1.5-fold change. Differentially expressed isoforms were detected by EBseq R package using FDR&lt;0.05. Tumor intrinsic subtypes were obtained using PAM50 as implemented in the genefu R package. The average IAA for the 47 Peruvian patients was 77% (SD=0.17). Twenty-seven patients were homozygous AA, 19 heterozygous AG and 1 GG for the rs140068132 variant. According to PAM50 classification, 10 tumors were Luminal A, 12 Luminal B, 15 HER2+ and 10 Basal. Among luminal tumors there was a suggestive trend towards lower expression of the ESR1 gene in patients carrying the protective allele (p=0.16). Including all subtypes, 27 genes were differentially expressed according to the rs140068132 genotype. Four of these genes are ER dependent or associated with ER status. The expression of the top gene, which is a transcriptional target of ER, is lost in patients with the protective allele. This association is mainly driven by its expression in luminal tumors and remained significant after adjusting for IAA. ESR1 isoforms were not differentially expressed by genotype, however significant differences were detected in the expression of isoforms for 115 genes, of which 18% have been reported to be transcriptional targets of ER or functionally related. Our preliminary results suggest that the rs140068132 variant decreases ER expression and affects the expression of functionally associated genes in luminal tumors. Further allele-specific expression analysis will elucidate if this variant is part of a cis-regulatory module.
Note: This abstract was not presented at the conference.
Citation Format: Valentina A. Zavala, Tatiana Vidaurre, Katie Marker, Sandro Casavilca, Lizeth Tamayo, Carlos Castañeda, Jeannie Vásquez, Fernando Valencia, Zaida Morante, M. Calderon, J. Abugattas, H. Gomez, H. Fuentes, C. Monge-Pimentel, Silvia Neciosup, Jovanny Zabaleta, Laura Fejerman. Assessment of the molecular mechanisms of a protective variant for breast cancer in Latinas [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr B080.