Abstract C082: Breast cancer risk in Hispanic/Latina women and the 6q25 chromosomal region: Fine mapping and eQTL identification
Authors: Zavala Valentina A. , Huang Xiaosong , Casavilca-Zambrano Sandro , Navarro-Vásquez Jeannie , Castañeda Carlos A. , Valencia Guillermo , Morante Zaida , Calderon Monica , Abugattas Julio E. , Gómez Henry , Fuentes Hugo A. , Liendo-Picoaga Ruddy , Cotrina Jose M. , Neciosup Silvia , Roque Katia , Vásquez Jule , MAs Luis , Gálvez-Nino Marco , Sánchez Sixto E. , Williams Michelle A. , Ziv Elad , Zabaleta Jovanny , Gelaye Bizu , Vidaurre Tatiana Vidaurre , Fejerman Laura 
Published: January 2023

Abstract
Breast cancer subtype distribution differs between populations with dissimilar genetic ancestry backgrounds. Several breast cancer risk single nucleotide polymorphisms (SNPs) were discovered in individuals of European and Asian origin. Hispanic/Latina women remain underrepresented in studies and public databases. The 6q25 locus contains multiple breast cancer risk-associated SNPs. Some SNPs within this region have been associated with the expression of genes (eQTLs), such as the Estrogen Receptor 1 gene (ESR1). Two breast cancer genetic association studies in Hispanics/Latinas identified two SNPs (rs140068132 and rs3778609), near ESR1, that correlate with Indigenous American ancestry and reduce the odds of breast cancer, especially for Estrogen Receptor-negative (ER-) disease. The underrepresentation of Latin American populations in public databases has hindered the study of the mechanisms by which these SNPs confer a protective effect. We integrated genetic and transcriptomic data from breast cancer patients with high Indigenous American ancestry to test the association between the protective variants in the 6q25 region and tumor gene expression. Breast cancer patients were recruited at the National Cancer Institute in Peru to be part of The Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC, N=1809). Healthy women from a pregnancy outcomes study in Peru were included as controls (N=3334). Genome-wide genotype data were available and missing genotypes were imputed using the TOPMED Imputation Server to perform fine-mapping within the 6q25 locus. Logistic regression was used to test the association between each SNP and breast cancer risk. We exome-sequenced 155 breast tumors of these patients. Transcripts per million counts and imputed genotypes within the 6q25 region were used for eQTL analysis. Colocalization was performed using summary statistics from the fine-mapping and eQTL analysis, including SNPs with minor allele frequency &gt;5%. Only two SNPs, rs140068132 and rs851984 were independently associated with breast cancer risk, as we previously reported. eQTL signals colocalized with the subregion in 6q25 that contains these breast cancer-associated SNPs. Within this subregion, the gene with more eQTLs using a nominal p-value of &lt;=0.01 was MTHFD1L (136 eQTLs), followed by ESR1 (58) and CCDC170 (32). Colocalization showed that MTHFD1L and ESR1 eQTLs were more likely to overlap with breast cancer risk SNPs, including rs140068132. The protective rs140068132-G variant was associated with lower expression of MTHFD1L. MTHFD1L has been found deregulated in breast cancer and higher expression is associated with poor prognosis. Our preliminary results suggest that the rs140068132-G variant in the 6q25 region identified in Hispanic/Latina women might exert its protective effect through the downregulation of MTHFD1L. Analyses with additional samples will allow us to confirm this result and further explore the functional implications of the rs140068132 variant.
Citation Format: Valentina A. Zavala, Xiaosong Huang, Sandro Casavilca-Zambrano, Jeannie Navarro-Vásquez, Carlos A. Castañeda, Guillermo Valencia, Zaida Morante, Monica Calderon, Julio E. Abugattas, Henry Gómez, Hugo A. Fuentes, Ruddy Liendo-Picoaga, Jose M. Cotrina, Silvia Neciosup, Katia Roque, Jule Vásquez, Luis MAs, Marco Gálvez-Nino, Sixto E. Sánchez, Michelle A. Williams, Elad Ziv, Jovanny Zabaleta, Bizu Gelaye, Tatiana Vidaurre Vidaurre, Laura Fejerman. Breast cancer risk in Hispanic/Latina women and the 6q25 chromosomal region: Fine mapping and eQTL identification [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C082.