Abstract B091: Genome and Transcriptome-Wide Association Studies of HER2-positive breast cancer in Hispanic/Latina women in the United States and women in Latin America

Abstract

Breast cancer is the most common cancer among women worldwide. Genome-Wide Association Studies (GWAS) have identified genetic variants associated with overall and estrogen receptor-specific breast cancer risk. However, genetic drivers of human epidermal growth factor receptor 2-positive (HER2+) disease remain poorly understood, particularly among United States (US) Hispanic/Latina women and women in Latin America (henceforth referred as H/L), who are at high risk of HER2+ disease. We conducted the first GWAS and fine-mapping of HER2+ breast cancer in H/L women to identify HER2-specific genetic variants. We leveraged data from eight studies comprising participants from seven Latin American countries and the US to conduct a HER2+ GWAS. We harmonized individual-level genotyping data (5,379 cases and 10,650 controls) and imputed to TopMed (r2@1.0.0). HER2+ status was defined as cases with 3+ staining by immunohistochemistry (IHC) or with gene amplification testing following a 2+ IHC result. We performed GWAS (9,381,563 variants) within each study in PLINK v1.9. Results were meta-analyzed using a fixed-effects model in METAL. We validated GWAS results in an external dataset of 68 HER2+ cases and 6,192 controls. We further analyzed SNPs distinctly associated with HER2+ disease in expression quantitative trait locus (eQTL), colocalization, and Transcriptome-Wide Association (TWAS) analyses using breast RNA-seq data to identify candidate genes driving our GWAS findings. We identified 202 genome-wide significant (p < 5e-8) and 238 suggestive (p < 1e-7) SNPs associated with HER2+ breast cancer. Of these associations, 138 were preferentially associated with HER2+ disease (p-heterogeneity <0.05). Clumping analyses highlighted three regions. Two lead SNPs (rs140068132 and rs41289379) mapped to the 6q25 region, which we previously associated with breast cancer risk in H/L women. In addition, rs12484512 at 22q12.3 showed a 49% per allele increase in the odds of HER2+ breast cancer (OR =1.49; 95% CI = 1.29-1.73; p = 8.6e-8). We are the first to report rs12484512 as associated with subtype-specific breast cancer risk. Our replication result conserved magnitude and directionality (OR = 1.48; 95% CI = 0.88-2.51). EQTL analysis suggested that rs12484512 regulates expression of the solute carrier family 5 member 4 (SLC5A4) gene. Colocalization analyses revealed a high posterior probability (PP = 0.76) that a single common variant within ±100 kb of rs12484512 could cause the GWAS and eQTL signal. TWAS demonstrated a genome wide significant association between SLC5A4 and HER2+ disease (p = 2.6e-5) but not HER2- disease (p=0.17). We present the first GWAS and fine-mapping study of HER2+ breast cancer in H/L women. We identified three subtype-specific variants, including the novel rs12484512, which highlights SLC5A4 as a potential contributor to HER2+ disease. Joel Sanchez Mendez, Xiaosong Huang, Paul C. Lott, Gloria I. Edejer, Tatiana Vidaurre, Sandro Casavilca-Zambrano, Jeannie Navarro-Vásquez, Jovanny Zabaleta, Christopher Haiman, Esther M. John, Mei-Chee Tai, Elad Ziv, Luis Carvajal-Carmona, Susan Neuhausen, Andrea Llera, Bizu Gelaye, Weang-Kee Ho, Laura Morelli, Maria C. Dalmasso, Luis I. Brusco, Alfredo Ramirez, Nora Artagaveytia, Eliana Abdelhay, Adrián Daneri-Navarro, Osvaldo Podhajcer, Bettina Müller, Javier Retamales, Carlos Velázquez, Laura Fejerman. Genome and Transcriptome-Wide Association Studies of HER2-positive breast cancer in Hispanic/Latina women in the United States and women in Latin America [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr B091.