Abstract 4615: Admixture mapping and gene expression analysis to identify candidate genes associated with HER2 positive breast cancer in Latinas
Authors: Zavala Valentina , Marker Katie M. , Vidaurre Tatiana , Navarro-Vasquez Jeannie , Casavilca Sandro , Calderon Mónica , Abugattas Julio , Gómez Henry , Fuentes Hugo , Liendo-Picoaga Ruddy , Cotrina Jose M. , Neciosup Silvia P. , Castaneda Carlos A. , Morante Zaida , Valencia Fernando , Serrano-Gomez Silvia J. , Zabaleta Jovanny , Fejerman Laura 
Published: September 2020

Abstract
The incidence of Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancer is higher in Latinas, both in the U.S. and in Latin America. Preliminary analyses of the Peruvian Genetics and Genomics of Breast Cancer (PEGEN-BC) study data set showed a strong association between the Indigenous American (IA) component of ancestry and HER2 status independently of stage at diagnosis and other factors. The aim of this study was to identify genetic loci associated with genetic ancestry and HER2+ breast cancer in patients with high IA ancestry. To achieve this aim we used admixture mapping and gene-expression guided fine mapping.
Breast cancer patients were recruited at the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru. A total of 1,850 patients have been recruited to date. DNA samples are currently available for a total of 1,380 patients. Genome wide genotypes were obtained with the Affymetrix Precision Medicine Research Array. After quality control, genome wide genotype data was available for 1,312 patients. After LD pruning and exclusion of SNPs with minor allele frequency &lt;0.05, we estimated global ancestry with the program ADMIXTURE and locus-specific ancestry using RFMix. Tumor subtypes were classified using immunohistochemistry markers for estrogen, progesterone and HER2 receptors. Admixture mapping was conducted using logistic regression models. The outcome variable was HER2 status (HER2+ =1, HER2- =0). Global Individual IA ancestry and age at diagnosis were included as covariates. For transcriptomic analysis within regions of interest we used exome sequencing data (Illumina NextSeq500 system) for total RNA extracted from 79 FFPE tumor tissues from the same cohort. Genes within regions with suggestive admixture mapping signals were further analyzed by comparing normalized RNA read counts by HER2+ status using the DEseq2 R package.
Admixture mapping analysis revealed two regions associated with IA ancestry in two chromosomal regions: 2q11-2q12 (OR=0.6, p=0.00009) and 3p14 (OR=1.5, p= 0.0004). Of the 44 genes within the 2q region, TGFBRAP1, member of the heat shock protein 90 family, was the only gene with suggestive differential expression by HER2 status (p=0.032). Of the 28 genes within the 3p14 region, we found significant differential expression for FLNB (lower expression in HER2+ tumours, 5%FDR= 0.03), which has been shown to supress tumour growth and metastasis.
Combining admixture mapping and transcriptomics is a promising approach to discover candidate genes associated with subtype-specific breast cancer risk. We are currently working to replicate suggestive findings and expand our sample size to increase power.
Citation Format: Valentina Zavala, Katie M. Marker, Tatiana Vidaurre, Jeannie Navarro-Vasquez, Sandro Casavilca, Mónica Calderon, Julio Abugattas, Henry Gómez, Hugo Fuentes, Ruddy Liendo-Picoaga, Jose M. Cotrina, Silvia P. Neciosup, Carlos A. Castaneda, Zaida Morante, Fernando Valencia, Silvia J. Serrano-Gomez, Jovanny Zabaleta, Laura Fejerman. Admixture mapping and gene expression analysis to identify candidate genes associated with HER2 positive breast cancer in Latinas [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4615.