Abstract 5237: Regulation of genes located in 6q25 by an Indigenous American genetic variant in breast cancer patients from Peru
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 , Liendo-Picoaga Ruddy , Cotrina Jose M. , Roque Katia , Vásquez Jule , Mas Luis , Gálvez-Nino Marco , Zabaleta Jovanny , Vidaurre Tatiana , Fejerman Laura 
Published: April 2023

Abstract
Genetic studies in women of Hispanic/Latina origin identified a single nucleotide polymorphism (SNP) in the 6q25 region, rs140068132, that correlates with Indigenous American (IA) ancestry and is protective against BC. The underrepresentation of Latin American populations in public databases has hindered the study of the mechanisms by which this SNP confers a protective effect. We aimed to identify IA germline variants associated with BC risk and to test their association with tumor gene expression in this region.
We performed a case-control fine-mapping analysis in the 6q25 region. BC patients part of the PEGEN-BC Study (N=1809) were included as cases and women from a pregnancy outcomes study in Peru as controls (N=3334). Genome-wide genotype data were available and missing genotypes were imputed using the TOPMED Imputation Server. Logistic regression was used to test the association between each SNP and BC risk. We exome-sequenced 247 breast tumors of PEGEN-BC patients. Tumor subtype was assigned by the pam50 method. We excluded patients diagnosed with stage IV disease, with tumors classified as normal-like or as uncertain, and carriers of the GG genotype for rs140068132, leaving 242 samples. Association between rs140068132 and gene expression of genes in the 6q25 region was tested adjusting by age at diagnosis and IA ancestry.
The strongest signal corresponded to rs140068132 (odds ratio (OR)=0.53, p=1.9e-21). The model adjusted by rs140068132 revealed three additional independent variants that correlate with Indigenous American ancestry: rs184135739 (OR=0.8, p=0.006), rs141057867 (OR=0.87, p=0.006) and rs140125124 (OR=1.23, p=0.015). Gene expression analysis stratified by subtype revealed that among HER2+ tumors (N=63), rs140068132 was associated with ARMT1 (fold change comparing AA to AG (FC)=1.6, p&lt;0.01), CCDC170 (FC=1.8, p&lt;0.01), MTHFD1L (FC=0.7, p&lt;0.01) and RMND1 (FC=1.4, p=0.013). Among Luminal-B (N=68) tumors, there was an association with ARMT1 (FC= 1.9, p=0.001), ESR1 (FC=1.4, p=0.04) and MTHFD1L (FC= 0.8, p=0.02). Only ESR1 was associated with the SNP (FC= 0.5, p= 0.03) among basal tumors (N=56). No association was identified among Luminal-A tumors (N=55). rs141057867 showed evidence of cis-association with CLDN20 (FC=1.4, p=0.014) among HER2+ subtypes and rs184135739 with ZC3H12D (FC=2.1, p=0.02) and SUMO4 (FC=1.8, p=0.023) among Lumina-A tumors.
Two of the three novel IA SNPs are protective against BC and show association with gene expression. The rs140068132-G variant regulates the expression of genes in the 6q25 region in a subtype-specific manner. A possible mechanism explaining the protective effect of the rs140068132 polymorphism might be linked to the lower expression of MTHFD1L among G-allele carriers in some subtypes. This gene is deregulated in cancer and its expression is negatively associated with cancer survival, including BC.
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 Fuentes, Ruddy Liendo-Picoaga, Jose M. Cotrina, Katia Roque, Jule Vásquez, Luis Mas, Marco Gálvez-Nino, Jovanny Zabaleta, Tatiana Vidaurre, Laura Fejerman. Regulation of genes located in 6q25 by an Indigenous American genetic variant in breast cancer patients from Peru. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5237.