Abstract 5235: Transcriptome-wide study of tumor samples from Peruvian women identifies dysregulated pathways in luminal tumors typically associated with more aggressive disease
Authors: Xu Chenghuiyun , Zavala-Cordero Valentina A. , Huang Xiaosong , Rocke David M. , Casavilca-Zambrano Sandro , Navarro-Vásquez Jeannie M. , Castañeda Carlos A. , Valencia Guillermo , Morante Zaida , Calderón Monica , Abugattas Julio E. , Gómez Henry , Fuentes Hugo A. , Liendo-Picoaga Ruddy , Cotrina Jose M. , Neciosup Silvia P. , Roque Katia , Vásquez Jule , Mas Luis , Gálvez-Nino Marco , Zabaleta Jovanny , Vidaurre Tatiana , Fejerman Laura 
Published: April 2023

Abstract
Purpose: Breast cancer incidence and outcomes differ by US census racial/ethnic category. Since large-scale genetic studies of human disease are predominately focused on populations of European ancestry, little is known about breast cancer molecular biology in Hispanic/Latinos which can widen cancer health disparities due to suboptimal translation of discoveries into clinical practice or public health policy. We aim to describe relevant pathways in breast cancer subtype differentiation in breast cancer patients from Peru.
Patients and Methods: Formalin fixed paraffin embedded tumor tissues samples were whole exome sequenced for a total of 271 patients, recruited by the Peruvian Breast Cancer Genomics Study (PEGEN-BC) from the Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima, Peru. Quality control was conducted to remove genes with low counts. Intrinsic tumor subtypes were classified using the PAM50 method using genefu package in R. Differential gene expression between subtypes 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. Pathway analyses were performed to explore differences among the subtypes using GSEA with fgsea package in R. Indigenous American ancestry proportions for participants were estimated using germline genome-wide genotypes and the program Admixture.
Results: The mean age of patients was 50 and the median Indigenous American ancestry was 79%. PAM50 classification of the sequenced samples defined 20.2% of tumors as LumA, 27.9% as LumB, 27.1% as HER2, 22.5% as Basal and 2.3% as Normal. Transcriptomic pathway analysis showed that most of the significantly changed pathways were similar to those previously described such as upregulation of high proliferation pathways in LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Top 10 significantly changed pathways show some unique findings: the epithelial-mesenchymal-transition (EMT) pathway is downregulated in Basal, comparing to LumA and HER2 tumors, which is unexpected given that the EMT is associated with stem cell features and poor outcomes. The E2F-targets pathway is upregulated in LumA when comparing to HER2 tumors, but downregulated when compared to Basal tumors.
Conclusions: We identified novel pathways associated with breast cancer subtypes in individuals with high Indigenous American ancestry from Peru and are working on testing the robustness of these findings. If our findings are confirmed, results would suggest a more aggressive profile of Luminal subtypes in the studied samples from Peru, with implications for treatment and survival.
Citation Format: Chenghuiyun Xu, Valentina A. Zavala-Cordero, Xiaosong Huang, David M. Rocke, Sandro Casavilca-Zambrano, Jeannie M. Navarro-Vásquez, Carlos A. Castañeda, Guillermo Valencia, Zaida Morante, Monica Calderón, Julio E. Abugattas, Henry Gómez, Hugo A. Fuentes, Ruddy Liendo-Picoaga, Jose M. Cotrina, Silvia P. Neciosup, Katia Roque, Jule Vásquez, Luis Mas, Marco Gálvez-Nino, Jovanny Zabaleta, Tatiana Vidaurre, Laura Fejerman. Transcriptome-wide study of tumor samples from Peruvian women identifies dysregulated pathways in luminal tumors typically associated with more aggressive disease. [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 5235.