Abstract 4084: Variants of <i>PEAK1, SLC2A4RG, PALB2, and XIRP2</i>: exploring their relationship with genetic ancestry in breast cancer patients across diverse racial/ethnic groups
Authors: Grace Enid Velez Crespo, Julie Dutil, Vivian Colón López
Journal: Cancer Research (2025)

Introduction: Breast cancer (BC) is the second leading cause of cancer death worldwide, affecting 1 in 8 women. Disparities in BC burden have been observed across different racial and ethnic groups, with Black or African American women experiencing higher mortality rates. Interestingly, although Hispanics/Latinas have 30% lower incidence rates than non-Hispanics, their tumors tend to be larger, more advanced, and more aggressive at diagnosis. While social determinants of health are involved in driving these disparities, biological factors are also at play. Although many advances have been made in BC research, there is still a lack of genetic studies with representation from diverse populations. Objective: We aim to study the role of inherited variants of four established drivers of BC (PEAK1, PALB2, XIRP2, SLC2A4RG) that show differences in frequencies among diverse populations with the risk of developing BC. Methods: Using the All of Us (AoU) research hub electronic health record (EHR), we identified BC cases and a control group comprised of participants who have not been diagnosed with any type of cancer. As an inclusion criterion for both groups, we selected participants with genomic information (Global Diversity Array) and ages from 20 to 80+. To identify variants in our genes of interest we used gene position boundaries (+/- 5,000 bp) and a minor allele frequency (MAF) threshold of 0.01. Chi-squares and general linear models (GLM) were performed to determine the association of candidate variants with BC risk. In addition, we used ancestry proportion estimates to evaluate the impact of genetic ancestry on associations. Statistical analyses and graphs were prepared in the R studio environment within the AoU platform. Genetic data access and wrangling were performed in the Jupyter Notebook environment using the Python language and PLINK software. Results: Our cohort includes 6,049 cases of BC, from which we identified 13% of Hispanics and 13% of Blacks or African Americans, respectively. Our preliminary results reveal a good representation of the admixture characterizing Hispanics, and Blacks or African Americans in the study cohort. We also identified 12 variants for PALB2, 27 for PEAK1, 2 for SLC2A4RG, and 99 for XIRP2. Significant associations with BC risk were observed for all 4 genes of interest (3 variants of PALB2,15 of PEAK1, 1 of SLC2A4RG, and 56 of XIRP2). Work is underway to measure the impact of genetic ancestry on these associations. Conclusion: These findings underscore the crucial role of genetic studies in shaping BC risk, emphasizing the importance of genetic-informed research to improve personalized medicine strategies. While many genes are involved in BC risk and development there remains a need to understand genetic variability across different populations to develop better diagnostic tools. Citation Format: Grace Enid Velez Crespo, Julie Dutil, Vivian Colón López. Variants of PEAK1, SLC2A4RG, PALB2, and XIRP2: exploring their relationship with genetic ancestry in breast cancer patients across diverse racial/ethnic groups [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4084.