Abstract 993: Exploring the tumor suppressive role of LRIG1 in breast cancer disparities

Abstract Background: Breast cancer (BC) is the second most common cause of cancer-related death among women in the United States (U.S.). Despite a lower incidence rate, African American (AA) women suffer a persistent 40% higher BC mortality rate compared to European American (EA) women. The aggressive breast tumor biology experienced by AA women is rooted in both genetic and environmental causes and we are interested in investigating the social and molecular drivers influencing this complex health disparities problem. In our recent study using breast tumor DNA extracted from a diverse cohort of women from the Baltimore, Maryland area, we performed a methylation array to compare differences in neighborhood conditions to DNA methylation levels, including differences by race. From this analysis, we identified the tumor suppressor LRIG1 as significantly hypomethylated among AA patients with deprived neighborhood conditions. This gene encodes a transmembrane protein predicted to downregulate growth receptor signaling, with lower expression associated with decreased survival. These findings were unique to the tumor, which points to epigenetic changes to LRIG1 impacting tumor mutational burden, gene expression, and protein expression. Objective: The goal of this project is to assess the relationship between LRIG1 genetic variants and molecular, clinical, and sociodemographic data in a diverse historical cohort of BC cases and controls. We hypothesize that LRIG1 single nucleotide polymorphism (SNP) genotypes will be more strongly linked to increased BC susceptibility and adverse clinical outcomes in AA women compared to EA women. Methods: We obtained breast tissue DNA from our previous cohort, including 216 breast tumors (AA=135, EA=81) and 203 normal breast tissues (AA=115, EA=88). We conducted DNA genotyping on a clinically relevant ancestrally informative SNP of LRIG1 (rs2306272) using PCR amplification and detection by fluorescent reporters. We analyzed the associations between LRIG1 rs2306272 SNP genotypes and race, BC risk factors, and clinical data. Results: Our experimental minor allele frequencies were in line with what is expected for AA and EA populations for this LRIG1 SNP. Chi-square tests showed associations between the LRIG1 rs2306272 genotypes and self-reported race (p<0.0001), family history of BC (p=0.0037), and breast tumor grade (p=0.0768). Conclusions: This is the first data showing clinical significance between rs2306272, self-reported race, and BC characteristics in patient samples. We will continue analyzing the rs2306272 SNP genotypes in our DNA cohort in addition to a second ancestrally relevant LRIG1 SNP, rs1403626. Furthermore, using matched methylation data, we will perform analyses to identify differentially methylated CpG sites for LRIG1 that may be influenced by genetic ancestry. Our investigations will further interrogate the impact of LRIG1 regulation in differential BC risk and outcomes. Citation Format: Angel Hokulani Pajimola, Brittany Jenkins-Lord. Exploring the tumor suppressive role of LRIG1 in breast cancer disparities [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 993.