Abstract 7401: Ancestral impact on family history of breast cancer and high-risk mutations among women from Lima, Peru

Abstract Family history of breast cancer (FHBC) and carrying a high penetrance mutation are strong predictors of breast cancer risk. Breast cancer associated genes have been characterized and pathogenic/likely pathogenic variants (P/LP) identified in different populations. However, characterization of family history and high-risk mutations within the Indigenous American genomic background is still understudied. The Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) is a case cohort of ∼2, 000 breast cancer patients from Lima, Peru. Demographic, and clinical information was collected from all participants. Targeted sequencing of 40 susceptibility genes was performed in 1, 364 women from the PEGEN-BC study. Variants were called by GATK HaplotypeCaller and annotated by ANNOVAR with the ClinVar database (v20240611). Global ancestry proportions (Indigenous American, European, African, and East Asian) were estimated for another project using the program Admixture (v1.3.0, k = 4). Mean differences of proportions between groups based on FHBC (1st to 3rd degree relatives) were tested using t-test and chi-squared test respectively. The association between FHBC and P/LP mutation status was tested using a logistic regression model stratified by ancestry (dichotomized: above and below the median European genetic ancestry), including age at diagnosis as a covariate. The average age of the study participants was similar between those with FHBC (49.6 years, standard deviation (sd)=11.1) and those without FHBC (49.9 years, sd=11.1). Average Indigenous American ancestry was 77% (sd=16) among participants with FHBC and 70% (sd=19) among those without (p<0.0001) and European ancestry was 21% (14) and 17% (11) respectively (p<0.0001). There were 62 (4%) carriers of P/LP variants among individuals without FHBC and 44 (10%) among those with FHBC (p<0.0001). Among participants with European ancestry below the median (<18%), the association between FHBC and P/LP status was not significant. However, among women with European ancestry above the median, the odds of carrying a P/LP variant if they had FHBC were 4.1 times (95%CI 2.16-7.77) higher than if they did not have FHBC (p<0.0001). These results may reflect disparities in patients knowledge of family history by ancestry, which correlates with factors such as socioeconomic status and level of education, as well as difference in the proportion of genetic variants contributing to familial aggregation of risk in different genetic ancestry backgrounds. Citation Format: Amanda F. Corpuz, Xiaosong Huang, Elad Ziv, Susan L. Neuhausen, Laura Fejerman, Tatiana Vidaurre. Ancestral impact on family history of breast cancer and high-risk mutations among women from Lima, Peru [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 7401.