Abstract 1006: Local genetic ancestry among breast cancer rare mutation carriers from Lima, Peru
Authors: Luqi Wang, Xiaosong Huang, Paul Lott, Elad Ziv, Susan L. Neuhausen, Tatiana Vidaurre, Laura Fejerman
Journal: Cancer Research (2025)

Genetic predisposition to breast cancer is understudied in populations of high Indigenous American (IA) genetic ancestry. This gap in knowledge can lead to lack of equity in risk assessment and prediction. This study aimed to identify pathogenic/likely pathogenic (P/LP) variants and variants of unknown significance (VUS) in known cancer susceptibility genes in women with breast cancer from Lima, Peru, and test their ancestry-specificity. Whole exome sequencing was performed on 40 susceptibility genes in 1,364 women from the Peruvian Genomics of Breast Cancer (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 using the program Admixture (v1.3.0, k = 4), and local ancestry inference was performed with RFMix v2 to determine the ancestral origins of specific chromosomal segments at each locus of identified variants. Among the 1,364 individuals analyzed, 135 (9.90%) carried P/LP variants, including 128 with one variant and 7 with two. The most frequently affected genes were BRCA1 (29/142, 20.42%), BRCA2 (24/142, 16.90%), ATM (20/142, 14.08%), PALB2 (18/142, 12.68%), and CHEK2 (14/142, 9.86%). VUSs were identified in 679 individuals (49.78%), with 503 carrying one VUS and 176 carrying multiple VUSs (2 to 5). The most commonly affected genes with VUSs were BARD1 (189/888, 28.28%), NF1 (96/888, 10.81%), ATM (67/888, 7.55%), and BRIP1 (43/888, 4.84%). Seven P/LP variants showed significant differences between the observed and expected ancestry of haplotypes when comparing IA to all other ancestries, with four of these variants located in BRCA1. Additionally, 36 VUSs exhibited significant differences in ancestry distribution, with CDH1 harboring the most variants (5), followed by CHEK2 and MSH6 (3 each). For all P/LP variants with a significant difference between the observed and expected haplotypes of IA and other ancestries, the observed frequency of IA haplotypes was lower than expected, whereas the observed frequency of haplotypes from other ancestries was higher than expected. A similar trend was observed for VUSs, except for three mutations where the observed IA haplotype frequency was higher than expected and the frequency of other haplotypes was lower than expected. Our findings suggest that population admixture influences the distribution of P/LP variants and VUSs in Latin American populations. The occurrence of breast cancer in these populations may be partly influenced by the infusion of non-IA haplotypes harboring risk associated variants to the local genomes. Citation Format: Luqi Wang, Xiaosong Huang, Paul Lott, Elad Ziv, Susan L. Neuhausen, Tatiana Vidaurre, Laura Fejerman. Local genetic ancestry among breast cancer rare mutation carriers 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 1006.