Abstract PS3-03-10: Whole exome sequencing reveals germline pathogenic variant landscape in multi-center Taiwanese breast cancer patient cohort at moderate to high hereditary genetic risks

Abstract Background: The incidence of breast cancer in East Asia has been steadily increasing, with cases presenting approximately a decade earlier than those observed in Western populations. This study utilizes whole-exome sequencing (WES) to investigate the prevalence of hereditary germline pathogenic or likely pathogenic variants (PV) in Taiwanese breast cancer patients identified as having moderate to high hereditary genetic risk. Method: Breast cancer patients with age at diagnosis less than 40 years, positive familial cancer history, bilateral cancer or multiple cancers, and triple negative breast cancer (TNBC) were enrolled from the Linkou, Taipei, and Kaohsiung hospital branches of Chang Gung Medical Foundation. BRCA1/2 likelihood was evaluated with the pathology-adjusted Manchester Scoring System (MSS3). (1) Whole-exome sequencing (WES) was conducted using the IDT Lotus DNA Library Prep Kit and xGen Exome Research Panel v2, with sequencing on the NovaSeq 6000 platform. Reads were aligned to the GRCh38 genome reference using DRAGEN v.3.9.3 with stringent quality metrics. Variants were filtered against databases such as dbSNP version 150 and Taiwan Biobank, annotated via wANNOVAR, and BRCA1/2 PVs were confirmed using Sanger sequencing. Results: A cohort of 525 breast cancer patients were enrolled, revealing 36 individuals (6.9%) carring confirmed germline BRCA1/2 PVs and another 28 patients (5.3%) carrying PVs in other non-BRCA hereditary breast and ovarian cancer (HBOC)-related genes (ATM, BARD1, BRIP1, CHEK2, MUTYH, PALB2, PMS2, RAD50, RAD51D, and TP53) (Table1). Among the risk groups classified by the Manchester Scoring System, 72.8% were categorized as low (<10% risk), 15.2% were moderate (10-20%), and 12% were high risk (>20%) groups. The detection rate of BRCA PV was 1.6% (6/382), 11.3% (9/80), and 33.3% (21/63), respectively, in low to high-risk Manchester categories. For patients diagnosed with breast cancer under age 40 (n= 291,55%), the prevalence of BRCA1/2 PV was observed at 7.2% (21/291). Among patients with TNBC (n=79), the proportion of patients with BRCA1/2 PVs was notably higher, at 16.5% (n=13). In cases of bilateral breast cancer (n=47) (synchronous or metachronous), 12.8% (n=6) had BRCA1/2 PVs. Among the 16 male breast cancer patients, no BRCA 1/2 PVs were detected. For individuals with a high Manchester Score but no detected BRCA1/2 PVs through sequencing, further analysis using the MLPA assay remains ongoing. Conclusion: Whole-exome sequencing has provided valuable insights into the prevalence and distribution of germline pathogenic variants in HBOC-related genes among Taiwanese breast cancer patients with moderate to high hereditary risk. (2) The occurrence rates of BRCA1/2 pathogenic variants in the overall cohort and within triple-negative breast cancer patients align with trends observed in other breast cancer populations. (3) 1. Evans DG, Harkness EF, Plaskocinska I, Wallace AJ, Clancy T, Woodward ER, et al. Pathology update to the Manchester Scoring System based on testing in over 4000 families. (1468-6244 (Electronic)).2. Felicio PS, Grasel RS, Campacci N, de Paula AE, Galvão HCR, Torrezan GT, et al. Whole-exome sequencing of non-BRCA1/BRCA2 mutation carrier cases at high-risk for hereditary breast/ovarian cancer. Hum Mutat. 2021;42(3):290-9.3. Lee NY, Hum M, Amali AA, Lim WK, Wong M, Myint MK, et al. Whole-exome sequencing of BRCA-negative breast cancer patients and case-control analyses identify variants associated with breast cancer susceptibility. Hum Genomics. 2022;16(1):61. Citation Format: W. Kuo, W. Shen, H. Chou, M. Peng, S. Huang, S. Chen, Y. Lin. Whole exome sequencing reveals germline pathogenic variant landscape in multi-center Taiwanese breast cancer patient cohort at moderate to high hereditary genetic risks [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-10.