Ehsan Ullah, Hikmat Abdel-Razeq, Sana Bentebbal, Abdullah Shaar, Nehad Alajez, Mohamad Saad, Julie V. Decock

Clinical Cancer Research (2025)

Familial breast cancer represents 5-10% of breast cancer cases, whereby the prevalence of germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 (gBRCAm) varies greatly among ethnic groups. In Jordan, pathogenic gBRCAm have been observed in over 10% of high-risk breast cancer patients tested as per the NCCN (National Comprehensive Cancer Network) guidelines. Almost half of pathogenic/likely pathogenic variants detected are non-BRCA1 or BRCA2 genes. Hence, the underlying genetic factors contributing to familial breast cancer remain unknown. Methods: This study aims to identify cancer risk variants and assess the performance of existing breast cancer polygenic risk scores (PRS) in a Middle Eastern cohort. We performed whole genome sequencing analyses on germline DNA of 180 patients with familial non-BRCA breast cancer (King Hussein Cancer Center, Jordan), and 6000 healthy subjects from the Qatar Precision Health Institute. Results: Whole genome analysis identified 88,783 single nucleotide variants that are pathogenic/likely pathogenic or are predicted to have a high impact on protein sequence. Approximately 12% of variants were found in cancer-associated genes, of which 74 were classified as pathogenic/likely pathogenic and high-impact variants. Five variants (in MSH3, XPA, PALB2, TP53, and RAD51) were only observed in patients and not in healthy control subjects, suggesting that they might be associated with cancer risk susceptibility. In addition, we found 37 pathogenic/likely pathogenic and high-impact variants in non-cancer related genes, which were only observed in patient samples and could be of interest for further study as novel genetic variants associated with an increased risk of developing breast cancer. Performance analysis of 120 existing breast cancer PRSs revealed that 84% of scores could discriminate breast cancer patients from controls. The four best-performing PRS (PGS003759, PGS003738, PGS003398, and PGS000510) demonstrated AUCs ranging from 0.664 to 0.702, indicative of a good performance in our cohort. Conclusions: In-depth genomic analysis of non-BRCA familial breast cancer patients from Jordan identified several rare variants in cancer-related genes as well as in novel non-cancer-related genes. Four distinct PRSs derived from European ancestry cohorts demonstrated a good performance in our cohort, suggesting an added clinical validity in patients of Arab ancestry. Our findings highlight the need for additional studies across ancestries to identify common and population-specific genetic variants that may predispose women to familial breast cancer.

https://aacrjournals.org/clincancerres/article/31/12_Supplement/P3-04-09/753326