Low prevalence of germline TP53 and PALB2 mutations in unselected cohort of breast cancer patients from Brunei Darussalam

Abstract

Background: Breast cancer is the most frequent malignancy affecting women worldwide. The majority of breast cancer occurs sporadically, with only 5-10% being caused by inheritance of susceptibility genes. In Brunei Darussalam, breast cancer is the leading cause of cancer in women. The prevalence and clinical relevance of breast cancer susceptibility genes in Brunei breast cancer patients is unknown. We investigated the prevalence and clinical relevance of germline TP53 and PALB2 genes, recognised to confer a high and moderate risk respectively, in the development of breast cancer in an unselected cohort of Brunei breast cancer patients. Methods: Genomic DNA was extracted from peripheral blood samples of 54 unselected Brunei breast cancer patients. The DNA samples were sequenced for germline BRCA1, BRCA2, TP53, and PALB2 variants using targeted panel sequencing on a Hi-Plex NGS platform. Identified variants were analysed for their pathogenicity classification based on clinical/population/mutation databases, in-silico data, and available functional data analysis. Chi-square test was used to determine the association between TP53 codon 72 and response to chemotherapy in Brunei breast cancer patients. Results: We identified two TP53 and five PALB2 missense variants in our study population. Five of the identified variants were classified as variants of uncertain significance (one in TP53 and four in PALB2) giving a prevalence of TP53 and PALB2 variant of uncertain significance carriers at 1.9% and 9.3%, respectively. No pathogenic TP53 and PALB2 mutation was identified in this study suggesting the rarity of these genes in breast cancer.TP53 codon 72 had no association with Brunei breast cancer patients’ response to chemotherapy supporting the benign characteristic of the variant P72R. Conclusions: Our current findings suggest that the contribution of germline TP53 and PALB2 genes in unselected Brunei breast cancer patients is rare, and a larger number of participants will be required to confirm this finding.