Haplotype analysis and linkage disequilibrium of BRCA genes in glioblastoma: Impact on treatment response

Abstract

Glioblastoma (GBM) is an aggressive primary brain tumor prevalent in adults, characterized as a common malignant neoplasm of the human central nervous system with the worst survival rate among cancers. Treatment of GBM involves the addition of the alkylating agent temozolomide (TMZ) to radiotherapy, which improves overall survival by preventing replication through alkyl group-mediated DNA cross-linking. Genes related to homologous recombination (HR)-dependent DNA repair, such as the breast cancer susceptibility genes (BRCA), specifically BRCA1 or BRCA2, contribute to cellular resistance to alkylating agents. We aimed to perform a haplotype-based study on the frequencies of BRCA1 mutations in GBM patients compared to healthy individuals and investigate their linkage disequilibrium (LD) with the data population. Blood samples from GBM patients (n = 15) and healthy controls (n = 25) were sequenced using the Ion Torrent PGM platform to identify the BRCA1 mutation. Subsequently, the reported variants were submitted to the LDlink tool for haplotype analysis, and their association with treatment response was assessed. Our results revealed that the BRCA1 haplotype block consisted of seven SNPs, whose frequencies were reported with strong LD when compared to all available population data. This block was found to be represented by eight haplotypes. Five of these haplotypes were previously reported (four haplotypes were commonly reported, and one was rare), while the remaining three haplotypes were newly reported in this study. The relationship between newly reported haplotypes and response to treatment revealed that patients with these haplotypes responded to TMZ either as a complete or partial response. In addition, one haplotype in the heterozygote form was reported in the control case. In conclusion, haplotype analysis for BRCA genes in GBM cases can aid in predicting treatment responses and identifying cancer risk factors in individuals.