Novel genetic structures associated with adverse response to chemotherapy in breast cancer.

Abstract

Introduction: The role of genetic variants in response to chemotherapy has been investigated in several studies. This study aimed to investigate genetic variants associated with response to chemotherapy in breast cancer (BC) patients. Methods: Significant variants (p < 5 × 10^-8) associated with response to chemotherapy were obtained from GWA studies. Candidate variants were identified by haplotype analysis (r2 ≥ 0.9, D'≥0.9) using 1000Genome LD data. To determine the effects of the variants on gene expression, expression quantitative trait loci (eQTL) were evaluated. To compare the expression of the identified genes in tumor samples, expression levels were compared between TCGA tumor types and adjacent normal tissues. Results: Six rs3820706, rs147451859, rs4784750, rs17587029, rs16830728, and rs16972207 variants were significantly associated with response to chemotherapy in BC patients (p < 5 × 10^-8). Seven novel haplotypic structures were identified to be associated with adverse response to chemotherapy in BC patients. These haplotypes formed two genetic structures associated with neutropenia, leukopenia, chemotherapy-induced cytotoxicity (GAG-TTAT), and chemotherapy-induced alopecia (CC-CAACTCCCGTTGCGG). These variants are located on PPCDC, NLRC5, STAM2, and TNFSF13B genes, and the expression of these genes significantly changed in BC tissues than normal tissues (P ≤ 0.05), also showing gene-gene correlation (P ≤ 0.05). Conclusions: These genetic variants and their associated novel haplotypic structures can predict adverse response to chemotherapy in BC patients and could potentially form BC-associated genetic panel for adverse response to chemotherapy.