Abstrakt
Membrane solute carrier (SLC) transporters play important role in transport of a wide spectrum of substrates including anticancer drugs and cancer-related physiological substrates. This study aimed to assess prognostic relevance of gene expression and genetic variability of selected SLC transporters in breast cancer.
Gene expression was determined by quantitative real-time PCR. All SLC46A1 and SLCO1A2 exons and surrounding non-coding sequences in blood DNA from patients with breast cancer (exploratory phase) were analyzed by next-generation sequencing technology.
Common variants (MAF>=5%) with in silico predicted functional relevance were further analyzed in a large cohort of breast cancer patients (n=815) and their prognostic and predictive potential was estimated (validation phase). Gene expression and bioinformatics analysis suggested SLC46A1 and SLCO1A2 to play a putative role in prognosis of breast cancer patients.
In total, 135 genetic variants (20 novel) were identified in both genes in the exploratory phase. Of these variants, 130 were non-coding, three missense, and two synonymous.
One common variant in SLCO1A2 and four variants in SLC46A1 were predicted to be pathogenic by in silico programs and subsequently validated. SLC46A1 haplotype block composed of rs2239911-rs2239910-rs8079943 was significantly associated with ERBB2/HER2 status and disease-free survival of hormonally treated patients.
This study revealed prognostic value of SLC46A1 haplotype block for breast cancer which should be further followed.