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SLC46A1 Haplotype with Predicted Functional Impact has Prognostic Value in Breast Carcinoma

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Abstract

Background and Objective

Membrane solute carrier transporters play an important role in the transport of a wide spectrum of substrates including anticancer drugs and cancer-related physiological substrates. This study aimed to assess the prognostic relevance of gene expression and genetic variability of selected solute carrier transporters in breast cancer.

Methods

Gene expression was determined by quantitative real-time polymerase chain reaction. All SLC46A1 and SLCO1A2 exons and surrounding non-coding sequences in DNA extracted from the blood of patients with breast cancer (exploratory phase) were analyzed by next-generation sequencing technology. Common variants (minor allele frequency ≥ 5%) with in silico-predicted functional relevance were further analyzed in a large cohort of patients with breast cancer (n = 815) and their prognostic and predictive potential was estimated (validation phase).

Results

A gene expression and bioinformatics analysis suggested SLC46A1 and SLCO1A2 to play a putative role in the prognosis of patients with breast cancer. 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. A SLC46A1 haplotype block composed of rs2239911-rs2239910-rs8079943 was significantly associated with ERBB2/HER2 status and disease-free survival of hormonally treated patients.

Conclusions

This study revealed the prognostic value of a SLC46A1 haplotype block for breast cancer that should be further studied.

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Authors and Affiliations

  1. Laboratory of Pharmacogenomics, Faculty of Medicine in Pilsen, Biomedical Center, Charles University, alej Svobody 76, 323 00, Pilsen, Czech Republic

    Viktor Hlavac, Radka Vaclavikova, Veronika Brynychova, Pavel Dvorak, Katerina Elsnerova & Pavel Soucek

  2. Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic

    Viktor Hlavac, Radka Vaclavikova, Veronika Brynychova & Pavel Soucek

  3. Department of Biology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic

    Pavel Dvorak

  4. Department of Oncosurgery, MEDICON, Prague, Czech Republic

    Renata Kozevnikovova

  5. Institute for the Care for Mother and Child, Prague, Czech Republic

    Karel Raus

  6. Department of Oncology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

    Katerina Kopeckova

  7. Department of Surgery, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic

    Sona Mestakova

  8. Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic

    David Vrana

  9. Department of Surgery, EUC Hospital and University of Tomas Bata in Zlin, Zlin, Czech Republic

    Jiri Gatek

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  1. Viktor Hlavac
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Corresponding author

Correspondence to Viktor Hlavac.

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Funding

This work was supported by the Ministry of Health of the Czech Republic, (grant no. 17-28470A to P.S.), the National Center of Medical Genomics (project no. CZ.02.1.01/0.0/0.0/16_013/0001634 to V.H.), the Czech Ministry of Education, Youth and Sports INTER-COST project no. LTC19020 (COST Action CA17104 STRATAGEM to R.V.), and the Charles University project “Center of clinical and experimental liver surgery” (no. UNCE/MED/006 to P.D.).

Conflicts of Interest/Competing interests

Viktor Hlavac, Radka Vaclavikova, Veronika Brynychova, Pavel Dvorak, Katerina Elsnerova, Renata Kozevnikovova, Karel Raus, Katerina Kopeckova, Sona Mestakova, David Vrana, Jiri Gatek, and Pavel Soucek have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

Procedures performed in the present study were in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Study protocol was approved by the Ethical Commission of the National Institute of Public Health in Prague (approval nos. 9799-4 and 15-25618A).

Consent to participate

All patients were informed about the study and those who agreed and signed an informed consent participated in the study.

Consent for publication

Not applicable.

Availability of data and material

The sequencing data that support the findings of this study are openly available in Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra) under accession no. PRJNA510917.

Code availability

Not applicable.

Authors’ contributions

Study conceptualization and interpretation of results (VH, PS), experimental work and evaluation of results (VH, RV, VB, KE), bioinformatics (PD), collection of clinical samples and patient follow-up and data management (RK, KR, KK, SM, DV, JG), and drafting the manuscript (all authors).

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Hlavac, V., Vaclavikova, R., Brynychova, V. et al. SLC46A1 Haplotype with Predicted Functional Impact has Prognostic Value in Breast Carcinoma. Mol Diagn Ther 25, 99–110 (2021). https://doi.org/10.1007/s40291-020-00506-2

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