Viktor Hlavac1,2, Radka Vaclavikova3,4, Veronika Brynychova3,4, Pavel Dvorak3,5, Katerina Elsnerova3, Renata Kozevnikovova6, Karel Raus7, Katerina Kopeckova8, Sona Mestakova9, David Vrana10, Jiri Gatek11, Pavel Soucek3,4. 1. Laboratory of Pharmacogenomics, Faculty of Medicine in Pilsen, Biomedical Center, Charles University, alej Svobody 76, 323 00, Pilsen, Czech Republic. viktor.hlavac@lfp.cuni.cz. 2. Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic. viktor.hlavac@lfp.cuni.cz. 3. Laboratory of Pharmacogenomics, Faculty of Medicine in Pilsen, Biomedical Center, Charles University, alej Svobody 76, 323 00, Pilsen, Czech Republic. 4. Toxicogenomics Unit, National Institute of Public Health, Prague, Czech Republic. 5. Department of Biology, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic. 6. Department of Oncosurgery, MEDICON, Prague, Czech Republic. 7. Institute for the Care for Mother and Child, Prague, Czech Republic. 8. Department of Oncology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. 9. Department of Surgery, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. 10. Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic. 11. Department of Surgery, EUC Hospital and University of Tomas Bata in Zlin, Zlin, Czech Republic.
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.
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.
Authors: I Hlavata; B Mohelnikova-Duchonova; R Vaclavikova; V Liska; P Pitule; P Novak; J Bruha; O Vycital; L Holubec; V Treska; P Vodicka; P Soucek Journal: Mutagenesis Date: 2012-03 Impact factor: 3.000
Authors: Gergely Szakács; Jill K Paterson; Joseph A Ludwig; Catherine Booth-Genthe; Michael M Gottesman Journal: Nat Rev Drug Discov Date: 2006-03 Impact factor: 84.694
Authors: Viktor Hlaváč; Veronika Brynychová; Radka Václavíková; Marie Ehrlichová; David Vrána; Václav Pecha; Renata Koževnikovová; Markéta Trnková; Jiří Gatěk; Dana Kopperová; Ivan Gut; Pavel Souček Journal: Pharmacogenomics Date: 2013-04 Impact factor: 2.533
Authors: Beatrice Mohelnikova-Duchonova; Veronika Brynychova; Viktor Hlavac; Matej Kocik; Martin Oliverius; Jan Hlavsa; Eva Honsova; Jan Mazanec; Zdenek Kala; Bohuslav Melichar; Pavel Soucek Journal: Cancer Chemother Pharmacol Date: 2013-08-11 Impact factor: 3.333
Authors: Freddie Bray; Jacques Ferlay; Isabelle Soerjomataram; Rebecca L Siegel; Lindsey A Torre; Ahmedin Jemal Journal: CA Cancer J Clin Date: 2018-09-12 Impact factor: 508.702
Authors: Katerina Elsnerova; Beatrice Mohelnikova-Duchonova; Ela Cerovska; Marie Ehrlichova; Ivan Gut; Lukas Rob; Petr Skapa; Martin Hruda; Alena Bartakova; Jiri Bouda; Pavel Vodicka; Pavel Soucek; Radka Vaclavikova Journal: Oncol Rep Date: 2016-01-28 Impact factor: 3.906