Role of genetic variants of membrane transporters in breast cancer

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F70883521%3A28150%2F18%3A63520824" target="_blank" >RIV/70883521:28150/18:63520824 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Role of genetic variants of membrane transporters in breast cancer

Popis výsledku v původním jazyce

Breast cancer is the most common cancer in women. One of the major obstacles to successful treatment is the multidrug resistance. Among other factors as activity of metabolic enzymes, variability of targets of cytostatics, impaired DNA repair or apoptosis; the expression of membrane transporters, e.g. Pglycoprotein, can cause such resistance. Gene expression in tumor cells of such transporters was previously associated with prognosis and response to neoadjuvant chemotherapy (ABCD2 and SLCO1A2). We aimed to investigate the germline enetic background of solute carrier (SLC) and ATPbinding cassette (ABC) transporters in breast cancer patients. We analyzed DNA samples from blood (n=105 patients) using nextgeneration sequencing (NGS) with target enrichment of 49 ABCs and 45 SLCs. The functional effects of genetic variants, coding and noncoding ones, were predicted by in silico tools and associated phenotypes were searched in public databases. Altogether, we found 1683 variants (15% coding) in SLCs; 20 missense variants were predicted as deleterious in silico and four were frameshift deletions. In ABCs, 2864 variants were found (24% coding – 139 deleterious, 7 frameshifts). About 10% of variants was novel. Selected variants were compared with response to therapy and prognostic clinical features of the patients. Five single nucleotide polymorphisms (SNPs) in SLC46A1 and SLCO1A2 were assessed in a historical cohort of breast cancer patients with clinical followup (n=819). In conclusion, SLC and ABC transporters contain clinically relevant genetic alterations and represent putative candidate genes of breast cancer prognosis or response to chemotherapy. Moreover, NGS is a novel and promising method for assessment of candidate biomarkers with potential for development of new therapeutics. Supported by grants no. AZV 1525618A, NPUI no. LO1503, and Conceptual evelopment of Research Organization program of MH CR (FNPl, 00669806).

Název v anglickém jazyce

Role of genetic variants of membrane transporters in breast cancer

Popis výsledku anglicky

Breast cancer is the most common cancer in women. One of the major obstacles to successful treatment is the multidrug resistance. Among other factors as activity of metabolic enzymes, variability of targets of cytostatics, impaired DNA repair or apoptosis; the expression of membrane transporters, e.g. Pglycoprotein, can cause such resistance. Gene expression in tumor cells of such transporters was previously associated with prognosis and response to neoadjuvant chemotherapy (ABCD2 and SLCO1A2). We aimed to investigate the germline enetic background of solute carrier (SLC) and ATPbinding cassette (ABC) transporters in breast cancer patients. We analyzed DNA samples from blood (n=105 patients) using nextgeneration sequencing (NGS) with target enrichment of 49 ABCs and 45 SLCs. The functional effects of genetic variants, coding and noncoding ones, were predicted by in silico tools and associated phenotypes were searched in public databases. Altogether, we found 1683 variants (15% coding) in SLCs; 20 missense variants were predicted as deleterious in silico and four were frameshift deletions. In ABCs, 2864 variants were found (24% coding – 139 deleterious, 7 frameshifts). About 10% of variants was novel. Selected variants were compared with response to therapy and prognostic clinical features of the patients. Five single nucleotide polymorphisms (SNPs) in SLC46A1 and SLCO1A2 were assessed in a historical cohort of breast cancer patients with clinical followup (n=819). In conclusion, SLC and ABC transporters contain clinically relevant genetic alterations and represent putative candidate genes of breast cancer prognosis or response to chemotherapy. Moreover, NGS is a novel and promising method for assessment of candidate biomarkers with potential for development of new therapeutics. Supported by grants no. AZV 1525618A, NPUI no. LO1503, and Conceptual evelopment of Research Organization program of MH CR (FNPl, 00669806).

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

30107 - Medicinal chemistry

Projekt

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Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

FEBS Open Bio

ISSN

2211-5463

e-ISSN

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Svazek periodika

8

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

1

Strana od-do

308

Kód UT WoS článku

000437674103311

EID výsledku v databázi Scopus

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