One of the principal mechanisms of chemotherapy resistance in highly frequent solid tumors, such as colorectal cancer (CRC), is the decreased activity of drug transport into tumor cells due to low expression of important membrane proteins, such as solute carrier (SLC) transporters. Sequence complementarity is a major determinant for target gene recognition by microRNAs (miRNAs). Single-nucleotide polymorphisms (SNPs) in target sequences transcribed into messenger RNA may therefore alter miRNA binding to these regions by either creating a new site or destroying an existing one. miRSNPs may explain the modulation of expression levels in association with increased/decreased susceptibility to common diseases as well as in chemoresistance and the consequent inter-individual variability in drug response. In the present study, we investigated whether miRSNPs in SLC transporter genes may modulate CRC susceptibility and patient's survival. Using an in silico approach for functional predictions, we analyzed 26 miRSNPs in 9 SLC genes in a cohort of 1368 CRC cases and 698 controls from the Czech Republic. After correcting for multiple tests, we found several miRSNPs significantly associated with patient's survival. SNPs in SLCO3A1, SLC22A2 and SLC22A3 genes were defined as prognostic factors in the classification and regression tree analysis. In contrast, we did not observe any significant association between miRSNPs and CRC risk. To the best of our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to SLC transporter genes and their impact on CRC susceptibility or patient's prognosis.

• MeSH
• 3' nepřekládaná oblast genetika   MeSH
• adjuvantní chemoterapie MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory krev   genetika   mortalita   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru epidemiologie   prevence a kontrola   MeSH
• messenger RNA krev   genetika   MeSH
• mikro RNA krev   metabolismus   MeSH
• následné studie MeSH
• přenašeče organických aniontů genetika   MeSH
• prognóza MeSH
• proteiny přenášející organické kationty genetika   MeSH
• regulace genové exprese u nádorů MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• transportér organických kationtů 2 genetika   MeSH
• vazebná místa genetika   MeSH
• výpočetní biologie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 3' nepřekládaná oblast MeSH
• messenger RNA MeSH
• mikro RNA MeSH
• přenašeče organických aniontů MeSH
• proteiny přenášející organické kationty MeSH
• SLC22A2 protein, human MeSH Prohlížeč
• SLCO3A1 protein, human MeSH Prohlížeč
• solute carrier family 22 (organic cation transporter), member 3 MeSH Prohlížeč
• transportér organických kationtů 2 MeSH

BACKGROUND: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. METHODS: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. RESULTS: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors. CONCLUSIONS: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.

• Klíčová slova
• Adverse drug reaction, Anti-neoplastic drugs, Cancer survivors, Childhood cancer, Cisplatin: carboplatin, Drug-induced ototoxicity, Genetic markers, Multicenter cohort study, Pharmacogenetics,
• MeSH
• antitumorózní látky škodlivé účinky   MeSH
• cisplatina škodlivé účinky   MeSH
• dítě MeSH
• farmakogenomické testování MeSH
• farmakogenomické varianty * MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• hodnocení rizik MeSH
• jednonukleotidový polymorfismus * MeSH
• karboplatina škodlivé účinky   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• nádory farmakoterapie   MeSH
• novorozenec MeSH
• ototoxicita MeSH
• percepční nedoslýchavost chemicky indukované   genetika   patofyziologie   MeSH
• předškolní dítě MeSH
• přežívající onkologičtí pacienti * MeSH
• prospektivní studie MeSH
• průřezové studie MeSH
• retrospektivní studie MeSH
• rizikové faktory MeSH
• sluch účinky léků   MeSH
• transportér organických kationtů 2 genetika   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Evropa MeSH
• Názvy látek
• antitumorózní látky MeSH
• cisplatina MeSH
• karboplatina MeSH
• SLC22A2 protein, human MeSH Prohlížeč
• transportér organických kationtů 2 MeSH

OBJECTIVES: The aim of this study was to investigate the prognostic significance of fourteen anticancer drug-relevant solute carrier transporters (SLCs) in pancreatic cancer in the context of clinical-pathological characteristics and the KRAS mutation status of tumors. METHODS: Tumors and non-neoplastic pancreatic tissues were obtained from 32 histologically verified patients with pancreatic ductal adenocarcinoma. The transcript profile of SLCs was assessed using quantitative real-time PCR. KRAS mutations in exon 2 were assessed by high-resolution melting analysis and confirmed by sequencing. RESULTS: SLC22A3 and SLC22A18 were upregulated and SLC22A1, SLC22A2, SLC22A11, SLC28A1, SLC28A3 and SLC29A1 were downregulated when compared with non-neoplastic pancreatic tissues. Moreover, significantly lower levels of SLC22A1, SLC22A11 and SLC29A1 were found in tumors with angioinvasion. There was also a significantly higher transcript level of SLC28A1 in tumors with regional lymph nodes affected by metastasis. The study found that a high expression of SLC28A1 was significantly associated with poor overall survival in unselected patients. In contrast, a high expression of SLC22A3 or SLC29A3 was significantly associated with longer overall survival in patients treated with nucleoside analogs. Protein expression of SLC22A1, SLC22A3 and SLC29A3 in tumor tissues of patients with pancreatic carcinoma was observed by immunoblotting for the first time. Finally, SLC levels were not found to be associated with KRAS mutation status in exon 2. CONCLUSIONS: This study identified a number of associations of transcript levels of SLCs with prognosis of pancreatic cancer patients.

• MeSH
• down regulace MeSH
• duktální karcinom pankreatu genetika   patologie   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfatické metastázy MeSH
• membránové transportní proteiny genetika   MeSH
• míra přežití MeSH
• mutace MeSH
• nádory slinivky břišní genetika   patologie   MeSH
• prognóza MeSH
• prospektivní studie MeSH
• proteiny přenášející organické kationty genetika   MeSH
• protoonkogenní proteiny p21(ras) MeSH
• protoonkogenní proteiny genetika   MeSH
• Ras proteiny genetika   MeSH
• regulace genové exprese u nádorů MeSH
• sekvenční analýza DNA MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• upregulace MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• KRAS protein, human MeSH Prohlížeč
• membránové transportní proteiny MeSH
• proteiny přenášející organické kationty MeSH
• protoonkogenní proteiny p21(ras) MeSH
• protoonkogenní proteiny MeSH
• Ras proteiny MeSH