Polymorphisms in microRNA binding sites of mucin genes as predictors of clinical outcome in colorectal cancer patients.
Polymorphisms in microRNA (miRNA) binding sites may affect miRNA/target gene interaction, resulting in differential mRNA/protein expression and susceptibility to common diseases. Mucins have been identified as markers of adverse prognosis. We hypothesized that genetic variations in miRNA binding sites located in mucin genes may modulate signaling response and the maintenance of genomic stability ultimately affecting cancer susceptibility, efficacy of chemotherapy and survival. In this study, we analyzed the association of single nucleotide polymorphisms in predicted miRNA target sites (miRSNPs) of mucin genes with colorectal cancer (CRC) risk and clinical outcome. Thirteen miRSNPs in 9 genes were assessed in 1111 cases and 1469 controls. No strongly significant associations were observed in the case-control study. Patients carrying the CC genotype of rs886403 in MUC21 displayed a shorter survival and higher recurrence risk when compared with TT carriers [overall survival (OS): hazard ratios (HR) 1.69; 95% confidence intervals (CI) 1.13-2.46; P = 0.01 and event-free survival (EFS): HR 1.99; 95% CI 1.38-2.84; P = 0.0002, respectively]. The observed associations were more striking after stratification for tumor site (in patients with colon cancer, OS: HR 2.63; 95% CI 1.69-4.10; P < 0.0001 and EFS: HR 2.65; 95% CI 1.72-4.07; P < 0.0001). In contrast, rectal cancer cases carrying the CC genotype of rs4729655 in MUC17 displayed a longer survival (OS: HR 0.27; 95% CI 0.14-0.54; P = 0.0002) than those with the most common genotype. To our knowledge, this is the first study investigating miRSNPs potentially affecting miRNA binding to mucin genes and revealing their impact on CRC susceptibility or patient's survival.
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic, vpolakova@biomed.cas.cz.|Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic.
Veronika
V
Vymetalkova
Human Genetics Foundation, 10126 Turin, Italy.
Barbara
B
Pardini
Human Genetics Foundation, 10126 Turin, Italy.
Fabio
F
Rosa
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic.|Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic.
Katerina
K
Jiraskova
Human Genetics Foundation, 10126 Turin, Italy.|Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
Cornelia
C
Di Gaetano
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic.|Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic.|Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic.
Petra
P
Bendova
Department of Surgery, First Faculty of Medicine, Charles University and Thomayer University Hospital, 14200 Prague, Czech Republic and.
Miloslav
M
Levy
Department of Oncology, Thomayer Hospital and First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic.
Veronika
V
Veskrnova
Department of Oncology, Thomayer Hospital and First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic.
Tomas
T
Buchler
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic.|Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic.|Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic.
Ludmila
L
Vodickova
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic.|Human Genetics Foundation, 10126 Turin, Italy.
Alessio
A
Naccarati
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, 14200 Prague, Czech Republic.|Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, 11000 Prague, Czech Republic.|Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic.
Pavel
P
Vodicka
D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009077:Mucins / Q000235:genetics* / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D015996:Survival Rate
D020413:3' Untranslated Regions; D014408:Biomarkers, Tumor; D035683:MicroRNAs; D009077:Mucins