Inherited polymorphisms in the RNA-mediated interference machinery affect microRNA expression and lung cancer survival

• Published in: British journal of cancer Vol. 103; no. 12; pp. 1870 - 1874
• Main Authors: Rotunno, M, Zhao, Y, Bergen, A W, Koshiol, J, Burdette, L, Rubagotti, M, Linnoila, R I, Marincola, F M, Bertazzi, P A, Pesatori, A C, Caporaso, N E, McShane, L M, Wang, E, Landi, M T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.12.2010; Nature Publishing Group
• Subjects: 631/337/384/331; 631/67/68; 692/699/67/1612; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; DEAD-box RNA Helicases - genetics; Drug Resistance; Epidemiology; Genetics and Genomics; Haplotypes; Humans; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Medical sciences; MicroRNAs - analysis; Molecular Medicine; Oncology; Pneumology; Polymorphism, Single Nucleotide; Ribonuclease III - genetics; RNA Interference; Tumors; Tumors of the respiratory system and mediastinum; lung cancer; polymorphism; microRNA biogenesis; survival; Lung disease; RNA interference; Genetic variability; Respiratory disease; Lung cancer; Micro RNA; Genotype; Malignant tumor; Hereditary; Survival; Gene silencing; Cancerology; Bronchus disease; Cancer; Polymorphism
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6605976

Background: MicroRNAs (miRs) have an important role in lung carcinogenesis and progression. Single-nucleotide polymorphisms (SNPs) in genes involved in miR biogenesis may affect miR expression in lung tissue and be associated with lung carcinogenesis and progression. Methods: We analysed 12 SNPs in POLR2A , RNASEN and DICER1 genes in 1984 cases and 2073 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We investigated miR expression profiles in 165 lung adenocarcinoma (AD) and 125 squamous cell carcinoma tissue samples from the same population. We used logistic and Cox regression models to examine the association of individual genotypes and haplotypes with lung cancer risk and with lung cancer-specific survival, respectively. SNPs-miR expression associations in cases were assessed using two-sample t -tests and global permutation tests. Results: A haplotype in RNASEN ( Drosha ) was significantly associated with shorter lung cancer survival (hazard ratio=1.86, 95% CI=1.19–2.92, P =0.007). In AD cases, a SNP within the same haplotype was associated with reduced RNASEN mRNA expression ( P =0.013) and with miR expression changes (global P =0.007) of miRs known to be associated with cancer (e.g., let-7 family, miR-21, miR-25, miR-126 and miR15a). Conclusion: Inherited variation in the miR-processing machinery can affect miR expression levels and lung cancer-specific survival.