Single Nucleotide Polymorphisms of microRNA Machinery Genes Modify the Risk of Renal Cell Carcinoma

Purpose: MicroRNAs (miRNA) are a class of small noncoding RNA molecules that have been implicated in a wide variety of basic cellular functions through posttranscriptional regulations on their target genes. Compelling evidence has shown that miRNAs are involved in cancer initiation and progression. We hypothesized that genetic variations of the miRNA machinery genes could be associated with the risk of renal cell carcinoma. Experimental Design: We genotyped 40 single nucleotide polymorphisms (SNP) from 11 miRNA processing genes (DROSHA, DGCR8, XPO5, RAN, DICER1, TARBP2, AGO1, AGO2, GEMIN3, GEMIN4, HIWI) and 15 miRNA genes in 279 Caucasian patients with renal cell carcinoma and 278 matched controls. Results: We found that two SNPs in the GEMIN4 gene were significantly associated with altered renal cell carcinoma risks. The variant-containing genotypes of Asn929Asp and Cys1033Arg exhibited significantly reduced risks, with odds ratios (OR) of 0.67 [95% confidence interval (95% CI), 0.47-0.96] and 0.68 (95% CI, 0.47-0.98), respectively. Haplotype analysis showed that a common haplotype of GEMIN4 was associated with a significant reduction in the risk of renal cell carcinoma (OR, 0.66; 95% CI, 0.45-0.97). We also conducted a combined unfavorable genotype analysis including five promising SNPs showing at least a borderline significant risk association. Compared with the low-risk reference group with one unfavorable genotype, the median-risk and high-risk groups exhibited a 1.55-fold (95% CI, 0.96-2.50) and a 2.49-fold (95% CI, 1.58-3.91) increased risk of renal cell carcinoma, respectively (P for trend < 0.001). Conclusions: Our results suggested that genetic polymorphisms of the miRNA-machinery genes may affect renal cell carcinoma susceptibility individually and jointly.

[1]  L. Looijenga,et al.  Molecular characterization of hiwi, a human member of the piwi gene family whose overexpression is correlated to seminomas , 2002, Oncogene.

[2]  W Marston Linehan,et al.  The genetic basis of cancer of the kidney. , 2003, The Journal of urology.

[3]  U. Kutay,et al.  Nuclear Export of MicroRNA Precursors , 2004, Science.

[4]  T. Golub,et al.  Impaired microRNA processing enhances cellular transformation and tumorigenesis , 2007, Nature Genetics.

[5]  R. Shiekhattar,et al.  TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing , 2005, Nature.

[6]  G. Hutvagner,et al.  A microRNA in a Multiple-Turnover RNAi Enzyme Complex , 2002, Science.

[7]  P. Donnelly,et al.  A new statistical method for haplotype reconstruction from population data. , 2001, American journal of human genetics.

[8]  Jason H. Moore,et al.  Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. , 2007, Cancer research.

[9]  Muller Fabbri,et al.  A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. , 2005, The New England journal of medicine.

[10]  Sven Diederichs,et al.  Sequence variations of microRNAs in human cancer: alterations in predicted secondary structure do not affect processing. , 2006, Cancer research.

[11]  James M. Pipas,et al.  SV40-encoded microRNAs regulate viral gene expression and reduce susceptibility to cytotoxic T cells , 2005, Nature.

[12]  B. Cullen,et al.  A Novel Assay for Viral MicroRNA Function Identifies a Single Nucleotide Polymorphism That Affects Drosha Processing , 2006, Journal of Virology.

[13]  K. Lindblad-Toh,et al.  Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals , 2005, Nature.

[14]  Joel S Parker,et al.  Extensive post-transcriptional regulation of microRNAs and its implications for cancer. , 2006, Genes & development.

[15]  A. Jemal,et al.  Cancer Statistics, 2008 , 2008, CA: a cancer journal for clinicians.

[16]  N. Iwai,et al.  Polymorphisms in human pre-miRNAs. , 2005, Biochemical and biophysical research communications.

[17]  Jianren Gu,et al.  Two variants of the human hepatocellular carcinoma‐associated HCAP1 gene and their effect on the growth of the human liver cancer cell line Hep3B , 2004, Genes, chromosomes & cancer.

[18]  G. Dreyfuss,et al.  Numerous microRNPs in neuronal cells containing novel microRNAs. , 2003, RNA.

[19]  M. von Knebel Doeberitz,et al.  Human eukaryotic initiation factor EIF2C1 gene: cDNA sequence, genomic organization, localization to chromosomal bands 1p34-p35, and expression. , 1999, Genomics.

[20]  Wen-Hsiung Li,et al.  Human polymorphism at microRNAs and microRNA target sites , 2007, Proceedings of the National Academy of Sciences.

[21]  Peng Jin,et al.  Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA. , 2007, Human molecular genetics.

[22]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[23]  Yuanqing Ye,et al.  Evaluation of genetic variants in microRNA-related genes and risk of bladder cancer. , 2008, Cancer research.

[24]  W. Marston Linehan,et al.  Genetic Basis of Cancer of the Kidney , 2004, Clinical Cancer Research.

[25]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[26]  Shuta Tomida,et al.  Reduced expression of Dicer associated with poor prognosis in lung cancer patients , 2005, Cancer science.

[27]  Rajiv Dhir,et al.  Up-regulation of dicer, a component of the MicroRNA machinery, in prostate adenocarcinoma. , 2006, The American journal of pathology.

[28]  Simion I. Chiosea,et al.  Overexpression of Dicer in precursor lesions of lung adenocarcinoma. , 2007, Cancer research.

[29]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[30]  M. Mann,et al.  miRNPs: a novel class of ribonucleoproteins containing numerous microRNAs. , 2002, Genes & development.