A functional polymorphism at microRNA-629-binding site in the 3'-untranslated region of NBS1 gene confers an increased risk of lung cancer in Southern and Eastern Chinese population.

The genetic variations in NBS1 gene have been reported to be associated with cancer risk. The polymorphisms in 3'-untranslated region (3'-UTR) of NBS1 might affect gene's function and thus contribute to cancer susceptibility. We hypothesized that these polymorphisms of NBS1 are associated with the lung cancer risk. In two independent case-control studies conducted in Southern and Eastern Chinese, we genotyped three tagSNPs (rs14448, rs13312986 and rs2735383) in Southern Chinese and then validated the discovered association in Eastern Chinese. No significant association was observed for rs13312986 and rs14448; we only found that the rs2735383CC genotype had a significantly increased risk of lung cancer under a recessive genetic model in the total 1559 cases versus 1679 controls (odds ratio = 1.40, 95% confidence interval = 1.18-1.66, P = 0.0001) when compared with GG or GC genotypes; the rs2735383CC genotype carriers had lower messenger RNA and protein expression levels in tumor tissues than those of other genotypes as quantitative polymerase chain reaction and western blot shown. Luciferase assay revealed that the rs2735383C allele had a lower transcription activity than G allele, and the hsa-miR-629 but not hsa-miR-499-5P had effect on modulation of NBS1 gene in vitro. We further observed that the X-ray radiation induced more chromatid breaks in lymphocyte cells from the carriers of rs2735383CC homozygote than those from the subjects with other genotypes (P = 0.0008). Our data suggested that the rs2735383G>C variation contributes to an increased risk of lung cancer by diminishing gene's expression through binding of microRNA-629 to the polymorphic site in the 3'-UTR of NBS1 gene.

[1]  C. Lim,et al.  The role of NBS1 in DNA double strand break repair, telomere stability, and cell cycle checkpoint control , 2006, Cell Research.

[2]  R. Hayes,et al.  Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity. , 2006, Carcinogenesis.

[3]  J. Rzeszowska-Wolny,et al.  Association between single-nucleotide polymorphisms of selected genes involved in the response to DNA damage and risk of colon, head and neck, and breast cancers in a Polish population , 2011, Journal of Applied Genetics.

[4]  Hao Tan,et al.  Association between the NBS1 E185Q polymorphism and cancer risk: a meta-analysis , 2009, BMC Cancer.

[5]  Ananya Choudhury,et al.  Analysis of variants in DNA damage signalling genes in bladder cancer , 2008, BMC Medical Genetics.

[6]  Giatromanolaki Alexandra,et al.  Increased chromosomal radiosensitivity in women carrying BRCA1/BRCA2 mutations assessed with the G2 assay. , 2010, International journal of radiation oncology, biology, physics.

[7]  R F Woolson,et al.  Statistical analysis of K 2 x 2 tables: a comparative study of estimators/test statistics for association and homogeneity. , 1990, Environmental health perspectives.

[8]  T. Brüning,et al.  DNA adducts and strand breaks in workers exposed to vapours and aerosols of bitumen: associations between exposure and effect , 2011, Archives of Toxicology.

[9]  K. Khanna,et al.  DNA double-strand breaks: signaling, repair and the cancer connection , 2001, Nature Genetics.

[10]  Constantin Sajdik,et al.  Genetic polymorphisms in AURKA and BRCA1 are associated with breast cancer susceptibility in a Chinese Han population , 2011, The Journal of pathology.

[11]  Randy D Gascoyne,et al.  Genetic variation in the NBS1, MRE11, RAD50 and BLM genes and susceptibility to non-Hodgkin lymphoma , 2009, BMC Medical Genetics.

[12]  K. Sperling,et al.  Nijmegen breakage syndrome: clinical manifestation of defective response to DNA double-strand breaks. , 2004, DNA repair.

[13]  C. Bassing,et al.  The sticky business of histone H2AX in V(D)J recombination, maintenance of genomic stability, and suppression of lymphoma , 2008, Immunologic research.

[14]  P. Jeggo,et al.  ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. , 2008, Molecular cell.

[15]  S. Singletary,et al.  Polymorphisms and haplotypes of the NBS1 gene are associated with risk of sporadic breast cancer in non-Hispanic white women , 2006, Carcinogenesis.

[16]  B. Sobhian,et al.  RAP80-directed tuning of BRCA1 homologous recombination function at ionizing radiation-induced nuclear foci. , 2011, Genes & development.

[17]  H. Putter,et al.  Model selection based on logistic regression in a highly correlated candidate gene region , 2007, BMC proceedings.

[18]  A. Naccarati,et al.  NBN 657del5 heterozygous mutations and colorectal cancer risk in the Czech Republic. , 2009, Mutation research.

[19]  E. Seemanová,et al.  Clinical variability and expression of the NBN c.657del5 allele in Nijmegen Breakage Syndrome. , 2009, Gene.

[20]  M. Löbrich,et al.  Homologous recombination protects mammalian cells from replication-associated DNA double-strand breaks arising in response to methyl methanesulfonate. , 2010, DNA repair.

[21]  K. Hemminki,et al.  Molecular genetic analysis of NBS1 in German melanoma patients , 2007, Melanoma research.

[22]  David J. Chen,et al.  Mechanism of cluster DNA damage repair in response to high-atomic number and energy particles radiation. , 2011, Mutation research.

[23]  Yifeng Zhou,et al.  Functional polymorphisms in the NBS1 gene and acute lymphoblastic leukemia susceptibility in a Chinese population , 2011, European journal of haematology.

[24]  J. Harper,et al.  Radiation induced DNA DSBs: Contribution from stalled replication forks? , 2010, DNA repair.

[25]  C. Mathew,et al.  Interaction of FANCD2 and NBS1 in the DNA damage response , 2002, Nature Cell Biology.

[26]  H. Tauchi,et al.  NBS1 regulates a novel apoptotic pathway through Bax activation. , 2008, DNA repair.

[27]  Michel C. Nussenzweig,et al.  Genomic Instability in Mice Lacking Histone H2AX , 2002, Science.

[28]  Kevin S. Xu,et al.  A Common Genetic Variant (97906C>A) of DAB2IP/AIP1 Is Associated with an Increased Risk and Early Onset of Lung Cancer in Chinese Males , 2011, PloS one.

[29]  Jack A. Taylor,et al.  SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies , 2009, Nucleic Acids Res..

[30]  Jun Qin,et al.  SMC1 is a downstream effector in the ATM/NBS1 branch of the human S-phase checkpoint. , 2002, Genes & development.

[31]  A. Goldman,et al.  Mre11 and Exo1 contribute to the initiation and processivity of resection at meiotic double-strand breaks made independently of Spo11. , 2011, DNA repair.

[32]  B. Qian,et al.  Association of genetic polymorphisms in DNA repair pathway genes with non-small cell lung cancer risk. , 2011, Lung cancer.

[33]  Hushan Yang,et al.  Genetic Susceptibility to Renal Cell Carcinoma: The Role of DNA Double-Strand Break Repair Pathway , 2008, Cancer Epidemiology Biomarkers & Prevention.

[34]  Israel Steinfeld,et al.  Novel Rank-Based Statistical Methods Reveal MicroRNAs with Differential Expression in Multiple Cancer Types , 2009, PloS one.

[35]  H. Morgenstern,et al.  Associations between NBS1 polymorphisms, haplotypes and smoking-related cancers. , 2010, Carcinogenesis.

[36]  Yifeng Zhou,et al.  Functional NBS1 polymorphism is associated with occurrence and advanced disease status of nasopharyngeal carcinoma , 2011, Molecular carcinogenesis.

[37]  John A. Tainer,et al.  Nbs1 Flexibly Tethers Ctp1 and Mre11-Rad50 to Coordinate DNA Double-Strand Break Processing and Repair , 2009, Cell.

[38]  A. Bolzán,et al.  Analysis of spontaneous and bleomycin-induced chromosome damage in peripheral lymphocytes of long-haul aircrew members from Argentina. , 2008, Mutation research.

[39]  S. Lees-Miller,et al.  Repair of ionizing radiation-induced DNA double-strand breaks by non-homologous end-joining. , 2009, The Biochemical journal.

[40]  S. Jackson,et al.  Sensing and repairing DNA double-strand breaks. , 2002, Carcinogenesis.

[41]  Yifeng Zhou,et al.  The polymorphism and haplotypes of PIN1 gene are associated with the risk of lung cancer in southern and eastern chinese populations , 2011, Human mutation.

[42]  D. Grobbee,et al.  Estimating interaction on an additive scale between continuous determinants in a logistic regression model. , 2007, International journal of epidemiology.

[43]  M. Spitz,et al.  172G>T variant in the 5' untranslated region of DNA repair gene RAD51 reduces risk of squamous cell carcinoma of the head and neck and interacts with a P53 codon 72 variant. , 2006, Carcinogenesis.

[44]  M. Kastan,et al.  Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage. , 2002, Genes & development.

[45]  Q. Wei,et al.  A functional variant (-1304T>G) in the MKK4 promoter contributes to a decreased risk of lung cancer by increasing the promoter activity. , 2010, Carcinogenesis.

[46]  J. Hoeijmakers.  Genome maintenance mechanisms for preventing cancer , 2001, Nature.