Functional variants in NBS1 and cancer risk: evidence from a meta-analysis of 60 publications with 111 individual studies

Mutagenesis. 2013 Nov;28(6):683-97. doi: 10.1093/mutage/get048. Epub 2013 Oct 10.


Several potentially functional variants of Nijmegen breakage syndrome 1 (NBS1) have been implicated in cancer risk, but individually studies showed inconclusive results. In this study, a meta-analysis based on 60 publications with a total of 39 731 cancer cases and 64 957 controls was performed. The multivariate method and the model-free method were adopted to determine the best genetic model. It was found that rs2735383 variant genotypes were associated with significantly increased overall risk of cancer under the recessive genetic model [odds ratio (OR) =1.12, 95% confidence interval (CI): 1.02-1.22, P = 0.013]. Similar results were found for rs1063054 under the dominant model effect (OR = 1.12, 95% CI: 1.01-1.23, P = 0.024). The I171V mutation, 657del5 mutation and R215W mutation also contribute to the development of cancer (for I171V, OR = 3.93, 95% CI: 1.68-9.20, P = 0.002; for 657del5, OR = 2.79, 95% CI: 2.17-3.68, P < 0.001; for R215W, OR = 1.77, 95% CI: 1.07-2.91, P = 0.025). From stratification analyses, an effect modification of cancer risks was found in the subgroups of tumour site and ethnicity for rs2735383, whereas the I171V, 657del5 and R215W showed a deleterious effect of cancer susceptibility in the subgroups of tumour site. However, rs1805794, D95N and P266L did not appear to have an effect on cancer risk. These results suggest that rs2735383, rs1063054, I171V, 657del5 and R215W are low-penetrance risk factors for cancer development.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Cell Cycle Proteins / genetics*
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • Multivariate Analysis
  • Mutation, Missense
  • Neoplasms / genetics*
  • Nuclear Proteins / genetics*
  • Penetrance
  • Polymorphism, Single Nucleotide*
  • Risk Factors


  • Cell Cycle Proteins
  • NBN protein, human
  • Nuclear Proteins