A Novel Mutation in the DNA Binding Domain of NFKB is Associated with Speckled Leukoplakia

  • Published : 2016.07.01


Background: Activation and inactivation of nuclear factor of kappa light chain gene enhancer in B cells (NFKB) is tightly regulated to ensure effective onset and cessation of defensive inflammatory signaling. However, mutations within NFKB, or change in activation and inactivation molecules have been reported in a few cancers. Although oral squamous cell carcinoma is one of the most prevalent forms of cancer in India, with a development associated with malignant transformation of precancerous lesions, the genetic status of NFKB and relative rates of change in oral precancerous lesions remain unknown. Hence in the present study we investigated all twenty four exons of NFKB gene in two precancerous lesions, namely oral submucous fibrosis (OSMF) and oral leukoplakia (OL) to understand its occurrence, incidence and assess its possible contribution to malignant transformation. Materials and Methods: Chromosomal DNA isolated from twenty five each of OSMF and OL tissue biopsy samples were subjected to PCR amplification with intronic primers flanking twenty four exons of the NFKB gene. The PCR amplicons were subsequently subjected to direct sequencing to elucidate the mutation status. Results: Sequence analysis identified a novel heterozygous mutation, c.419T>A causing substitution of leucine with glutamine at codon 140 (L140Q) in an OL sample. Conclusions: The identification of a substitution mutation L140Q within the DNA binding domain of NFKB in OL suggests that NFKB mutation may be relatively an early event during transformation. To the best of our knowledge, this study is the first to have identified a missense mutation in NFKB in OL.


  1. Atsumi T, Singh R, Sabharwal L, et al (2014). Inflammation amplifier, a new paradigm in cancer biology. Cancer Res, 74, 8-14.
  2. Birbach A, Gold P, Binder BR, et al (2002). Signaling molecules of the NF-kappa B pathway shuttle constitutively between cytoplasm and nucleus. J Biol Chem, 277, 10842-51.
  3. Das S, Shenoy S (2015). Sneak Peek into Tobacco Habits and Associated Insidious Oral Lesions in an Odisha Sample Population. Asian Pac J Cancer Prev, 16, 7007-9.
  4. Gao J, Wang X, Zheng F, Dong S, Qiu X (2015). Novel keratin 5 mutation in a family with epidermolysis bullosa simplex. Exp Ther Med, 10, 2432-6.
  5. Hayden MS, Ghosh S (2012). $NF-{\kappa}B$, the first quarter-century: remarkable progress and outstanding questions. Genes Dev, 26, 203-34.
  6. Hoesel B, Schmid JA (2013). The complexity of $NF-{\kappa}B$ signaling in inflammation and cancer. Mol Cancer, 12, 86.
  7. Jayaraman B, Valiathan GM, Jayakumar K, et al (2012). Lack of mutation in p53 and H-ras genes in phenytoin induced gingival overgrowth suggests its non cancerous nature. Asian Pac J Cancer Prev, 13, 5535-8.
  8. Kanarek N, Ben-Neriah Y (2012). Regulation of $NF-{\kappa}B$ by ubiquitination and degradation of the $I{\kappa}Bs$. Immunol Rev, 246, 77-94.
  9. Khan S, Lopez-Dee Z, Kumar R, Ling J (2013). Activation of NFkB is a novel mechanism of pro-survival activity of glucocorticoids in breast cancer cells. Cancer Lett, 337, 90-5.
  10. Lawrence T, Bebien M, Liu GY, Nizet V, Karin M (2005). IKKalpha limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature, 434, 1138-43.
  11. Mehta DT, Annamalai T, Ramanathan A (2014). Lack of mutations in protein tyrosine kinase domain coding exons 19 and 21 of the EGFR gene in oral squamous cell carcinomas. Asian Pac J Cancer Prev, 15, 4623-7.
  12. Rial NS, Choi K, Nguyen T, Snyder B, Slepian MJ (2012). Nuclear factor kappa B ($NF-{\kappa}B$): a novel cause for diabetes, coronary artery disease and cancer initiation and promotion? Med Hypotheses, 78, 29-32.
  13. Wang X, Lu P, Xu L, et al (2011). Updated meta-analysis of NFkappaB1 -94ins/Delattg promoter polymorphism and cancer risk based on 19 case-control studies. Asian Pac J Cancer Prev, 12, 2479-84.
  14. Wu K, Bonavida B (2009). The activated NF-kappaB-Snail-RKIP circuitry in cancer regulates both the metastatic cascade and resistance to apoptosis by cytotoxic drugs. Crit Rev Immunol, 29, 241-54.
  15. Xie TX, Xia Z, Zhang N, Gong W, Huang S (2010). Constitutive NF-kappaB activity regulates the expression of VEGF and IL-8 and tumor angiogenesis of human glioblastoma. Oncol Rep, 23, 725-32.
  16. Yardimci G, Kutlubay Z, Engin B, Tuzun Y (2014). Precancerous lesions of oral mucosa. World J Clin Cases, 2, 866-72.