RASSF1A gene inactivation in non-small cell lung cancer and its clinical implication

Int J Cancer. 2003 Aug 10;106(1):45-51. doi: 10.1002/ijc.11184.


Methylation-associated inactivation of RASSF1, a putative tumor suppressor identified at 3p21.3, is reported in several cancers. We examined RASSF1 in non-small lung cancer (NSCLC) to search for clinical implications. RT-PCR analysis showed no expression of RASSF1A in 12 of 20 lung cancer cell lines. Loss of expression correlated well with promoter methylation status of these lines. Sequence analysis revealed 2 polymorphisms (codons 21 and 133) in RASSF1A transcripts, but not in RASSF1C transcripts. No somatic mutations were found. Of 7 cell lines with K-ras mutations at codon 12 or 61, 2 lost expression of RASSF1A, whereas in 13 cell lines with wild-type K-ras gene, 10 lost RASSF1A gene expression (p = 0.0521). We investigated methylation status of this putative tumor suppressor gene in 100 primary NSCLCs to determine whether there is a clinical significance. Forty-two of primary NSCLCs demonstrated methylated allele. There is no correlation between promoter methylation of RASSF1A and clinicopathological findings, including histological type or grade, tumor staging, p53 and K-ras mutational status, or patients' survival. In the cases of Stage I and II disease, however, RASSF1A methylation was associated with earlier recurrence (p = 0.0247). Epigenetic silencing of RASSF1A is a frequent event in non-small lung cancer and will provide novel opportunities to develop diagnosis and therapy of NSCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • DNA Methylation
  • DNA Mutational Analysis
  • Female
  • Genes, Tumor Suppressor
  • Genes, p53 / genetics
  • Genes, ras / genetics
  • Humans
  • Lung Neoplasms / metabolism*
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Proteins / biosynthesis*
  • Polymorphism, Genetic
  • Promoter Regions, Genetic
  • Proportional Hazards Models
  • Reverse Transcriptase Polymerase Chain Reaction
  • Time Factors
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*


  • Neoplasm Proteins
  • RASSF1 protein, human
  • Tumor Suppressor Proteins