5′CpG island hypermethylation and aberrant transcript splicing both contribute to the inactivation of the FHIT gene in resected non-small cell lung cancer

Ching Tzao, Hui Yuan Tsai, Jung Ta Chen, Chih Yi Chen, Yi Ching Wang

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The relative contribution of promoter hypermethylation and aberrant splicing to the inactivation of the fragile histidine triad (FHIT) gene is unclear. Using genetic and epigenetic analyses, the current investigation examines the loss of protein and mRNA expression, and 5′CpG hypermethylation and allelic imbalance of the FHIT gene in a series of 129 non-small cell lung cancer (NSCLC) samples, in parallel with clinicopathological analyses. We found that 50% of NSCLC patients had aberrant protein expression, which was more frequent in squamous cell carcinomas (SQ) (69%) than in adenocarcinomas (AD) (28%) (P <0.0001). 5′CpG hypermethylation of FHIT was identified in 31% of patients. Abnormally-sized FHIT transcripts were also observed in 24% of patients and were attributed to various exonic deletions, mainly in the region of exons 4-8. Allelic imbalance of the FHIT locus and its correlation with the status of Fhit expression, 5′CpG hypermethylation, and aberrant splicing, indicated that biallelic inactivation of Fhit expression could be induced by 5′CpG hypermethylation of one allele and alternative splicing in the other allele. Moreover, an 83% concordance in the methylation status of FHIT was demonstrated between 12 samples of bronchial precancerous lesions taken before surgery and their matched resected tumours. Our data suggest that FHIT 5′CpG hypermethylation and splicing alterations are both predominant mechanisms involved in the aberrant expression of the FHIT gene, and that FHIT 5′CpG methylation may be potentially used as a supplemental detection marker for NSCLC.

Original languageEnglish
Pages (from-to)2175-2183
Number of pages9
JournalEuropean Journal of Cancer
Volume40
Issue number14
DOIs
Publication statusPublished - Sep 2004
Externally publishedYes

Fingerprint

Histidine
Islands
Non-Small Cell Lung Carcinoma
Genes
Allelic Imbalance
Methylation
Alleles
Alternative Splicing
Epigenomics
Squamous Cell Carcinoma
Exons
Proteins
Adenocarcinoma
Messenger RNA

Keywords

  • 5′CpG hypermethylation
  • Alternative splicing
  • Bronchial lesions
  • FHIT gene
  • LOH
  • NSCLC

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

Cite this

5′CpG island hypermethylation and aberrant transcript splicing both contribute to the inactivation of the FHIT gene in resected non-small cell lung cancer. / Tzao, Ching; Tsai, Hui Yuan; Chen, Jung Ta; Chen, Chih Yi; Wang, Yi Ching.

In: European Journal of Cancer, Vol. 40, No. 14, 09.2004, p. 2175-2183.

Research output: Contribution to journalArticle

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abstract = "The relative contribution of promoter hypermethylation and aberrant splicing to the inactivation of the fragile histidine triad (FHIT) gene is unclear. Using genetic and epigenetic analyses, the current investigation examines the loss of protein and mRNA expression, and 5′CpG hypermethylation and allelic imbalance of the FHIT gene in a series of 129 non-small cell lung cancer (NSCLC) samples, in parallel with clinicopathological analyses. We found that 50{\%} of NSCLC patients had aberrant protein expression, which was more frequent in squamous cell carcinomas (SQ) (69{\%}) than in adenocarcinomas (AD) (28{\%}) (P <0.0001). 5′CpG hypermethylation of FHIT was identified in 31{\%} of patients. Abnormally-sized FHIT transcripts were also observed in 24{\%} of patients and were attributed to various exonic deletions, mainly in the region of exons 4-8. Allelic imbalance of the FHIT locus and its correlation with the status of Fhit expression, 5′CpG hypermethylation, and aberrant splicing, indicated that biallelic inactivation of Fhit expression could be induced by 5′CpG hypermethylation of one allele and alternative splicing in the other allele. Moreover, an 83{\%} concordance in the methylation status of FHIT was demonstrated between 12 samples of bronchial precancerous lesions taken before surgery and their matched resected tumours. Our data suggest that FHIT 5′CpG hypermethylation and splicing alterations are both predominant mechanisms involved in the aberrant expression of the FHIT gene, and that FHIT 5′CpG methylation may be potentially used as a supplemental detection marker for NSCLC.",
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