Abstract
Aberrant transcripts of FHIT (fragile histidine triad) have been reported in several types of primary tumors and cell lines, including gastric carcinoma. The role of these aberrant transcripts in tumorigenesis is not clear yet. Forty-eight aberrant-sized FHIT transcripts with various lengths and number in 35 cases of gastric adenocarcinomas were further characterized. Aberrant transcripts, with deletions and/or insertions, were frequently observed in 20 cases of tumors. Sequence analysis demonstrated that different types of aberrant transcripts used normal splice sites but skipped exons, contained the inserts with the part of intron 5 sequences, or used the FHIT cDNA sequence 179-180 as a cryptic splice acceptor site. Most of aberrant transcripts lacked exon 5 and were presumably non-functional as the translation initiation codon is located in exon 5. Additionally, other transcripts, indicative of additional splice processing, either deletions or insertions, were expressed in several tumors. Taken together, our data indicate that the FHIT gene expression is frequently altered in gastric adenocarcinomas by aberrant splicing, and suggest that different types of aberrant transcripts may result during the multi-step splice processing.
Highlights
Fragile sites are specific chromosomal regions prone to genetic instability, chromosomal breakage and rearrangements, and their disruption may play a mechanistic role in carcinogenesis
The results provide the evidence that fragile histidine triad (FHIT) is frequently altered in gastric adenocarcinomas by aberrant splicing and activation of cryptic splice acceptor sites within intron 5 and/or exon 6, and suggest that different types of aberrant transcripts may result during the multi-step splice processing
To study abnormal FHIT transcription in gastric carcinogenesis, 35 gastric adenocarcinomas were analyzed for a 707-bp cDNA fragment, which encompass exon 3 to 10 of the FHIT gene, using nested reverse transcription-polymerase chain reaction (RT-PCR) and sequencing
Summary
Fragile sites are specific chromosomal regions prone to genetic instability, chromosomal breakage and rearrangements, and their disruption may play a mechanistic role in carcinogenesis. The FHIT (fragile histidine triad) gene, a putative tumor suppressor gene, is located at human chromosome 3p14.2, a region of high fragility (FRA3B) and recombination, as well as of specific deletions and translocation in several cancers (Ohta et al, 1996; Croce et al, 1999). Homozygous deletions within the FHIT locus, genomic DNA rearrangements, and aberrant FHIT transcripts have been described in a variety of human cancer cell lines and tumor tissues, including lung cancer (Sozzi et al, 1996b), gastrointestinal tumors (Ohta et al, 1996), breast cancers (Ahmadian et al, 1997), head and neck squamous cell carcinomas (Virgilio et al, 1996), and Merkel cell carcinomas (Sozzi et al, 1996a). Despite numerous reports on the status of the FHIT gene, the question of whether the FHIT gene acts as a classical tumor suppressor is still controversial
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