These results suggest that alterations in the FHIT gene may play an important role in breast cancer tumorigenesis and suggest that the MIT gene product functions in the control of the tumorigenic phenotype in a large variety of human neoplasms.
Small cell lung tumors (80%) and non-small cell lung cancers (40%) showed abnormalities in RNA transcripts of FHIT, and 76% of the tumors exhibited loss of FHIT alleles.
These data indicate that abnormal transcription of the FHIT gene is common in HNSCC cell lines; however, other tumor suppressor gene(s) may reside at the same chromosomal region.
To our knowledge, this is the first report of HDs encompassing the FHIT gene region in primary tumor samples and underscores the usefulness of high resolution genetic analysis of tumor genomes in determining the chromosomal aberrations underlying the malignant progression of CC.
One putative target, 3p14.2, contains the common fragile site, FRA3B, a hereditary renal carcinoma-associated 3;8 translocation and the candidate tumor suppressor gene, FHIT.
Our findings support the conclusion that FHIT/FRA3B abnormalities are associated with lung cancer pathogenesis but that FHIT abnormalities differ from the types of mutations and lack of wild-type transcript found in classic tumor suppressor genes, and functional studies are needed to define the role of FHIT in thoracic tumorigenesis.
Analysis of genomic DNA from 20 patients showed homozygous deletions involving exon 5 of FHIT in 4/20 (20%) esophageal adenocarcinomas, and 7/20 (35%) tumors demonstrated hemizygous loss.
Here, we report that in a primary pleomorphic adenoma of the parotid gland, the FHIT gene, which spans the chromosome 3p14.2 fragile site FRA3B, and is frequently disrupted in tumors, acts as a fusion partner of HMGIC.
Loss of heterozygosity affecting at least one locus of the FHIT gene was observed in 41 of 51 tumors in the smokers group (80%) but in only 9 of 40 tumors in nonsmokers (22%).
None of the five 3p14.2 markers detected any homozygous deletions in tumor samples, but 69/94 (73%) of the tumors had LOH for the region, which includes the recently identified FHIT gene.
Present observations on a possible association of FHIT with tumor development leave a number of questions unanswered, so that provisionally it cannot be considered a tumor suppressor.
Because the FHIT gene sustains biallelic intragenic deletions rather than mutations, there has not been evidence that the FHIT gene frequently plays a role in kidney cancer, although replacement of Fhit expression in a Fhit-negative renal carcinoma cell line suppressed tumor growth in nude mice.
We conclude that the FHIT gene and other uncharacterized tumour-suppressor genes at 3p14.2 are unlikely to be involved in the pathogenesis of acute leukaemia or progression of CML from chronic phase to blast crisis.
Furthermore, a reduction of Fhit protein expression in tumor cells was associated with a poorer survival of patients with stage I NSCLC, irrespective of histological subtypes of tumors (P = 0.005; log-rank test).
These findings suggest that methylation of the 5' CpG island of the FHIT gene is closely associated with transcriptional inactivation and might be involved in tumor development of the esophagus.