Abnormal FHIT transcripts found in both lung cancer and normal lung tissue

Abstract

Occurrence of abnormal transcripts of the FHIT (fragile histidine triad) gene has been reported in various types of cancer. On the other hand, aberrant transcripts are sometimes found in non-neoplastic tissues, so the relationship between the presence of abnormal transcripts of the FHIT gene and cancer pathogenesis is controversial. We investigated alterations in the FHIT locus, detected by nested reverse transcription-polymerase chain reaction and/or allelic status, in 88 primary lung cancers and normal lung tissues, and 22 normal lung tissues with metastatic lung cancer as a control. The frequencies of abnormal transcripts were 59% in lung cancer, 35% in paired normal lung, and 64% in normal control lung; the difference in frequencies between lung cancer and paired normal lung was significant, while that between lung cancer and normal control lung was not. Sequence analysis revealed that there were no cancer-specific abnormal transcripts entirely missing two or more exons, nor were the abnormal transcripts of lung cancer identical with those of paired normal lung in the same individual. Furthermore, we found no correlation between loss of heterozygosity in the FHIT locus and occurrence of abnormal FHIT transcripts. These results suggest that the presence of abnormal FHIT transcripts, in terms of their frequency and variety, is not cancer-specific in lung carcinogenesis, and the abnormality may be mainly due to abnormal splicing and processing of the transcripts. To estimate the precise function of the FHIT gene, further study of the FHIT protein in lung carcinogenesis is needed.

Loss of FHIT protein expression is related to high proliferation, low apoptosis and worse prognosis in non-small-cell lung cancer

“…The reported frequency of LOH at FHIT gene in NSCLC is between 20 and 70% of cases. 5,11,[17][18][19][20][21][22][23][24] Our results are similar to the highest frequency, with LOH in one or more microsatellites in 67.8% of 96 informative tumors. The differences between all series probably could be explained by the different markers used and the method of detection and evaluation of LOH.…”

“…Since when different groups use the same methods, the frequencies are similar around 60%. 11,12,18,22 Loss of immunoexpression of FHIT, the protein encoded by this gene, has been described in several 39 and it is higher than the frequency reported by others. 13,23,33,38 These discrepancies may be due to differences in immunohistochemical techniques, stain interpretation or different distributions of histological types.…”

“…3 Frequent allelic losses and homozygous deletions, [3][4][5][6][7][8][9][10][11][12][13][14][15][16] as well as the loss of heterozygosity (LOH) in microsatellites located at FHIT gene 5,11,12,[17][18][19][20][21][22][23][24] have been described at the FHIT locus in several human solid tumors arising from epithelial cells, including lung cancer.…”

Loss of Fragile Histidine Triad Gene Expression in Advanced Lung Cancer Is Consequent to Allelic Loss at 3p14 Locus and Promoter Methylation

“…In four cases, there were aberrant smaller-sized transcripts in addition to the normal transcript. In NSCLC, presence of both aberrant and normal FHIT transcripts were seen in 40% (11), 59% (22), and 100% tumors (23). Sequence analysis of aberrant products showed that majority of these products lacked either exon 5, which contains the start codon, or exon 8, containing the histidine triad motif important for its functional activity.…”

Prevalence of Fragile Histidine Triad Expression in Tumors from Saudi Arabia: A Tissue Microarray Analysis

“…These results suggest that the suppressor activity of FHIT could be related with apoptosis and with the alteration of cell cycle regulator factors. Frequent allelic losses and homozygous deletions (8,9,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24), as well as the loss of heterozygosity in microsatellites located at the FHIT gene have been described at the FHIT locus in several human solid tumors arising from epithelial cells (13,19,20,(25)(26)(27)(28)(29)(30)(31)(32). Studies comparing FHIT expression with the status of the FHIT gene have shown significant concordance in a variety of malignancies.…”