The FHIT gene is alternatively spliced in normal kidney and renal cell carcinoma

Luan, Xiaodong; Shi, Guangping; Zohouri, Mahnaz; Paradee, William; Smith, Jeremy C.; Decker, H.J.; Cannizzaro, Linda A.

doi:10.1038/sj.onc.1201164

Cited by 23 publications

(23 citation statements)

References 12 publications

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“…Deletions in the coding region of FHIT transcripts have been reported in a variety of cancers including lung, gastric, oesophageal and breast tumours (Hayashi et al, 1997;Huebner et al, 1997). More recently at least two groups have reported deletions in FHIT transcripts from normal tissues, but characterised these as di erent from deletions present in tumours (Fong et al, 1997;Luan et al, 1997). In contrast, we saw similar types of deletions in both tumour and normal samples.…”

Section: Discussionsupporting

confidence: 61%

Aberrant splicing of the TSG101 and FHIT genes occurs frequently in multiple malignancies and in normal tissues and mimics alterations previously described in tumours

Sa¹,

Barski²,

et al. 1997

Oncogene

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Intragenic deletions of TSG101, the human homolog of a mouse gene (tsg101) that acts to suppress malignant cell growth, were reported in human breast tumours. We screened TSG101 for somatic mutations in DNA and RNA samples isolated from a variety of common human malignancies, EBV-immortalised B-cells, and normal lung parenchyma. Intragenic TSG101 deletions in RNA transcripts were frequently found in all types of samples. Analysis of DNA failed to show genomic rearrangements corresponding to transcripts containing deletions in the same samples. The breakpoints of most transcript deletions coincide with genuine or cryptic splice site sequences, suggesting that they result from alternative or aberrant splicing. A similar spectrum of transcript deletions has previously been described in the putative tumour suppressor gene FHIT. We analysed FHIT in the same series of RNA samples and detected truncated FHIT transcripts frequently in both tumour and normal tissues. In addition, transcripts from TSG101, FHIT and seven other genes were analysed in RNA isolated from normal peripheral blood lymphocytes. Large TSG101 and FHIT intragenic transcript deletions were detected and these appeared to be the predominant transcript iǹ aged' lymphocytes. Similar alterations were not detected in transcripts of the other genes which were analysed. Our ®ndings demonstrate that truncated TSG101 and FHIT transcripts are commonly detected in both normal and malignant tissues and that a signi®cant fraction of these are likely to be the result of aberrant splicing. While we cannot exclude that alterations in TSG101 and FHIT occur during cancer development, our data indicate that in this context the commonly observed transcript abnormalities are misleading.

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Section: Discussionsupporting

confidence: 61%

Aberrant splicing of the TSG101 and FHIT genes occurs frequently in multiple malignancies and in normal tissues and mimics alterations previously described in tumours

Sa¹,

Barski²,

et al. 1997

Oncogene

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“…As the FHIT open reading frame is contained in exons 5 ± 9 (Figure 1a), it is unlikely that most of these alternatively spliced transcripts encode functional proteins. The absence of exon 8, which contains the histidine triad domain, is also one of the most frequent variation observed in breast cancer , squamous cell carcinomas of the head and neck (Virgilio et al, 1996), renal cell carcinomas (Luan et al, 1997), and also in normal fetal brain cDNA (Boldog et al, 1997), whereas loss of exon 3, that¯anks the t(3;8) translocation, has been observed in the prostate cancer-derived cell line LNCaP .…”

Section: Discussionmentioning

confidence: 99%

“…FHIT which encompasses approximately 1 Mb of human genomic DNA, including the FRA3B common fragile region, encodes a typical dinucleoside 5',5''-P1, P3-triphosphate (Ap3A) hydrolase (Barnes et al, 1996). In addition to its disruption in a kindred with a reciprocal t(3;8) chromosomal translocation, abnormal transcripts containing deletions of one or more coding exons, together with homozygous deletion of the region containing the gene and genomic DNA rearrangements have been found in many established cancer cell lines and solid tumors Mao et al, 1996;Negrini et al, 1996;Panagopoulos et al, 1996;Sozzi et al, 1996a,b;Thiagalingam et al, 1996;Virgilio et al, 1996;Yanagisawa et al, 1996;Druck et al, 1997;Fong et al, 1997;Hayashi et al, 1997;Hendricks et al, 1997;Luan et al, 1997). These results make FHIT a candidate TSG for several human neoplasms.…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of the FHIT gene in human prostate cancer

et al. 1998

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A variety of studies suggest that the FHIT gene, which encompasses the fragile site at 3p14.2, is a candidate tumor suppressor gene in several forms of human cancer. To determine whether the FHIT gene is altered in prostate carcinomas, we examined 15 prostate tumors, four normal prostate tissue specimens and RNA from a pool of 62 normal human prostate tissues (Clontech) for the integrity of FHIT transcripts, using a robust singlestage PCR and a nested PCR method. In each case a major FHIT-speci®c full-length product was observed. Additional aberrantly sized products, which were more numerous in the nested PCR strategy, were present at a far lower level than the full-length transcripts in 14 of 15 tumors, three of four normal human prostate tissues and in the pooled normal prostate RNA. Sequence analysis revealed that these aberrant products corresponded to alternatively spliced FHIT transcripts, which were neither more numerous nor more prominent in the tumors than in the normal prostate specimens. Deletion at the FHIT locus was also evaluated by using three intragenic polymorphic markers (D13S1481, D3S1300, and D3S1234). Allelic loss was observed in two tumors, but these genomic alterations did not correspond to the aberrant FHIT transcripts. DNA analysis, furthermore, suggested that the tumor heterogeneity was not a likely explanation for presence of normal and alternatively spliced FHIT transcripts in the prostate tumors. In conclusion, we detected neither frequent loss of heterozygosity nor tumor speci®c transcripts of the FHIT gene in human prostate cancer.

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“…32,34 A wide discrepancy has also been reported in renal carcinomas, where transcript alterations were described in 51% of clear-cells and 10% of papillary sporadic renal carcinoma cells, while absent or Fhit protein reduction occurred in 88% and 26%, respectively. [37][38][39] Further studies have reported loss of Fhit not due to altered transcript but to promoter hypermethylation of the FHIT gene in breast, gallbladder and NSCL cancers. 36,[40][41][42] On the other hand, we recently showed that downregulation of Fhit protein recently showed that downregulation of Fhit protein levels in the presence of a normal mRNA can occur through Fhit protein posttranslational modification.…”

Section: E S B I O S C I E N C E D O N O T D I S T R I B U T Ementioning

confidence: 99%

Fhit Expression Protects Against HER2-Driven Breast tumor Development: Unraveling the Molecular Interconnections

et al. 2007

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The FHIT gene is alternatively spliced in normal kidney and renal cell carcinoma

Cited by 23 publications

References 12 publications

Aberrant splicing of the TSG101 and FHIT genes occurs frequently in multiple malignancies and in normal tissues and mimics alterations previously described in tumours

Aberrant splicing of the TSG101 and FHIT genes occurs frequently in multiple malignancies and in normal tissues and mimics alterations previously described in tumours

Molecular analysis of the FHIT gene in human prostate cancer

Fhit Expression Protects Against HER2-Driven Breast tumor Development: Unraveling the Molecular Interconnections

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