Chromosome 3p14 Homozygous Deletions and Sequence Analysis of FRA3B

Boldog, Ferenc; Gemmill, Robert M.; West, James; Robinson, Misi; Robinson, Linda J.; Li, Efang; Roche, Joëlle; Todd, S.; Waggoner, Barbara T.; Lundstrom, Ron; Jacobson, Jan; Mullokandov, Michael; Klinger, H.P.; Drabkin, Harry A.

doi:10.1093/hmg/6.2.193

Cited by 120 publications

(127 citation statements)

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“…All FHIT-speci®c variants observed in a given specimen by nested PCR were also found using the appropriate primer pair. These alternatively spliced transcripts were clearly no more prominent in the tumors than in the normal prostate specimens in keeping with results from Boldog et al (1997). The present result con®rms that FHIT variants are present at a far lower level (51%) than the full-length transcript in both normal and neoplastic prostate tissue.…”

Section: Discussionsupporting

confidence: 89%

“…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%

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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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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Molecular analysis of the FHIT gene in human prostate cancer

et al. 1998

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“…First, although in agreement with previous reports of other human malignancies Ohta et al, 1996;Sozzi et al, 1996a,b), aberrant transcripts of the FHIT gene were frequently detected in the tumorous liver tissues, they also existed in the nontumorous liver tissues. Recently, Boldog et al reported the presence of the aberrant FHIT transcripts in the normal fetal brain cDNA and concluded that the alternative splicing definitely occurs in normal human tissues (Boldog et al, 1997). This is consistent with our findings and may explain the currently and most previously reported abnormal FHIT transcripts.…”

Section: Microsatellite Polymorphism Analysissupporting

confidence: 92%

Aberrant FHIT transcripts in hepatocellular carcinomas

Chen

Chen²,

Chang³

1998

Br J Cancer

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Summary To study abnormalities of the FHIT gene in human hepatocellular carcinoma (HCC), eight liver cancer cell lines, 18 matched tumorous and non-tumorous tissues from patients with HCC and three normal liver tissues were analysed by microsatellite polymorphism analysis and reverse transcription of FHITmRNA followed by polymerase chain reaction (PCR) amplification and sequencing of the products.No loss of heterozygosity at chromosome 3p14.2 as defined by markers D3S1300 and D3S1312 was detected in any of the specimens. In addition, a normal transcript of the gene without any sequence change was found to be expressed in all the cell lines, 17 of the 18 tumorous and all 21 non-tumorous liver tissues tested. Although five out of eight liver cancer cell lines (62.5%), 12 out of 18 HCC tissues (66.7%) and 8 out of 18 paired non-tumorous liver tissues (44.4%) displayed abnormal faint bands of smaller size, sequence analysis revealed that they were aberrant FH/Ttranscripts lacking three or more exons and might represent alternatively spliced transcripts only. In conclusion, these studies indicate that abnormalities of the FHIT gene transcripts occur in a fairly high frequency of tumorous and non-tumorous liver tissues.However, it might not be causally related to the hepatocarcinogenesis. Keywords: FHIT; HCC; RT-PCRHepatocellular carcinoma (HCC) is one of the most common human malignancies in the world, especially in areas such as China and sub-Saharan Africa (Okuda, 1992;Wright et al, 1992). It usually carries a grave prognosis. The precise aetiology of HCC is not yet clear, however it is well known that HCC is frequently associated with a background of chronic liver disease (Beasley et al, 1981). Predisposing factors include hepatitis B virus or hepatitis C virus infection and aflatoxin BI exposure (Okuda, 1992;Wright et al, 1992;Chen, 1993). Hepatocarcinogenesis is therefore considered as a multifactorial and multistep process that includes the activation of oncogenes and the inactivation of tumour-suppressor genes (Ding and Habib, 1994;Sugimura, 1992).Recently, the FHIT gene (fragile histidine triad gene), a candidate tumour-suppressor gene, was identified at 3pl4.2 . The gene spans the t(3;8) translocation breakpoint of familial renal cell carcinoma and contains the FRA3B fragile site (Cohen et al, 1979;Paradee et al, 1995;Ohta et al, 1996). It is the target of homozygous deletions in various human cancer cell lines, such as colon and gastric cancer cell lines . In addition, aberrant transcripts of the FHIT gene have been identified in 50% of primary gastrointestinal tumours , 80% of small-cell lung cancers and at least 40% of non-small-cell lung cancers (Sozzi et al, 1996a).In the current study, we examined 18 cases of HCCs and eight liver cancer cell lines for the presence of FHIT abnormalities. Microsatellite polymorphism analysis using primers at chromosome 3pl4 and reverse transcription (RT) of FHIT mRNA followed by the polymerase chain reaction (PCR) and sequencing of the products were performed.Received 2...

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“…The structural alterations of FRA3B might interfere with the normal splicing and thus result in the generation of numerous aberrant transcripts. Indeed, homozygous deletions in the FHIT gene mostly involve intronic sequences within the FHIT gene locus (Boldog et al, 1997), suggesting that partial deletions of the FHIT gene might affect transcription fidelity. Previous reports indicated that breakage and rearrangements of DNA within the FHIT gene resulted in occurrence of aberrant transcripts and subsequently reduced FHIT protein expression Baffa et al, 1998).…”

Section: Discussionmentioning

confidence: 99%