The FHIT Gene, Spanning the Chromosome 3p14.2 Fragile Site and Renal Carcinoma–Associated t(3;8) Breakpoint, Is Abnormal in Digestive Tract Cancers

Ohta, Masataka; Inoue, Hiroshi; Cotticelli, M. Grazia; Kastury, Kumar; Baffa, Raffaele; Palazzo, Juan; Siprashvili, Zurab; Mori, Masaki; McCue, Peter A.; Druck, Teresa; Croce, Carlo M.; Huebner, Kay

doi:10.1016/s0092-8674(00)81034-x

Cited by 909 publications

(917 citation statements)

References 26 publications

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“…In all invasive cancers and CIS lesions most of the 3p arm was deleted, and in all 12 patients the extent of the losses in CIS and invasive carcinomas was greater than the 3p allele loss found in the corresponding normal and preneoplastic foci. Recent attention has focused on the FHIT at 3p14.2, a candidate tumor suppressor gene for lung and other cancers, which spans FRA3B, the most common of the aphidocolin-inducible fragile sites Ohta et al, 1996;Sozzi et al, 1996). While it is tempting to speculate that breaks at FRA3B destabilize the entire short arm of chromosome 3, leading to multiple deletions, allelic losses at other more telomeric 3p regions appeared at histologically earlier stages than losses within and around the FHIT gene.…”

Section: Discussionmentioning

confidence: 99%

Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma

et al. 1999

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To understand the molecular pathways involved in the pathogenesis of squamous cell lung carcinoma, we obtained DNA from 94 microdissected foci from 12 archival surgically resected tumors including histologically normal epithelium (n=13), preneoplastic lesions (n=54), carcinoma is situ (CIS) (n=15) and invasive tumors (n=12). We determined loss of heterozygosity (LOH) at 10 chromosomal regions (3p12, 3p14.2, 3p14.1-21.3, 3p21, 3p22-24, 3p25, 5q22, 9p21, 13q14 RB, and 17p13 TP53) frequently deleted in lung cancer, using 31 polymorphic microsatellite markers, including 24 that spanned the entire 3p arm. Our major ®ndings are as follows: (1) Thirty one percent of histologically normal epithelium and 42% of mildly abnormal (hyperplasia/metaplasia) specimens had clones of cells with allelic loss at one or more regions; (2) There was a progressive increase of the overall LOH frequency within clones with increasing severity of histopathological changes; (3) The earliest and most frequent regions of allelic loss occurred at 3p21, 3p22-24, 3p25 and 9p21; (4) The size of the 3p deletions increased with progressive histologic changes; (5) TP53 allelic loss was present in many histologically advanced lesions (dysplasia and CIS); (6) Analyses of 58 normal and non-invasive foci having any molecular abnormality, indicated that 30 probably arose as independent clonal events, while 28 were potentially of the same clonal origin as the corresponding tumor; (7) Nevertheless, when the allelic losses in the 30 clonally independent lesions and their clonally unrelated tumors were compared the same parental allele was lost in 113 of 125 (90%) of comparisons. The mechanism by which this phenomenon (known as allele speci®c mutations) occurs is unknown; (8) Four patterns of allelic loss in clones were found. Histologically normal or mildly abnormal foci had a negative pattern (no allelic loss) or early pattern of loss while all foci of CIS and invasive tumor had an advanced pattern. However dysplasias demonstrated the entire spectrum of allelic loss patterns, and were the only histologic category having the intermediate pattern. Our ®ndings indicate that multiple, sequentially occurring allele speci®c molecular changes commence in widely dispersed, apparently clonally independent foci, early in the multistage pathogenesis of squamous cell carcinomas of the lung.

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Section: Discussionmentioning

confidence: 99%

Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma

et al. 1999

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“…16 Of the common chromosomal fragile site loci, FRA3B and FRA16D are the most frequently expressed. 17 The tumor suppressor gene fragile histidine triad (FHIT) spans the FRA3B fragile site, 18 and abnormal FHIT transcription and low FHIT expression were detected in various human cancers, including oral squamous cell carcinomas. 19,20 Studies of the two most frequently affected common fragile site loci, FRA3B and FRA16D, have provided compelling evidence that these regions are indeed prone to DNA instability in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias

et al. 2008

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SummaryOral leukoplakia is the most prevalent and potentially malignant disorder of the oral mucosa. Previous studies have demonstrated that molecular changes of the WWOX gene (WW-domain containing oxidoreductase), a candidate tumor suppressor gene located at 16q23.3-24.1 that spans FRA16D, the second most common fragile site, are present in several malignant neoplasias, including oral squamous cell carcinoma. In this report, the role of the WWOX gene was investigated in 23 cases of oral leukoplakias. Using nested RT-PCR and immunohistochemistry, altered mRNA transcription and/or reduced Wwox protein expression was observed in 35% of the lesions when compared with normal mucosa. The majority of lesions (4/6) with altered transcripts had a reduction in the expression of Wwox protein. Although normal WWOX expression was found in some lesions with dysplasia, all lesions with WWOX mRNA and/or protein expression showed histological evidence of dysplasia and none of the cases without dysplasia presented this alteration. These results show that the WWOX gene alteration is an early genetic alteration and may contribute to oral carcinogenesis.

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“…Druck et al (1995) found that 31/35 clear cell RCCs showed a common region of loss between D3S1312 and D3S1481, which¯ank the hRCC (hereditary renal cell carcinoma) translocation breakpoint. Ohta et al (1996) recently reported the identi®cation of the FHIT gene, which spans both the hRCC breakpoint and FRA3B. The FHIT gene consists of 10 exons and codes for a 1.1 Kb transcript.…”

Section: Introductionmentioning

confidence: 99%

Frequent breakpoints in the region surrounding FRA3B in sporadic renal cell carcinomas

et al. 1997

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The constitutive fragile site at chromosomal band 3p14.2, FRA3B, is the most active common fragile site in the human genome. We have localized aphidicolininduced breakpoints to two distinct clusters, separated by 200 Kb, in FRA3B (Paradee et al., 1996). Sequence analysis of these regions identi®ed two polymorphic microsatellite markers immediately adjacent to each of these breakpoint clusters. In this report we have used these two new microsatellites and 14 additional 3p microsatellites to analyse chromosome 3p breakage and loss in 94 sporadic RCC samples, including nonpapillary, papillary and oncocytomas. We have found heterozygous loss of 3p14 sequences in 460% of the RCC samples, including both clear cell and papillary renal cell carcinomas. We have found frequent breakage in the region immediately surrounding FRA3B, demonstrating that FRA3B does play a role in chromosome breakage and loss in RCC. In contrast to other reports, 450% of the papillary tumors also showed LOH of 3p markers. We also observed microsatellite instability (MIN) with most of the tested markers in seven of eight oncocytomas and one of 69 clear cell carcinomas. The MIN in some oncocytomas was of the RER+ (replication error) type I phenotype. None of the ®ve 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 identi®ed FHIT gene.

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The FHIT Gene, Spanning the Chromosome 3p14.2 Fragile Site and Renal Carcinoma–Associated t(3;8) Breakpoint, Is Abnormal in Digestive Tract Cancers

Cited by 909 publications

References 26 publications

Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma

Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma

Molecular alterations in the tumor suppressor gene WWOX in oral leukoplakias

Frequent breakpoints in the region surrounding FRA3B in sporadic renal cell carcinomas

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