The FHIT Gene at 3p14.2 Is Abnormal in Lung Cancer

Sozzi, Gabriella; Veronese, Maria Luisa; Negrini, Massimo; Baffa, Raffaele; Cotticelli, M. Grazia; Inoue, Hiroshi; Tornielli, Silvana; Pilotti, Silvana; Gregorio, Laura De; Pastorino, Ugo; Pierotti, Marco A.; Ohta, Masataka; Huebner, Kay; Croce, Carlo M.

doi:10.1016/s0092-8674(00)81078-8

Cited by 511 publications

(417 citation statements)

References 22 publications

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“…The murine Fhit gene was cloned and mapped to an aphidicolininducible fragile site on chromosome 14 (Pekarsky et al, 1998;Glover et al, 1998). Chromosomal deletions and truncated mRNA products involving Fhit were noted in multiple primary murine lung tumors and lung cancer cell lines, consistent with the analysis of FHIT in human cancer (Sozzi et al, 1996). Gene disruption experiments are underway to further examine the in vivo role of Fhit in tumorigenesis and development (Pekarsky et al, 1998).…”

Section: Murine Lung Cancer: Pathologic and Molecular Characterizationsupporting

confidence: 61%

“…SCLC specimens demonstrate overexpression of the myc family of protooncogenes due to gene ampli®cation in 10 ± 40% of the tumors (Little et al, 1983;Johnson et al, 1987;Takahashi et al, 1989;Noguchi et al, 1990); 80% have p53 mutations or deletions Hensel et al, 1991;Takahashi et al, 1991;Sameshima et al, 1992); and 90% have deletions of Rb (Yokota et al, 1988;Hensel et al, 1990). Chromosome 3p deletions, which occur at a chromosomal fragile site and often include the FHIT gene, are found in 50% of NSCLC and 90% of SCLC primary tumors (Brauch et al, 1987;Sozzi et al, 1996). Additional observations include cyclin D1 overexpression in a majority of NSCLC cell lines, which may result in Rb inactivation (Schauer et al, 1994); overexpression of the tyrosine kinase growth factor receptor cerbB2/neu in 10 ± 30% of NSCLC tumors and cell lines, which correlates with a worse prognosis Weiner et al, 1990); and overexpression of bcl-2 in 10 ± 25% of NSCLC specimens, with increased survival for the subset of squamous cell carcinoma patients that had bcl-2 increased expression (Pezzela et al, 1993).…”

Section: Human Lung Cancer: Molecular Characterizationmentioning

confidence: 99%

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Modeling human lung cancer in mice: similarities and shortcomings

1999

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Lung cancer kills more Americans yearly than any other neoplastic process. Mortality rates have changed little over the past several decades, despite improvements in surgical techniques, radiation therapy and chemotherapy. The identi®cation of mutations in oncogenes and tumor suppressor genes in human lung tumor specimens, including K-ras, p53, p16 INK4a and Rb, o ers molecular explanations for tumor development and resistance to therapy. Mouse models of human lung cancer may advance our understanding of this disease. The examination of mice which develop lung cancer either spontaneously or due to carcinogen exposure, and the creation of mouse strains harboring the speci®c genetic mutations found in human lung cancer are among strategies being pursued.

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Section: Murine Lung Cancer: Pathologic and Molecular Characterizationsupporting

confidence: 61%

Section: Human Lung Cancer: Molecular Characterizationmentioning

confidence: 99%

Modeling human lung cancer in mice: similarities and shortcomings

1999

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“…The alterations reported in TSG101 in primary breast tumours are similar in type to alterations reported in another candidate tumour suppressor gene, FHIT Sozzi et al, 1996). The FHIT (fragile histidine triad) gene is located at the fragile site locus FRA3B on chromosome 3p14.2, a region of the genome which shows LOH in a variety of cancers including small cell lung cancers (SCLC) and non-small cell lung cancers (NSCLC) (Sozzi et al, 1996).…”

Section: Introductionsupporting

confidence: 52%

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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“…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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The FHIT Gene at 3p14.2 Is Abnormal in Lung Cancer

Cited by 511 publications

References 22 publications

Modeling human lung cancer in mice: similarities and shortcomings

Modeling human lung cancer in mice: similarities and shortcomings

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

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

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