542 Abnormalities of FHIT and the FRA3B fragile site at 3p14.2 in lung cancer and associated preneoplastic lesions

Fong, K. M.; Biesterveld, Eric J.; Virmani, Arvind K.; Wistuba, Ignacio I.; Sekido, Yuki; Bader, Scott; Ahmadian, Mohsen; Ong, SuFey; Rassool, Feyruz V.; Zimmerman, PV; Giaccone, G.; Gazdar, Adi F.; Minna, JD

doi:10.1016/s0169-5002(97)89922-9

Cited by 19 publications

(34 citation statements)

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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: 62%

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: 62%

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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“…These alterations include deletions of one or more exons and insertion of variously sized intron sequences at the RNA level. The abnormal FHIT gene transcripts were not always correlated with deletions at the genomic DNA level (Druck et al, 1997;Fong et al, 1997). While most SCLC lines express both shortened TSG101 and aberrantly spliced FHIT transcripts, we did observe two SCLCs that did not express the shortened TSG101 transcript but did express abnormal FHIT transcripts .…”

Section: Discussionmentioning

confidence: 48%

“…The FHIT gene, located at 3p14, is a candidate tumor suppressor gene identi®ed by the positional cloning method. Abnormal transcripts were observed in 80% of SCLCs, 40% of NSCLCs, about 40% of HNSCCs and in several other tumor types (Sozzi et al, 1996;Mao et al, 1996;Fong et al, 1997). These alterations include deletions of one or more exons and insertion of variously sized intron sequences at the RNA level.…”

Section: Discussionmentioning

confidence: 99%

TSG101 is not mutated in lung cancer but a shortened transcript is frequently expressed in small cell lung cancer

Proctor

Fan

et al. 1998

Oncogene

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TSG101 is a candidate tumor suppressor gene whose deletion in NIH3T3 cells leads to spontaneous lung metastases in nude mice. Aberrant transcripts of TSG101 have been identi®ed in 47% of primary breast carcinomas, without evidence of intragenic deletions at the TSG101 locus on 11p15. To investigate the possible role of TSG101 in lung cancer, which often shows 11p allele loss, we performed transcript analysis and mutational analysis of TSG101 in lung cancer cell lines. Reverse transcriptase RT ± PCR and Northern analysis detected a common TSG101 transcript, shortened because of an internal deletion, which was expressed simultaneously with the wild-type transcript in 89% of small cell lung cancer (SCLC) lines. In contrast, the wild-type transcript was expressed alone in normal tissues, primary non-small cell lung cancer (NSCLC) specimens, and the majority of NSCLC cell lines. Sequence of the shortened SCLC transcript was identical to that of the most common aberrant transcript identi®ed in breast cancer, consisting of a deletion of exons 2 ± 4 and part of 1 and 5. Southern analysis of SCLC lines expressing the shortened transcript did not detect any intragenic deletions. Single strand conformational polymorphism (SSCP) analysis and direct sequencing of TSG101 cDNAs also identi®ed no mutations or deletions. These results suggest that TSG101 is not mutated in lung cancer but that aberrant splicing of TSG101 occurs in SCLC.

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“…Deletions in this region are very frequent in lung and kidney carcinomas and were also observed in a variety of other common tumors, such as breast cancer, head and neck cancer, gastrointestinal cancer, esophageal cancer, and cervical cancer (see Croce et al, 1999;Huebner and Croce, 2001;Wistuba et al, 1997;Fong et al, 1997;Greenspan et al, 1997;Muller et al, 1998;Helland et al, 2000;Zo¨chbauer-Muller et al, 2001b).…”

Section: Chromosome Region 3p142 (Fhit Gene Region)mentioning

confidence: 99%

Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers

Zabarovsky¹,

2002

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Loss of heterozygosity (LOH) involving several chromosome 3p regions accompanied by chromosome 3p deletions are detected in almost 100% of small (SCLCs) and more than 90% of non-small (NSCLCs) cell lung cancers. In addition, these changes appear early in the pathogenesis of lung cancer and are found as clonal lesions in the smoking damaged respiratory epithelium including histologically normal epithelium as well as in epithelium showing histologic changes of preneoplasia. These 3p genetic alterations lead to the conclusion that the short arm of human chromosome 3 contains several tumor suppressor gene(s) (TSG(s)). Although the first data suggesting that 3p alterations were involved in lung carcinogenesis were published more than 10 years ago, only recently has significant progress been achieved in identifying the candidate TSGs and beginning to demonstrate their functional role in tumor pathogenesis. Some of the striking results of these findings has been the discovery of multiple 3p TSGs and the importance of tumor acquired promoter DNA methylation as an epigenetic mechanism for inactivating the expression of these genes in lung cancer. This progress, combined with the well known role of smoking as an environmental causative risk factor in lung cancer pathogenesis, is leading to the development of new diagnostic and therapeutic strategies which can be translated into the clinic to combat and prevent the lung cancer epidemic. It is clear now that genetic and epigenetic abnormalities of several genes residing in chromosome region 3p are important for the development of lung cancers but it is still obscure how many of them exist and which of the numerous candidate TSGs are the key players in lung cancer pathogenesis. We review herein our current knowledge and describe the most credible candidate genes.

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542 Abnormalities of FHIT and the FRA3B fragile site at 3p14.2 in lung cancer and associated preneoplastic lesions

Cited by 19 publications

References 0 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

TSG101 is not mutated in lung cancer but a shortened transcript is frequently expressed in small cell lung cancer

Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers

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