FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations

Kwun M. Fong, Eric J. Biesterveld, Arvind Virmani, Ignacio Wistuba, Yoshitaka Sekido, Scott A. Bader, Mohsen Ahmadian, S. Tiong Ong, Feyruz V. Rassool, Paul V. Zimmerman, Giuseppe Giaccone, Adi F. Gazdar, John D. Minna

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Abstract

We evaluated primary lung cancers, tumor cell lines, and preneoplastic bronchial lesions for molecular genetic abnormalities in the candidate tumor suppressor gene FHIT, which spans the FRA3B fragile site at 3p14.2. 3p14.2 allele loss was very frequent in 32 lung cancer cell lines [100% of small cell lung cancer and 88% of non-small cell lung cancer (NSCLC)] and 108 primary NSCLC cancers (45%), with numerous breakpoints indicating involvement of several distinct regions in the FRA3B site. 3p14 allele loss was least frequent in the adenocarcinoma subtype and occurred at the relatively late carcinoma in situ stage of preneoplastic bronchial lesions found in NSCLC patients. Homozygous deletions within the FHIT/FRA3B region were found in 6 of 135 (4.4%) thoracic cancer cell lines. Northern blot showed low or absent FHIT expression in most thoracic cancer cell lines tested, whereas reverse transcription-PCR showed that 59-62% exhibited aberrant FHIT transcripts but nearly always (93-100%) also expressing the wild-type transcripts. Aberrant transcripts included precise deletions of FHIT exons, insertion of non-FHIT sequences between exons and insertions replacing exons. Complete open reading frame single-strand conformational polymorphism analysis of 102 lung cancer cDNAs revealed only one nonsplicing mutation. Normal cells including bronchial epithelium, lung, and trachea expressed wild-type FHIT transcript and a variant transcript deleted for exon 8 but not the other aberrant transcripts, arguing against exon 8-deleted FHIT transcripts being tumor specific. Our findings support the conclusion that FHIT/FRA3B abnormalities are associated with lung cancer pathogenesis but that FHIT abnormalities differ from the types of mutations and lack of wild-type transcript found in classic tumor suppressor genes, and functional studies are needed to define the role of FHIT in thoracic tumorigenesis.

Original languageEnglish (US)
Pages (from-to)2256-2267
Number of pages12
JournalCancer research
Volume57
Issue number11
StatePublished - Jun 1 1997

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Exons
Lung Neoplasms
Complementary DNA
Alleles
Non-Small Cell Lung Carcinoma
Thorax
Neoplasms
Tumor Suppressor Genes
Cell Line
Mutation
Carcinoma in Situ
Small Cell Lung Carcinoma
Trachea
Tumor Cell Line
Northern Blotting
Open Reading Frames
Reverse Transcription
Molecular Biology
Carcinogenesis
Adenocarcinoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. / Fong, Kwun M.; Biesterveld, Eric J.; Virmani, Arvind; Wistuba, Ignacio; Sekido, Yoshitaka; Bader, Scott A.; Ahmadian, Mohsen; Ong, S. Tiong; Rassool, Feyruz V.; Zimmerman, Paul V.; Giaccone, Giuseppe; Gazdar, Adi F.; Minna, John D.

In: Cancer research, Vol. 57, No. 11, 01.06.1997, p. 2256-2267.

Research output: Contribution to journalArticle

Fong, KM, Biesterveld, EJ, Virmani, A, Wistuba, I, Sekido, Y, Bader, SA, Ahmadian, M, Ong, ST, Rassool, FV, Zimmerman, PV, Giaccone, G, Gazdar, AF & Minna, JD 1997, 'FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations', Cancer research, vol. 57, no. 11, pp. 2256-2267.
Fong, Kwun M. ; Biesterveld, Eric J. ; Virmani, Arvind ; Wistuba, Ignacio ; Sekido, Yoshitaka ; Bader, Scott A. ; Ahmadian, Mohsen ; Ong, S. Tiong ; Rassool, Feyruz V. ; Zimmerman, Paul V. ; Giaccone, Giuseppe ; Gazdar, Adi F. ; Minna, John D. / FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations. In: Cancer research. 1997 ; Vol. 57, No. 11. pp. 2256-2267.
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abstract = "We evaluated primary lung cancers, tumor cell lines, and preneoplastic bronchial lesions for molecular genetic abnormalities in the candidate tumor suppressor gene FHIT, which spans the FRA3B fragile site at 3p14.2. 3p14.2 allele loss was very frequent in 32 lung cancer cell lines [100{\%} of small cell lung cancer and 88{\%} of non-small cell lung cancer (NSCLC)] and 108 primary NSCLC cancers (45{\%}), with numerous breakpoints indicating involvement of several distinct regions in the FRA3B site. 3p14 allele loss was least frequent in the adenocarcinoma subtype and occurred at the relatively late carcinoma in situ stage of preneoplastic bronchial lesions found in NSCLC patients. Homozygous deletions within the FHIT/FRA3B region were found in 6 of 135 (4.4{\%}) thoracic cancer cell lines. Northern blot showed low or absent FHIT expression in most thoracic cancer cell lines tested, whereas reverse transcription-PCR showed that 59-62{\%} exhibited aberrant FHIT transcripts but nearly always (93-100{\%}) also expressing the wild-type transcripts. Aberrant transcripts included precise deletions of FHIT exons, insertion of non-FHIT sequences between exons and insertions replacing exons. Complete open reading frame single-strand conformational polymorphism analysis of 102 lung cancer cDNAs revealed only one nonsplicing mutation. Normal cells including bronchial epithelium, lung, and trachea expressed wild-type FHIT transcript and a variant transcript deleted for exon 8 but not the other aberrant transcripts, arguing against exon 8-deleted FHIT transcripts being tumor specific. Our findings support the conclusion that FHIT/FRA3B abnormalities are associated with lung cancer pathogenesis but that FHIT abnormalities differ from the types of mutations and lack of wild-type transcript found in classic tumor suppressor genes, and functional studies are needed to define the role of FHIT in thoracic tumorigenesis.",
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T1 - FHIT and FRA3B 3p14.2 allele loss are common in lung cancer and preneoplastic bronchial lesions and are associated with cancer-related FHIT cDNA splicing aberrations

AU - Fong, Kwun M.

AU - Biesterveld, Eric J.

AU - Virmani, Arvind

AU - Wistuba, Ignacio

AU - Sekido, Yoshitaka

AU - Bader, Scott A.

AU - Ahmadian, Mohsen

AU - Ong, S. Tiong

AU - Rassool, Feyruz V.

AU - Zimmerman, Paul V.

AU - Giaccone, Giuseppe

AU - Gazdar, Adi F.

AU - Minna, John D.

PY - 1997/6/1

Y1 - 1997/6/1

N2 - We evaluated primary lung cancers, tumor cell lines, and preneoplastic bronchial lesions for molecular genetic abnormalities in the candidate tumor suppressor gene FHIT, which spans the FRA3B fragile site at 3p14.2. 3p14.2 allele loss was very frequent in 32 lung cancer cell lines [100% of small cell lung cancer and 88% of non-small cell lung cancer (NSCLC)] and 108 primary NSCLC cancers (45%), with numerous breakpoints indicating involvement of several distinct regions in the FRA3B site. 3p14 allele loss was least frequent in the adenocarcinoma subtype and occurred at the relatively late carcinoma in situ stage of preneoplastic bronchial lesions found in NSCLC patients. Homozygous deletions within the FHIT/FRA3B region were found in 6 of 135 (4.4%) thoracic cancer cell lines. Northern blot showed low or absent FHIT expression in most thoracic cancer cell lines tested, whereas reverse transcription-PCR showed that 59-62% exhibited aberrant FHIT transcripts but nearly always (93-100%) also expressing the wild-type transcripts. Aberrant transcripts included precise deletions of FHIT exons, insertion of non-FHIT sequences between exons and insertions replacing exons. Complete open reading frame single-strand conformational polymorphism analysis of 102 lung cancer cDNAs revealed only one nonsplicing mutation. Normal cells including bronchial epithelium, lung, and trachea expressed wild-type FHIT transcript and a variant transcript deleted for exon 8 but not the other aberrant transcripts, arguing against exon 8-deleted FHIT transcripts being tumor specific. Our findings support the conclusion that FHIT/FRA3B abnormalities are associated with lung cancer pathogenesis but that FHIT abnormalities differ from the types of mutations and lack of wild-type transcript found in classic tumor suppressor genes, and functional studies are needed to define the role of FHIT in thoracic tumorigenesis.

AB - We evaluated primary lung cancers, tumor cell lines, and preneoplastic bronchial lesions for molecular genetic abnormalities in the candidate tumor suppressor gene FHIT, which spans the FRA3B fragile site at 3p14.2. 3p14.2 allele loss was very frequent in 32 lung cancer cell lines [100% of small cell lung cancer and 88% of non-small cell lung cancer (NSCLC)] and 108 primary NSCLC cancers (45%), with numerous breakpoints indicating involvement of several distinct regions in the FRA3B site. 3p14 allele loss was least frequent in the adenocarcinoma subtype and occurred at the relatively late carcinoma in situ stage of preneoplastic bronchial lesions found in NSCLC patients. Homozygous deletions within the FHIT/FRA3B region were found in 6 of 135 (4.4%) thoracic cancer cell lines. Northern blot showed low or absent FHIT expression in most thoracic cancer cell lines tested, whereas reverse transcription-PCR showed that 59-62% exhibited aberrant FHIT transcripts but nearly always (93-100%) also expressing the wild-type transcripts. Aberrant transcripts included precise deletions of FHIT exons, insertion of non-FHIT sequences between exons and insertions replacing exons. Complete open reading frame single-strand conformational polymorphism analysis of 102 lung cancer cDNAs revealed only one nonsplicing mutation. Normal cells including bronchial epithelium, lung, and trachea expressed wild-type FHIT transcript and a variant transcript deleted for exon 8 but not the other aberrant transcripts, arguing against exon 8-deleted FHIT transcripts being tumor specific. Our findings support the conclusion that FHIT/FRA3B abnormalities are associated with lung cancer pathogenesis but that FHIT abnormalities differ from the types of mutations and lack of wild-type transcript found in classic tumor suppressor genes, and functional studies are needed to define the role of FHIT in thoracic tumorigenesis.

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