Fong K M, Biesterveld E J, Virmani A, Wistuba I, Sekido Y, Bader S A, Ahmadian M, Ong S T, Rassool F V, Zimmerman P V, Giaccone G, Gazdar A F, Minna J D
Hamon Center for Therapeutic Oncology Research and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8593, USA.
Cancer Res. 1997 Jun 1;57(11):2256-67.
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.
我们评估了原发性肺癌、肿瘤细胞系和癌前支气管病变，以检测候选抑癌基因FHIT的分子遗传异常，该基因跨越位于3p14.2的FRA3B脆性位点。3p14.2等位基因缺失在32个肺癌细胞系中非常常见[小细胞肺癌中为100%，非小细胞肺癌（NSCLC）中为88%]，在108例原发性NSCLC中也很常见（45%），有众多断点表明FRA3B位点的几个不同区域受累。3p14等位基因缺失在腺癌亚型中最少见，且发生在NSCLC患者癌前支气管病变相对较晚的原位癌阶段。在135个胸癌细胞系中有6个（4.4%）发现FHIT/FRA3B区域内的纯合缺失。Northern印迹显示，在大多数检测的胸癌细胞系中FHIT表达低或无表达，而逆转录PCR显示59 - 62%表现出异常的FHIT转录本，但几乎总是（93 - 100%）也表达野生型转录本。异常转录本包括FHIT外显子的精确缺失、外显子之间非FHIT序列的插入以及取代外显子的插入。对102个肺癌cDNA进行的完全开放阅读框单链构象多态性分析仅发现一个非剪接突变。包括支气管上皮、肺和气管在内的正常细胞表达野生型FHIT转录本和缺失外显子8的变异转录本，但不表达其他异常转录本，这表明缺失外显子8的FHIT转录本并非肿瘤特异性。我们的研究结果支持以下结论：FHIT/FRA3B异常与肺癌发病机制相关，但FHIT异常不同于经典抑癌基因中发现的突变类型和野生型转录本的缺失，需要进行功能研究来确定FHIT在胸肿瘤发生中的作用。
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