Loss of FHIT function in lung cancer and preinvasive bronchial lesions.
Loss of FHIT function in lung cancer and preinvasive bronchial lesions.
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发表时间：
1998-11
期刊：
影响因子：
11.2
通讯作者：
G. Sozzi;U. Pastorino;Luisa Moiraghi;E. Tagliabue;F. Pezzella;C. Ghirelli;S. Tornielli;L. Sard;K. Huebner;M. Pierotti;C. Croce;S. Pilotti
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作者：
G. Sozzi;U. Pastorino;Luisa Moiraghi;E. Tagliabue;F. Pezzella;C. Ghirelli;S. Tornielli;L. Sard;K. Huebner;M. Pierotti;C. Croce;S. Pilotti
我们以前克隆和鉴定的肿瘤抑制基因FHIT（脆性组氨酸三联体）在染色体3p14.2，并发现该基因是改变了人类肿瘤，包括肺癌的缺失。为了评估失活的频率和特异性及其在临床环境中的相关性，我们已经产生了针对Fhit蛋白的抗体，并通过免疫组化研究了其在一系列非小细胞肺癌和正常支气管粘膜以及一系列浸润前病变中的表达。结果表明，Fhit蛋白的缺失在非小细胞肺癌（73%）和癌前病变（93%）中最为常见，吸烟者肿瘤中的缺失率（75%）显著高于非吸烟者（39%; P < 0.0005），并且在肿瘤和癌前病变中比p53过表达（73%对46%）是独立的且更频繁的事件。与腺癌相比，鳞状细胞癌中Fhit表达缺失的病例百分比较高（87%对57%; P < 0.00001），而其他组织类型（大细胞，粘膜表皮）显示中间值（69%）。原发性肺癌和癌前病变中FHIT表达的丢失率很高，这支持了FHIT改变在支气管细胞的生长控制中起重要作用的观点。FHIT失活在鳞状细胞癌中特别重要，鳞状细胞癌通常与前体发育异常病变相关。肺癌发生中Fhit丢失的总体高频率和早熟性以及目前描述的免疫组织化学方法的发展表明该基因在肺癌的早期检测和化学预防研究中作为中间生物标志物的潜在用途。
We previously cloned and characterized the tumor suppressor gene FHIT (fragile histidine triad) at chromosome 3p14.2 and found that this gene is altered by deletions in human tumors, including lung cancer. To assess the frequency and specificity of inactivation and its relevance in a clinical setting, we have produced antibodies against the Fhit protein and studied its expression in a series of non-small cell lung cancers and normal bronchial mucosa and a spectrum of preinvasive lesions by immunohistochemistry. The data indicate that the loss of Fhit protein is the most frequent alteration in non-small cell lung cancer (73%) and precancerous lesions (93%), is significantly higher in the tumors of smokers (75%) than in those of nonsmokers (39%; P < 0.0005), and is an independent and more frequent event than p53 overexpression in tumors and precancerous lesions (73 versus 46%). The percentage of cases lacking Fhit expression was higher in the squamous type compared to adenocarcinoma (87 versus 57%; P < 0.00001), whereas other histotypes (large cell, mucoepidermal) showed an intermediate value (69%). Loss of Fhit expression in a very high percentage of primary lung carcinomas and precancerous lesions supports the notion that FHIT alterations play an important role in the growth control of bronchial cells. FHIT inactivation is particularly important in squamous cell carcinomas that are often associated with precursor dysplastic lesions. The overall high frequency and precocity of Fhit loss in lung carcinogenesis and the development of the presently described immunohistochemical approach suggest a potential use of this gene in the early detection of lung cancer and in chemopreventive studies as an intermediate biomarker.