Tockman M S
Johns Hopkins University School of Hygiene and Public Health, Department of Environmental Health Sciences, Baltimore, Maryland 21205, USA.
J Cell Biochem Suppl. 1996;25:177-84.
Lung cancer is the leading cause of cancer-related deaths in western countries. The prognosis for patients with lung cancer depends primarily on the stage of the tumor at the time of clinical diagnosis. New understanding of tumor biology has turned attention away from detection of clinical lung cancer, usually metastatic at presentation, toward recognition of genetic and protein markers which precede malignancy. Mutations of four types of genes contribute to the process of epithelial carcinogenesis by modifying control of cell growth. Examples of three of these changes have been detected in pre-malignant sputum, and validated in subsequent tumor. We have identified gene products (tumor associated and differentiation protein antigens), mutations of k-ras and p53, and microsatellite alterations as potential markers of subsequent malignancy. We consider the morphologic progression seen in archived sputum cells as the paradigm of neoplastic development in the lung. Although the NCl collaborative trials had shown that this progression is not recognized sufficiently often (sensitive) to be useful for lung cancer screening, this progression may be used to assess the timing of gene and peptide markers of carcinogenesis. Previous work has shown that at the time Johns Hopkins Lung Project sputum cells express moderately atypical metaplasia, 53% (8/15) of sputum specimens expressed common (codon 12) k-ras or (codons 273 or 281) p53 mutations. Other investigators have reported that earlier morphologic changes (metaplasia) accompany 3p and 9p losses of heterozygosity. These observations suggest that 3p and 9p loss likely precede k-ras or p53 mutations. Our preliminary data demonstrate that over-expression of a 31 kD tumor associated antigen recently purified, sequenced, and identified as heterogeneous nuclear ribonucleoprotein (hnRNP) A2 (with cross reactivity to splice variant B1), is expressed in most lung cancer cases before any morphologic abnormality. Comparison of the accuracy of this marker with sputum cytology will determine its value for early lung cancer detection. Preliminary evidence confirms this marker greatly improves the accuracy of standard sputum cytology for detection of lung carcinogenesis. Clinical intervention trials must be undertaken to determine whether modulation of hnRNP overexpression is useful as an intermediate endpoint for chemoprevention.
肺癌是西方国家癌症相关死亡的主要原因。肺癌患者的预后主要取决于临床诊断时肿瘤的分期。对肿瘤生物学的新认识已将注意力从通常在就诊时已发生转移的临床肺癌检测，转向对恶性肿瘤发生之前的基因和蛋白质标志物的识别。四种类型基因的突变通过改变细胞生长控制，促进上皮细胞癌变过程。在癌前痰液中已检测到其中三种变化的实例，并在后续肿瘤中得到验证。我们已将基因产物（肿瘤相关和分化蛋白抗原）、k-ras和p53突变以及微卫星改变确定为后续恶性肿瘤的潜在标志物。我们将存档痰液细胞中所见的形态学进展视为肺部肿瘤发生发展的范例。尽管美国国立癌症研究所的协作试验表明，这种进展未被充分频繁地识别（敏感性不足），无法用于肺癌筛查，但这种进展可用于评估癌变过程中基因和肽类标志物出现的时间。先前的研究表明，在约翰霍普金斯肺癌项目中，当痰液细胞表现出中度非典型化生时，53%（8/15）的痰液标本表达常见的（密码子12）k-ras或（密码子273或281）p53突变。其他研究人员报告称，早期形态学变化（化生）伴随着3p和9p杂合性缺失。这些观察结果表明，3p和9p缺失可能先于k-ras或p53突变。我们的初步数据表明，最近纯化、测序并鉴定为不均一核核糖核蛋白（hnRNP）A2（与剪接变体B1有交叉反应）的一种31 kD肿瘤相关抗原的过表达，在大多数肺癌病例中在任何形态学异常出现之前就已表达。将该标志物的准确性与痰液细胞学进行比较，将确定其在早期肺癌检测中的价值。初步证据证实，该标志物大大提高了标准痰液细胞学检测肺癌发生的准确性。必须进行临床干预试验，以确定调节hnRNP过表达作为化学预防的中间终点是否有用。
