Molecular classification of the lung cancer

我们提出肺腺癌在临床病理学上可分为两种主要亚型。一种是具有终末呼吸单位（TRU）形态和生物学特征的亚型，包括II型肺泡细胞、Clara细胞和无纤毛细支气管上皮细胞。另一种是腺癌，具有支气管表面上皮和支气管腺上皮的特征。我们发现这种差异很好地解释了肺腺癌的临床病理多样性，其表达谱分析结果发表在J Clin Oncol（2006）。根据目前假定的肺癌顺序发展模式，我们使用侵袭前到侵袭性病变的全谱，检测了KRAS和EGFR基因突变。尽管KRAS和EGFR基因突变的相互排斥性即使在浸润前病变中也保持不变，但病变的发生率沿着假定的进展模式是完全不同的。33%的AAH、12%的原位癌、8%的微创腺癌和0%的高分化腺癌中KRAS基因突变，而EGFR突变的频率波动不大，分别为25%、51%、36%、86%和67%。这些结果与基因靶向小鼠模型的发现一致;表达致癌KRAS的小鼠发生AAH，但未发生浸润性腺癌，而在表达突变EGFR的小鼠中观察到一系列浸润前至浸润性腺癌。综上所述，这表明AAH可以通过KRAS或EGFR基因突变发展，但携带KRAS基因突变的AAH可能不会进一步发展为浸润性癌症。

We have proposed that lung adenocarcinomas can clinicopathologically divide into two major subtypes. One is the subtype that showed morphology and biological features of terminal respiratory unit (TRU), including type II pneumocytes, Clara cells and non-ciliated bronchiolar epithelium. The other is an adenocarcinoma that shares with the features of bronchial surface epithelium and bronchial glandular epithelium. We found that this distinction well explained clinicopathological diversity of the lung adenocarcinomas, of which results using expression profiling analysis were published in J Clin Oncol (2006).In the subsequent study, we focused on precancerous lesions of the adenocarcinomas. Using the full spectrum of preinvasive to invasive lesions under the current putative schema of the sequential development of lung cancer, we examined KRAS and EGFR gene mutations. Although the mutually exclusive nature of KRAS and EGFR gene mutations was maintained even in preinvasive lesions, the incidences of the lesions along the putative progression schema were quite different. The KRAS gene was mutated in 33% of AAH, 12% of carcinomas in situ, 8% of minimally invasive adenocarcinomas, and 0% of well-differentiated adenocarcinomas, whereas the frequencies of EGFR mutation did not fluctuate greatly, at 25%, 51%, 36%, 86%, and 67%, respectively. These results were consistent with the findings of the gene-targeted mice model ; the mice expressing oncogenic KRAS developed AAH, but not invasive adenocarcinoma, whereas a spectrum of preinvasive to invasive adenocarcinomas was observed in the mice expressing mutant EGFR. Taken together, it is suggested that AAH could develop by either KRAS or EGFR gene mutation, but AAH harboring a KRAS gene mutation might not further progress to an invasive cancer.