| Research Abstract |
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.
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