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(American Journal of Pathology. 2000;157:2133-2141.)
© 2000 American Society for Investigative Pathology

Regular Articles

Different Subtypes of Human Lung Adenocarcinoma Caused by Different Etiological Factors

Evidence from p53 Mutational Spectra

Takehisa Hashimoto^*, Yoshio Tokuchi^*, Moriaki Hayashi^*, Yasuhito Kobayashi, Kazunori Nishida, Shin-ichi Hayashi^*, Yuichi Ishikawa^§, Ken Nakagawa, Jun-ichi Hayashi and Eiju Tsuchiya^*

From the Laboratory of Cancer Diagnosis and Therapy,^*
Saitama Cancer Center Research Institute, Saitama; the Department of Pathology,
Saitama Cancer Center, Saitama; the Department of Pathology,^§
Cancer Institute, Tokyo; the Department of Chest Surgery, Cancer Institute Hospital, Tokyo; and the Department of Thoracic and Cardiovascular Surgery,
Niigata University School of Medicine, Niigata, Japan

Human lung adenocarcinomas are only relatively weakly associated with tobacco smoke, and other etiological factors need to be clarified. These may also vary with the histopathology. Because the p53 mutation status (frequency and spectrum) of a carcinoma can provide clues to causative agents, we subclassified 113 adenocarcinomas into five cell types: hobnail, columnar/cuboidal, mixed, polygonal, and goblet (54, 23, 18, 13, and 5, respectively) and investigated relationships with p53 mutations and smoking history. In the hobnail cell type, a low mutational frequency (37%) and a high proportion of transitions (65%), especially G:C to A:T transitions at CpG dinucleotides (45%) associated with spontaneous mutations, were found with a weak relation to tobacco smoke. In contrast, a high mutation frequency (70%) with a higher proportion of transversions (50%), especially G:C to T:A (44%) on the nontranscribed DNA strand, caused by exogenous carcinogenic agents like tobacco smoke, were observed for the columnar cell type, as with squamous cell carcinomas. These results indicate that two major subtypes of lung adenocarcinoma exist, one probably caused by tobacco smoke, and the other possibly due to spontaneous mutations. For the prevention of lung adenocarcinomas, in addition to stopping tobacco smoking, the elucidation of endogenous mechanisms is important.

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