Different subtypes of human lung adenocarcinoma caused by different etiological factors. Evidence from p53 mutational spectra

Abstract

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.

Figure 1.

Cell types of adenocarcinomas. A: Hobnail cell type: apical portions of carcinoma cells protrude or bulge into the lumen. Note hobnail- or tadpole-shaped cells. B: Columnar/cuboidal cell type: carcinoma composed of nonciliated columnar or cuboidal cells without or with only small amounts of mucus in their cytoplasm. Apical portions of the cells are flat. C: Polygonal cell type: carcinoma composed of polygonal cells with or without mucus in their cytoplasm, proliferating in sheets. D: Goblet cell type: carcinoma cells have abundant mucus in their cytoplasm (hematoxylin and eosin staining; original magnification, ×200).

Figure 2.

A: Frequencies of p53 mutations. B: Rates of transitions and transversions. C: Rates of G:C and A:T transitions. D: Smokers’ and nonsmokers’ rates with reference to adenocarcinoma histology and cell type. *Percentage (No. of cases/Total no. of examined cases). ^†χ test. ^‡Percentage (No. of cases/Total no. of mutated cases). ^§Fisher’s exact probability test.