Different Subtypes of Human Lung Adenocarcinoma Caused by Different Etiological Factors

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.

Mutations in the epidermal growth factor receptor gene are linked to smoking-independent, lung adenocarcinoma

“…These findings are consistent with Lynch et al (2004), Kosaka et al (2004), and Marchetti et al (2005). Adenocarcinomas that develop in nonsmokers frequently display features of BAC and papillary type tumours, whereas those that develop in smokers frequently include poorly differentiated and solid subtype tumours (Hashimoto et al, 2000;Yang et al, 2002;Nordquist et al, 2004). High incidence of harbouring EGFR mutations in nonsmokers adenocarcinoma well-explains this predilection on pathological findings.…”

“…However, lung cancer also develops in nonsmokers, and 30 -40% of the lung cancer patients in Japan have never smoked history are female, and their major histological tumour type is adenocarcinoma (Sobue et al, 1994;Akazawa et al, 2003). While several reports have shown that the adenocarcinomas that occurred in nonsmokers were distinct from those that developed in smokers in terms of their histological subclassification, prognosis, gene expression pattern, and gene alterations (Tsuchiya et al, 1988;Hashimoto et al, 2000;Ahrendt et al, 2001;Bhattacharjee et al, 2001;Koga et al, 2001;Noda et al, 2001;Vahakangas et al, 2001;Yang et al, 2002), few significant genetic alterations have been reported in adenocarcinomas that developed in nonsmokers.…”

EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset

“…In addition, they often featured mucin production, as proven by Alcian Blue staining (Figure 1b) with acinar structures. As for the cell types originally proposed by Hashimoto et al, 18 the columnar cell type was characteristic of EML4-ALK lung cancers ( Figure 1). …”

“…17 Mutation analysis of TP53 was also performed as described earlier. 18 Genomic DNAs from fresh tumor samples were prepared and exons 4-8 and 10 of the TP53 gene were analyzed by the PCR -single-strand conformation polymorphism and DNA sequencing. For case #4808, TP53 mutation analysis was performed using DNA extracted from formalin-fixed paraffin-embedded tissue and a method based on direct sequencing, because no fresh sample was available for this study at the time of the current study.…”

Proteomic screening of completely resected tumors in relation to survival in patients with stage I non-small cell lung cancer

“…In the present study, therefore, we focused specifically on recurrence of stage I adenocarcinomas that had been completely resected, and followed the outcome of the patients over a 5-year period. The histology of the adenocarcinoma was also further restricted to the well differentiated type with a hobnail cell morphology, which is the most common cell type of this tumor (11). It was expected that the results would help to clarify the changes in protein function that induce micro-metastasis in early-stage NSCLC, and indicate possible new avenues for the development of drugs to suppress tumor recurrence.…”