Smoking-related and non-smoking-related carcinogensis in adenocarcinoma of the lung.

22001 Background: Recently, female, never-smoking patients with adenocarcinoma of the lung appear to increase worldwide. However, molecular basis of these lung cancers is not well understood.,We sequenced EGFR, HER2, KRAS gene and transmembrare region of the MET in a cohort of 211 lung adenocarcinoma. In addition, we searched for mutation of the TP53, LKB1 and PIK3CA gene in 195, 71 and 68 adenocarcinomas, respectively.,EGFR, HER2, KRAS and MET mutations were found in 103 (49%), 5 (2%), 29 (14%) and 7 (3%), respectively. These four mutations had a strict mutual exclusionary relationship. All the 7 MET mutations deleted exon 14 that contained a putative binding site for c-cbl that degraded MET. In 4 of 7 tumors, we found different intronic mutations resulting in disruption of splicing consensus. There was a striking difference among these patients in terms of incidence of never-smokers and other features (Table). Never-smokers were frequent in patients with EGFR or HER2 tumors but rare in KRAS tumors. In contrast, incidence of the TP53 mutation was not significantly different by the mutated oncogenes. However, G to T transversion of the TP53 gene, a hallmark of tobacco-related carcinogenesis, was almost absent in EGFR tumors. LKB1 mutations were found in 3 of 71 (4%), all of which were in male smokers and each of them either had EGFR, TP53 or KRAS mutation. Two identical PIK3CA mutations (E545K) were found in 68 adenocarcinomas (3%). These two patients were female, never smokers and they both had EGFR L858R mutation.,There appeared to exist two classes of cancer genes in lung adenocarcinomas. EGFR, HER2, PIK3CA gene mutations were associated with non-smoking-related carcinonogenesis, while KRAS, G to T TP53, LKB1 gene mutation were associated with smoking-related one. Also these cancer genes could be divided into two categories. One included genes whose mutations occur in mutually exclusionary fashion and the other includes genes without such relationship. [Table: see text] No significant financial relationships to disclose.