Carcinogenesis Advance Access published online on February 24, 2008
Carcinogenesis, doi:10.1093/carcin/bgn048
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Association of KRAS Polymorphisms with Risk for Lung Adenocarcinoma Accompanied by Atypical Adenomatous Hyperplasias
1 Biology Division, National Cancer Center Research Institute
2 Thoracic Oncology Division
3 Thoracic Surgery Division
4 Cancer Information Services and Surveillance Division, Center for Cancer Control and Information Services, National Cancer Center, Tokyo, Japan
5 Department of Biostatistics/Epidemiology and Preventive Health Sciences, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
6 Diagnostic Pathology Division, National Cancer Center Hospital, Tokyo, Japan
7 First Department of Internal Medicine, Gunma University School of Medicine, Showa-machi, Gunma, Japan
8 Present affiliation: Department of Surgical Pathology, Hokkaido University Hospital
9To whom correspondence should be addressed. E-mail: jyokota{at}gan2.ncc.go.jp.
The Pulmonary adenoma susceptibility 1 (Pas1) gene affects susceptibility to the development of lung adenomas in mice, with a subset of the adenomas progressing to adenocarcinoma (ADC). In this study, genotype distributions for 10 polymorphisms in the human counterparts for three mouse candidate Pas1 genes, KRAS, CASC1/LAS1 and LRMP, were examined in a hospital-based case-control study consisting of 364 lung ADC cases and 253 controls. All the ADC cases were subjected to lobectomy and subsequent pathological investigation of atypical adenomatous hyperplasia (AAH), a putative precursor for peripheral lung ADC, including bronchioloalveolar carcinoma, in the resected lobes. Eighty-one (22 %) of the ADC cases carried at least one AAH lesion in addition to the primary ADC, and 34 (9%) of them carried multiple AAH lesions. None of the 10 polymorphisms examined showed significant associations with overall lung ADC risk (P>0.05). However, minor allele carriers for two polymorphisms in the KRAS gene, KRAS-1 and -6, showed significantly increased odds ratios (ORs) for ADC accompanied by multiple AAHs (OR=3.0; 95% confidence interval [CI]=1.4-6.2, P=0.004 and OR=2.4; 95% CI=1.1-4.7, P=0.02, respectively). Minor haplotypes including the minor allele for the KRAS-6 polymorphism showed increased ORs for ADC accompanied by multiple AAHs, and KRAS transcripts from the minor allele for this polymorphism were more abundantly detected in lung tissues than those from the major allele. Thus, KRAS polymorphisms were indicated to be involved in risk for the development of AAHs that progress to ADC by causing differential KRAS oncogene expression in the lungs.
Key Words: atypical adenomatous hyperplasia • lung adenocarcinoma • KRAS • Pas1
Received October 14, 2007; revised January 16, 2008; accepted February 7, 2008.