Carcinogenesis Advance Access originally published online on February 24, 2008
Carcinogenesis 2008 29(5):957-963; doi:10.1093/carcin/bgn048
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Association of KRAS polymorphisms with risk for lung adenocarcinoma accompanied by atypical adenomatous hyperplasias
1 Biology Division, National Cancer Center Research Institute, Tokyo 1040045, Japan
2 Thoracic Oncology Division
3 Thoracic Surgery Division, National Cancer Center Hospital, Tokyo 1040045, Japan
4 Cancer Information Services and Surveillance Division, Center for Cancer Control and Information Services, National Cancer Center, Tokyo 1040045, Japan
5 Department of Biostatistics/Epidemiology and Preventive Health Sciences, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan
6 Diagnostic Pathology Division, National Cancer Center Hospital, Tokyo 1040045, Japan
7 First Department of Internal Medicine, Gunma University School of Medicine, Showa-machi, Gunma 3718511, Japan
8 Present address: Department of Surgical Pathology, Hokkaido University Hospital, Sapporo 0608648, Japan
* To whom correspondence should be addressed. Tel: +81 3 3542 2511; Fax: +81 3 3542 0807;Email: 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.
Abbreviations: AAH, atypical adenomatous hyperplasia; ADC, adenocarcinoma; BAC, bronchioloalveolar carcinoma; Casc, cancer susceptibility candidate; cDNA, complementary DNA; CI, confidence interval; Kras, Kirsten rat sarcoma oncogene; Las, lung adenoma susceptibility; LD, linkage disequilibrium; LRMP, lymphoid-restricted membrane protein; OR, odds ratio; Pas1, pulmonary adenoma susceptibility 1; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism
Received October 14, 2007; revised January 16, 2008; accepted February 7, 2008.