Journal of the National Cancer Institute Advance Access originally published online on September 11, 2007
JNCI Journal of the National Cancer Institute 2007 99(18):1401-1409; doi:10.1093/jnci/djm128
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Published by Oxford University Press 2007.
ARTICLES |
Lung Cancer Survival and Functional Polymorphisms in MBL2, an Innate-Immunity Gene
Affiliations of authors: Laboratory of Human Carcinogenesis (SRP, LEM, SA, EDB, CCH) and Section on Genomic Variation, Pediatric Oncology Branch (SJC), National Cancer Institute, National Institutes of Health, Bethesda, MD; Lombardi Comprehensive Cancer Center and Cancer Genetics and Epidemiology Program, Georgetown University School of Medicine, Washington, DC (CL, PGS)
Correspondence to: Curtis C. Harris, MD, Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Rm 3068, Bldg 37, 37 Convent Dr, Bethesda, MD 20892-4258 (e-mail: harrisc{at}mail.nih.gov).
Background: The relationship among chronic inflammation, innate immunity, and cancer is well established. Mannose-binding lectin (MBL) is a key player in innate immunity. Five polymorphisms in the promoter and first exon of the MBL2 gene alter the expression and function of MBL in humans and are associated with inflammation-related disease susceptibility. These five polymorphisms create six well-characterized haplotypes that result in lower (i.e., LYB, LYC, HYD, and LXA) or higher (i.e., HYA and LYA) serum MBL concentrations. We investigated whether survival of patients with lung cancer was associated with these polymorphisms.
Methods: We used a multivariable Cox proportional hazards model to study the association between MBL2 polymorphisms and their haplotypes and diplotypes in 558 white and 173 African American patients with non–small-cell lung cancer in the Baltimore, MD, area and lung cancer mortality. Smoking history and race were obtained from interviews, tumor stage was obtained from medical records, and cause of death was obtained from the National Death Index. All statistical tests were two-sided.
Results: We found a statistically significant association between the X allele of the promoter Y/X polymorphism (which results in a lower serum MBL concentration) and improved lung cancer survival among white patients (risk ratio [RR] of death from lung cancer with X/X or X/Y genotype compared with Y/Y genotype = 0.61, 95% confidence interval [CI] = 0.46 to 0.81) but not among African American patients (RR = 1.11, 95% CI = 0.69 to 1.77). The associations among white patients were strongest in heavy smokers and were independent of stage. We also found a statistically significant interaction between the Y/X polymorphism and race for lung cancer survival (Pinteraction = .019). The MBL2 LXA haplotype and XA/B diplotype, which are also associated with low serum MBL levels, were statistically significantly associated with improved lung cancer survival among white patients.
Conclusion: The functional Y/X polymorphism of the innate-immunity gene MBL2 and MBL2 haplotypes and diplotypes appear to be associated with lung cancer survival among white patients.
| CONTEXT AND CAVEATS Prior knowledge The innate-immunity MBL2 gene encodes the mannose-binding lectin (MBL) protein, which activates the lectin pathway of the complement system, enhances opsonophagocytosis, and modulates the cytokine response to inflammation. Altered function or expression of MBL caused by polymorphisms within the secretor haplotype block of the MBL2 gene has been associated with increased susceptibility to inflammation-related disorders and certain cancers. Study design A prospective study to examine the association between five polymorphisms within the MBL2 secretor haplotype block and disease-specific survival among 558 white patients and 173 African American patients with non–small-cell lung cancer in the metropolitan area of Baltimore, MD. Contribution The functional MBL2 Y/X promoter polymorphism and the secretor haplotypes and diplotypes associated with low serum MBL concentrations were associated with improved lung cancer–specific survival among white patients but not among African American patients. Implications Genetic polymorphisms in genes in the innate immune response pathway that modulate inflammation could be a prognostic factor in lung cancer patients. Limitations This study had fewer African American patients than white patients and thus had reduced power to assess associations among African American patients. Stage and histotype information was not available on all patients. Clinical follow-up information was restricted to death certificate data.
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Manuscript received March 8, 2007; revised June 28, 2007; accepted July 23, 2007.
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J Natl Cancer Inst 2007 99: 1353.