Genetic variation in innate immunity and inflammation pathways associated with lung cancer risk
Version of Record online: 18 JAN 2013
Copyright © 2013 American Cancer Society
Volume 119, Issue 9, page 1761, 1 May 2013
How to Cite
Young, R. P. and Hopkins, R. J. (2013), Genetic variation in innate immunity and inflammation pathways associated with lung cancer risk. Cancer, 119: 1761. doi: 10.1002/cncr.27953
- Issue online: 22 APR 2013
- Version of Record online: 18 JAN 2013
Shiels et al1 report an association between a nuclear factor of kappa light polypeptide gene enhancer of B-cells 1 (NFκB1) gene variant (rs4648127) and lung cancer, suggesting this transcription factor, which is central to regulating inflammatory genes, may underlie a patient's susceptibility to lung cancer. This result requires further scrutiny.
There is growing evidence that genetic susceptibility to lung cancer includes genetic factors underlying a predisposition toward chronic obstructive pulmonary disease (COPD),2 a disease characterized by exaggerated airway inflammation. This is likely because COPD, a highly heritable disease trait (unlike lung cancer), predates lung cancer in up to 90% of cases and confers a 4-fold to 6-fold greater risk above that from age and smoking exposure.2, 3 This is highly relevant to the study by Shiels et al1 because their report of an association between the NFκB1 gene and lung cancer may be mediated through the gene's effect on a predisposition toward COPD. We have previously shown a “mediating effect” in 2 other “lung cancer” genes (GSTM1 [glutathione S-transferase Mu 1] and CHRNA3/5).2 The possibility that the association reported by Shiels et al is actually through its association with COPD requires testing but would be consistent with molecular studies that indicate a critical role for NFκB1 activation in patients with COPD.4
A second important observation from the study by Shiels et al is that a positive family history of lung cancer was found in only 18% of patients with lung cancer (vs 11% in controls; odds ratio [OR], 1.8; P = .005),1 which was similar to our own case-control study finding of 19% (vs 9% in healthy controls; OR, 2.4; P < .001).5 Therefore, although a positive family history roughly doubles a smoker's risk of lung cancer, on its own it has very poor sensitivity (positive in 18%-19% of cases). Similarly, in the study by Shiels et al, although having the cytosine- thymine CT/TT (protective) genotype for the NFκB1 gene variant nearly halves the risk (OR, 0.56; P = .009), it is present in only 10% of cases.1 When we used a panel of protective and susceptibility genotypes to better reflect the net effect of a number of inflammatory and DNA repair genes (N = 19),5 we found the genetic risk “score” spanned an OR of 1 to 10 (in which subject scores were stratified by quintiles). We concluded that combining single nucleotide polymorphism genotype data was much more predictive than family history alone and added significantly to clinical data in lung cancer risk prediction.5
CONFLICT OF INTEREST DISCLOSURES
Dr. Young and the funding of his research have been supported by grants from the University of Auckland, the Health Research Council of New Zealand, and Synergenz BioSciences Ltd, who hold patents for gene-based risk tests of lung cancer.