Genetic Predisposition to Lung Cancer

Whereas tobacco smoking is the predominant risk factor for lung cancer, there are several lines of evidence to suggest that genetic susceptibility modulates this risk. EPIC investigators have participated in several genome-wide association study (GWAS) approaches and have identified several intriguing loci with more common population frequencies. At chromosome 15q25, a locus that contains several nicotinic acetylcholine receptors, the same variants associated with lung cancer risk are also associated with propensity to smoke, leading to the suggestion that this association may be due only to smoking behaviour versus joint effects directly on lung cancer risk and smoking1,2. Similar studies have variants at 5p15.33, a region containing the hTERT and CLPTM1L genes3, hMSH5 in the chromosome 6 MHC region1, RAD52, and CDNK2A4. Many of these same loci also show relevance to a particular histology (MHC, CDKN2A, RAD52, hTERT), indicating that for lung cancer, histological subtype is an important consideration.

  1. Hung RJ et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 2008 Apr 3;452(7187):633-7. PMID: 18385738

  2. Timofeeva MN et al. Genetic polymorphisms in 15q25 and 19q13 loci, cotinine levels, and risk of lung cancer in EPIC. Cancer Epidemiol Biomarkers Prev. 2011 Oct;20(10):2250-61. PMID: 21862624

  3. McKay JD et al. Lung cancer susceptibility locus at 5p15.33. Nat Genet. 2008 Dec;40(12):1404-6. PMID: 18978790

  4. Timofeeva MN et al. Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls. Hum Mol Genet. 2012 Nov 15;21(22):4980-95. PMID: 22899653