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. 2006 Jun;16(6):693-701.
doi: 10.1101/gr.5120106.

Variants in the GH-IGF axis confer susceptibility to lung cancer

Matthew F Rudd  1 , Emily L Webb, Athena Matakidou, Gabrielle S Sellick, Richard D Williams, Helen Bridle, Tim Eisen, Richard S Houlston; GELCAPS Consortium
Affiliations

Variants in the GH-IGF axis confer susceptibility to lung cancer

Matthew F Rudd et al. Genome Res. 2006 Jun.

Abstract

We conducted a large-scale genome-wide association study in UK Caucasians to identify susceptibility alleles for lung cancer, analyzing 1529 cases and 2707 controls. To increase the likelihood of identifying disease-causing alleles, we genotyped 1476 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 871 candidate cancer genes, biasing SNP selection toward those predicted to be deleterious. Statistically significant associations were identified for 64 nsSNPs, generating a genome-wide significance level of P=0.002. Eleven of the 64 SNPs mapped to genes encoding pivotal components of the growth hormone/insulin-like growth factor (GH-IGF) pathway, including CAMKK1 E375G (OR=1.37, P=5.4x10(-5)), AKAP9 M463I (OR=1.32, P=1.0x10(-4)) and GHR P495T (OR=12.98, P=0.0019). Significant associations were also detected for SNPs within genes in the DNA damage-response pathway, including BRCA2 K3326X (OR=1.72, P=0.0075) and XRCC4 I137T (OR=1.31, P=0.0205). Our study provides evidence that inherited predisposition to lung cancer is in part mediated through low-penetrance alleles and specifically identifies variants in GH-IGF and DNA damage-response pathways with risk of lung cancer.

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Figures

Figure 1.
Figure 1.
Inter-relationship between genes involved in the GH-IGF pathway containing SNPs associated with risk of lung cancer. Interactions were established using Pathway Assist software and are color-coded as follows: blue (expression), gray (regulation), and red (protein binding). Supporting publications are indicated with the corresponding NCBI Entrez PubMed ID in square brackets. (1) Binding [12,888,636]; (2) Binding [11,832,396]; (3) Expression [11,849,991]; (4) Expression [11,606,442]; (5) Binding [11,126,270]; (6) Binding [15,140,223]; (7) Binding [10,982,804]; (8) Binding [11,751,588]; (9) Regulation [14,517,795]; (10) Regulation [11,395,482]; (11) Regulation [15,047,863]. Validated nsSNPs with frequency data from Caucasian populations were not available in dbSNP Build 123 for genes AKT1, ARG2, FGF2, IGF1, PZDK1, and PRKCE. Bell et al. (2005) found association between lung cancer and SNP T790M.
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