Ordered subset analysis identifies loci influencing lung cancer risk on chromosomes 6q and 12q

Abstract

Background: Genetic susceptibility for cancer can differ substantially among families. We use trait-related covariates to identify a genetically homogeneous subset of families with the best evidence for linkage in the presence of heterogeneity.

Methods: We performed a genome-wide linkage screen in 93 families. Samples and data were collected by the familial lung cancer recruitment sites of the Genetic Epidemiology of Lung Cancer Consortium. We estimated linkage scores for each family by the Markov chain Monte Carlo procedure using SimWalk2 software. We used ordered subset analysis (OSA) to identify genetically homogenous families by ordering families based on a disease-associated covariate. We performed permutation tests to determine the relationship between the trait-related covariate and the evidence for linkage.

Results: A genome-wide screen for lung cancer loci identified strong evidence for linkage to 6q23-25 and suggestive evidence for linkage to 12q24 using OSA, with peak logarithm of odds (LOD) scores of 4.19 and 2.79, respectively. We found other chromosomes also suggestive for linkages, including 5q31-q33, 14q11, and 16q24.

Conclusions: Our OSA results support 6q as a lung cancer susceptibility locus and provide evidence for disease linkage on 12q24. This study further increased our understanding of the inheritability for lung cancer. Validation studies using larger sample size are needed to verify the presence of several other chromosomal regions suggestive of an increased risk for lung cancer and/or other cancers.

Impact: OSA can reduce genetic heterogeneity in linkage study and may assist in revealing novel susceptibility loci.

Figure 1

OSA results on chromosome 6q. The blue curve represents OSA results using the largest number of affected individuals in the family; the green curve represents OSA results using the lowest proportion of smokers in the family; and the yellow curve represents OSA results using the smallest incidence rate of digestive cancer in the family. For each horizontal dash line, the part under the curve with the same color represents its corresponding1-LOD-unit support interval. Three intervals overlap over one region of 160.0-164.0 cM.

Figure 2

OSA results on chromosome 12. The horizontal line represents 1-LOD-unit support interval(110.6-143.5 cM)