A susceptibility locus on chromosome 6q greatly increases lung cancer risk among light and never smokers

Abstract

Cigarette smoking is the major cause for lung cancer, but genetic factors also affect susceptibility. We studied families that included multiple relatives affected by lung cancer. Results from linkage analysis showed strong evidence that a region of chromosome 6q affects lung cancer risk. To characterize the effects that this region of chromosome 6q region has on lung cancer risk, we identified a haplotype that segregated with lung cancer. We then performed Cox regression analysis to estimate the differential effects that smoking behaviors have on lung cancer risk according to whether each individual carried a risk-associated haplotype or could not be classified and was assigned unknown haplotypic status. We divided smoking exposures into never smokers, light smokers (<20 pack-years), moderate smokers (20 to <40 pack-years), and heavy smokers (>or=40 pack-years). Comparing results according to smoking behavior stratified by carrier status, compared with never smokers, there was weakly increasing risk for increasing smoking behaviors, with the hazards ratios being 3.44, 4.91, and 5.18, respectively, for light, moderate, or heavy smokers, whereas among the individuals from families without the risk haplotype, the risks associated with smoking increased strongly with exposure, the hazards ratios being, respectively, 4.25, 9.17, and 11.89 for light, moderate, and heavy smokers. The never smoking carriers had a 4.71-fold higher risk than the never smoking individuals without known risk haplotypes. These results identify a region of chromosome 6q that increases risk for lung cancer and that confers particularly higher risks to never and light smokers.

Figure 1

Heterogeneity LOD scores from analysis of chromosome 6 for 93 families selected to include multiple relatives with lung cancer. Subset 1 includes families with 2 or 3 individuals affected by lung cancer, Subset 2 includes families with 5 or more individuals in two or more generations, Subset 3 comprises individuals with 4 or more individuals in a sibship who had lung cancer

Figure 2

Time to lung cancer among carriers (left panel), noncarriers (middle panel), and individuals with unknown carrier status (right panel). Smoking strata are shown with the black line reserved for nonsmokers, the red line for light smokers (1-19 pack years), the green line is for 20-39 pack years and the blue line is for heavier smokers (40 or more pack years). Tick marks on lines indicate ages at censoring due to either currently alive without lung cancer or death from a competing cause.