A Major Lung Cancer Susceptibility Locus Maps to Chromosome 6q23–25

Abstract

Lung cancer is a major cause of death in the United States and other countries. The risk of lung cancer is greatly increased by cigarette smoking and by certain occupational exposures, but familial factors also clearly play a major role. To identify susceptibility genes for familial lung cancer, we conducted a genomewide linkage analysis of 52 extended pedigrees ascertained through probands with lung cancer who had several first-degree relatives with the same disease. Multipoint linkage analysis, under a simple autosomal dominant model, of all 52 families with three or more individuals affected by lung, throat, or laryngeal cancer, yielded a maximum heterogeneity LOD score (HLOD) of 2.79 at 155 cM on chromosome 6q (marker D6S2436). A subset of 38 pedigrees with four or more affected individuals yielded a multipoint HLOD of 3.47 at 155 cM. Analysis of a further subset of 23 multigenerational pedigrees with five or more affected individuals yielded a multipoint HLOD score of 4.26 at the same position. The 14 families with only three affected relatives yielded negative LOD scores in this region. A predivided samples test for heterogeneity comparing the LOD scores from the 23 multigenerational families with those from the remaining families was significant (P=.007). The 1-HLOD multipoint support interval from the multigenerational families extends from C6S1848 at 146 cM to 164 cM near D6S1035, overlapping a genomic region that is deleted in sporadic lung cancers as well as numerous other cancer types. Parametric linkage and variance-components analysis that incorporated effects of age and personal smoking also supported linkage in this region, but with somewhat diminished support. These results localize a major susceptibility locus influencing lung cancer risk to 6q23-25.

Systematic review of the relationship between family history and lung cancer risk

“…Ultimately, verification of a genetic predisposition must come from the identification of causal mutations. Recently, following a genomewide linkage scan, a candidate locus for lung cancer predisposition has been reported (Bailey-Wilson et al, 2004). If confirmed, this would provide the most convincing evidence to date of a genetic susceptibility outside rare Mendelian disorders.…”

Risk factors for lung cancer in Iowa women: Implications for prevention

“…A recent study in Detroit, Michigan [19] found an increased risk for early-onset lung cancer among those with a first-degree relative with lung cancer after adjusting for race, age, sex, and pack-years of smoking (OR=1.71, 95% CI=1.16-2.52). With regard to the genetic component of such familial risk, a susceptibility locus for lung cancer has recently been identified on chromosome six [20].…”

Genetic Epidemiology of Cigarette Smoke–Induced Lung Disease

“…Family linkage studies have been used to identify genes for lung cancer, lung function, and COPD (30)(31)(32). The only linkage study in lung cancer successfully identified a region on 6q24 linked to familial lung cancer (30,33).…”

“…The only linkage study in lung cancer successfully identified a region on 6q24 linked to familial lung cancer (30,33). With fine mapping, the RGS17 gene was identified as a putative lung cancer susceptibility gene (34).…”