Lung Cancer Risk Prediction Using Common SNPs Located in GWAS-Identified Susceptibility Regions.
BACKGROUND
Genome-wide association studies (GWAS) have consistently identified specific lung cancer susceptibility regions. We evaluated the lung cancer-predictive performance of single-nucleotide polymorphisms (SNPs) in these regions.


METHODS
Lung cancer cases (N = 778) and controls (N = 1166) were genotyped for 77 SNPs located in GWAS-identified lung cancer susceptibility regions. Variable selection and model development used stepwise logistic regression and decision-tree analyses. In a subset nested in the Pittsburgh Lung Screening Study, change in area under the receiver operator characteristic curve and net reclassification improvement were used to compare predictions made by risk factor models with and without genetic variables.


RESULTS
Variable selection and model development kept two SNPs in each of three GWAS regions, rs2736100 and rs7727912 in 5p15.33, rs805297 and rs1802127 in 6p21.33, and rs8034191 and rs12440014 in 15q25.1. The ratio of cases to controls was three times higher among subjects with a high-risk genotype in every one as opposed to none of the three GWAS regions (odds ratio, 3.14; 95% confidence interval, 2.02-4.88; adjusted for sex, age, and pack-years). Adding a three-level classified count of GWAS regions with high-risk genotypes to an age and smoking risk factor-only model improved lung cancer prediction by a small amount: area under the receiver operator characteristic curve, 0.725 versus 0.717 (p = 0.056); overall net reclassification improvement was 0.052 across low-, intermediate-, and high- 6-year lung cancer risk categories (<3.0%, 3.0%-4.9%, ≥ 5.0%).


CONCLUSIONS
Specifying genotypes for SNPs in three GWAS-identified susceptibility regions improved lung cancer prediction, but probably by an extent too small to affect disease control practice.
Departments of *Epidemiology and †Biostatistics, Graduate School of Public Health, Pittsburgh, Pennsylvania; Departments of ‡Medicine, §Radiology, and ‖Cardiothoracic Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and ¶Department of Pharmacology, School of Medicine, University of Minnesota, Minneapolis, Minnesota.
Joel L
JL
Weissfeld
Yan
Y
Lin
Hui-Min
HM
Lin
Brenda F
BF
Kurland
David O
DO
Wilson
Carl R
CR
Fuhrman
Arjun
A
Pennathur
Marjorie
M
Romkes
Tomoko
T
Nukui
Jian-Min
JM
Yuan
Jill M
JM
Siegfried
Brenda
B
Diergaarde
D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors