Genetic susceptibility variants for lung cancer: replication study and assessment as expression quantitative trait loci.
Many single nucleotide polymorphisms (SNPs) have been associated with lung cancer but lack confirmation and functional characterization. We retested the association of 56 candidate SNPs with lung adenocarcinoma risk and overall survival in a cohort of 823 Italian patients and 779 healthy controls, and assessed their function as expression quantitative trait loci (eQTLs). In the replication study, eight SNPs (rs401681, rs3019885, rs732765, rs2568494, rs16969968, rs6495309, rs11634351, and rs4105144) associated with lung adenocarcinoma risk and three (rs9557635, rs4105144, and rs735482) associated with survival. Five of these SNPs acted as cis-eQTLs, being associated with the transcription of IREB2 (rs2568494, rs16969968, rs11634351, rs6495309), PSMA4 (rs6495309) and ERCC1 (rs735482), out of 10,821 genes analyzed in lung. For these three genes, we obtained experimental evidence of differential allelic expression in lung tissue, pointing to the existence of in-cis genomic variants that regulate their transcription. These results suggest that these SNPs exert their effects on cancer risk/outcome through the modulation of mRNA levels of their target genes.
Department of Predictive and Preventive Medicine, Milan, Italy.
Giulia
G
Pintarelli
Department of Predictive and Preventive Medicine, Milan, Italy.
Chiara Elisabetta
CE
Cotroneo
Department of Predictive and Preventive Medicine, Milan, Italy.
Sara
S
Noci
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Matteo
M
Dugo
Department of Predictive and Preventive Medicine, Milan, Italy.
Antonella
A
Galvan
Genomics of Renal Diseases and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Simona
S
Delli Carpini
Genomics of Renal Diseases and Hypertension Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Lorena
L
Citterio
School of Nephrology, Università Vita-Salute San Raffaele, Milan, Italy.
Paolo
P
Manunta
Department of Surgery, Ospedale San Giuseppe, Milan, Italy.
Matteo
M
Incarbone
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
Davide
D
Tosi
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
Luigi
L
Santambrogio
Department of Predictive and Preventive Medicine, Milan, Italy.
Tommaso A
TA
Dragani
Department of Predictive and Preventive Medicine, Milan, Italy.
Francesca
F
Colombo
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004268:DNA-Binding Proteins / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D035942:Iron Regulatory Protein 2 / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics
D004268:DNA-Binding Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; C000593243:PSMA4 protein, human; D046988:Proteasome Endopeptidase Complex; D035942:Iron Regulatory Protein 2