A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.
Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
Hung
Rayjean J
RJ
International Agency for Research on Cancer (IARC), Lyon 69008, France.
McKay
James D
JD
Gaborieau
Valerie
V
Boffetta
Paolo
P
Hashibe
Mia
M
Zaridze
David
D
Mukeria
Anush
A
Szeszenia-Dabrowska
Neonilia
N
Lissowska
Jolanta
J
Rudnai
Peter
P
Fabianova
Eleonora
E
Mates
Dana
D
Bencko
Vladimir
V
Foretova
Lenka
L
Janout
Vladimir
V
Chen
Chu
C
Goodman
Gary
G
Field
John K
JK
Liloglou
Triantafillos
T
Xinarianos
George
G
Cassidy
Adrian
A
McLaughlin
John
J
Liu
Geoffrey
G
Narod
Steven
S
Krokan
Hans E
HE
Skorpen
Frank
F
Elvestad
Maiken Bratt
MB
Hveem
Kristian
K
Vatten
Lars
L
Linseisen
Jakob
J
Clavel-Chapelon
Françoise
F
Vineis
Paolo
P
Bueno-de-Mesquita
H Bas
HB
Lund
Eiliv
E
Martinez
Carmen
C
Bingham
Sheila
S
Rasmuson
Torgny
T
Hainaut
Pierre
P
Riboli
Elio
E
Ahrens
Wolfgang
W
Benhamou
Simone
S
Lagiou
Pagona
P
Trichopoulos
Dimitrios
D
Holcátová
Ivana
I
Merletti
Franco
F
Kjaerheim
Kristina
K
Agudo
Antonio
A
Macfarlane
Gary
G
Talamini
Renato
R
Simonato
Lorenzo
L
Lowry
Ray
R
Conway
David I
DI
Znaor
Ariana
A
Healy
Claire
C
Zelenika
Diana
D
Boland
Anne
A
Delepine
Marc
M
Foglio
Mario
M
Lechner
Doris
D
Matsuda
Fumihiko
F
Blanche
Helene
H
Gut
Ivo
I
Heath
Simon
S
Lathrop
Mark
M
Brennan
Paul
P
D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005060:Europe; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D021122:Protein Subunits / Q000235:genetics*; D011978:Receptors, Nicotinic / Q000235:genetics*
D021122:Protein Subunits; D011978:Receptors, Nicotinic