Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals.
BACKGROUND
Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens.


METHODS
We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies.


RESULTS
Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P < 0.001). The variant was associated with heavy smoking (>20 CPD) [odds ratio (OR) = 1.13, 95% confidence interval (CI) 0.96-1.34, P = 0.13 for heterozygotes and 1.81, 95% CI 1.39-2.35 for homozygotes, P < 0.0001]. The strong association between the variant and LC risk (OR = 1.30, 95% CI 1.23-1.38, P = 1 x 10(-18)), was virtually unchanged after adjusting for this smoking association (smoking adjusted OR = 1.27, 95% CI 1.19-1.35, P = 5 x 10(-13)). Furthermore, we found an association between the variant allele and an earlier age of LC onset (P = 0.02). The association was also noted in UADT cancers (OR = 1.08, 95% CI 1.01-1.15, P = 0.02). Genome wide association (GWA) analysis of over 300 000 SNPs on 11 219 subjects did not identify any additional variants related to smoking behaviour.


CONCLUSIONS
This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.
International Agency for Research on Cancer (IARC), Lyon, France.
Esther H
EH
Lips
Valerie
V
Gaborieau
James D
JD
McKay
Amelie
A
Chabrier
Rayjean J
RJ
Hung
Paolo
P
Boffetta
Mia
M
Hashibe
David
D
Zaridze
Neonilia
N
Szeszenia-Dabrowska
Jolanta
J
Lissowska
Peter
P
Rudnai
Eleonora
E
Fabianova
Dana
D
Mates
Vladimir
V
Bencko
Lenka
L
Foretova
Vladimir
V
Janout
John K
JK
Field
Triantafillos
T
Liloglou
George
G
Xinarianos
John
J
McLaughlin
Geoffrey
G
Liu
Frank
F
Skorpen
Maiken Bratt
MB
Elvestad
Kristian
K
Hveem
Lars
L
Vatten
Epic
E
Study
Simone
S
Benhamou
Pagona
P
Lagiou
Ivana
I
Holcátová
Franco
F
Merletti
Kristina
K
Kjaerheim
Antonio
A
Agudo
Xavier
X
Castellsagué
Tatiana V
TV
Macfarlane
Luigi
L
Barzan
Cristina
C
Canova
Ray
R
Lowry
David I
DI
Conway
Ariana
A
Znaor
Claire
C
Healy
Maria Paula
MP
Curado
Sergio
S
Koifman
Jose
J
Eluf-Neto
Elena
E
Matos
Ana
A
Menezes
Leticia
L
Fernandez
Andres
A
Metspalu
Simon
S
Heath
Mark
M
Lathrop
Paul
P
Brennan
D000368:Aged; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011978:Receptors, Nicotinic / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects*; D014029:Tobacco Use Disorder / Q000235:genetics*
D011978:Receptors, Nicotinic