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.
Lips
Esther H
EH
International Agency for Research on Cancer (IARC), Lyon, France.
Gaborieau
Valerie
V
McKay
James D
JD
Chabrier
Amelie
A
Hung
Rayjean J
RJ
Boffetta
Paolo
P
Hashibe
Mia
M
Zaridze
David
D
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
Field
John K
JK
Liloglou
Triantafillos
T
Xinarianos
George
G
McLaughlin
John
J
Liu
Geoffrey
G
Skorpen
Frank
F
Elvestad
Maiken Bratt
MB
Hveem
Kristian
K
Vatten
Lars
L
Study
Epic
E
Benhamou
Simone
S
Lagiou
Pagona
P
Holcátová
Ivana
I
Merletti
Franco
F
Kjaerheim
Kristina
K
Agudo
Antonio
A
Castellsagué
Xavier
X
Macfarlane
Tatiana V
TV
Barzan
Luigi
L
Canova
Cristina
C
Lowry
Ray
R
Conway
David I
DI
Znaor
Ariana
A
Healy
Claire
C
Curado
Maria Paula
MP
Koifman
Sergio
S
Eluf-Neto
Jose
J
Matos
Elena
E
Menezes
Ana
A
Fernandez
Leticia
L
Metspalu
Andres
A
Heath
Simon
S
Lathrop
Mark
M
Brennan
Paul
P
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