A functional copy number variation in the WWOX gene is associated with lung cancer risk in Chinese
Lei Yang
3
Bin Liu
2
3
Binfang Huang
2
3
Jieqiong Deng
0
Hongbin Li
5
Bolan Yu
4
Fuman Qiu
3
Mei Cheng
3
Hui Wang
3
Rongrong Yang
3
Xiaorong Yang
3
Yifeng Zhou
0
Jiachun Lu
3
0
Soochow University Laboratory of Cancer Molecular Genetics, Medical College of Soochow University
, Suzhou 215123,
China
1
The Author 2013. Published by Oxford University Press. All rights reserved
2
Guangzhou No.12 Hospital affiliated to Guangzhou Medical University
, 1 Tianqiang Road, Guangzhou 510620,
China
3
The Institute for Chemical Carcinogenesis, The State Key Lab of Respiratory Disease, Guangzhou Medical University
, 195 Dongfengxi Road, Guangzhou 510182,
China
4
The Key Laboratory for Major Obstetric Diseases of Guangdong Province, Third Affiliated Hospital of Guangzhou Medical University
, Guangzhou 510150,
China
5
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University
, Harbin 150040,
China
WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that has been reported to lose function due to genetic alterations in several cancers. WWOX maps to the common chromosomal fragile site FRA16D and several copy number variations (CNVs) were found within this gene. In this study, we investigated the association between the CNVs of WWOX and lung cancer risk in four independent case - control studies, which are on 2942 lung cancer cases and 3074 cancer-free controls of southern, eastern and northern Chinese. A common CNV-67048 was genotyped by the Taqman real-time PCR, and its biological effect was accessed with protein expression and sequencing assays. We found that in comparison with the common 2-copy genotype, the carriers of loss variant genotypes (1-copy or 0-copy) had a significantly increased risk of lung cancer (adjusted OR 5 1.39, 95% CI 5 1.24 - 1.55, P 5 9.0131029) in a dose - response manner (Ptrend 5 1.12 3 10210), and the WWOX protein expressions in lung cancer tissues were significantly lower (P 5 0.036), accompanying a higher rate of exons absence (P 5 0.021) in subjects with loss genotypes of CNV-67048. Our data suggest that the loss genotypes of CNV-67048 in WWOX predispose their carriers to lung cancer; this might be related with altered WWOX gene expression and exons absence in them.
-
INTRODUCTION
Although an abundance of association studies, especially
the genome-wide association studies (GWAS), has reported
that a lot of single-nucleotide polymorphisms (SNPs) are
associated with risks of various cancers, only a small proportion of
cancer heritability can be explained by those SNPs, reflecting
that some missing heritability existed (1). Recently,
increasing evidence suggests that the copy number variation (CNV)
might hold the key to account for a large proportion of the
missing heritability (1 3). CNV is a prevalent genetic
aberration that covers .1 kb duplication or deletion, which may
contribute to phenotypic variations by altering biological
functions or genes expression (4,5). Therefore, if CNVs are located
in tumor suppressor genes or oncogenes, corresponding to
loss-of-function mutations or gain-of-function mutations
would possibly alter the predisposition to cancer.
Human WW domain-containing oxidoreductase (WWOX) is
an identified tumor suppressor gene. As a pro-apoptotic
molecule, WWOX regulates several cancer-related signaling
pathways and genes (6 8), and it frequently loses function in the
initiation of tumorigenesis as well as neoplastic process
(9,10). Not only does WWOX directly suppress the
carcinogenic effects of oncogenes such as c-Jun, erbB4, MDM2 (11 13),
but it also activates tumor suppressor genes such as p53, p73 to
induce cell apoptosis (14 16). WWOX knockout mice had
increased lung carcinoma susceptibility (10), whereas
transfection of WWOX in an animal model caused dramatic
suppression of tumorigenesis (17,18). In addition, loss expression of
WWOX protein has been found in various tumors (19,20),
and WWOX is down-regulated by exposure to environmental
carcinogens such as Benzo[a]pyrene diol epoxide (9).
The human WWOX gene (OMIM: 605131) is located on
chromosome 16q23.3 24.1, a region spanning over the
common fragile site 16D (FRA16D). Loss of heterozygosis
(LOH), homozygous deletions and chromosomal
translocations in WWOX has been reported in several types of cancer
(21 24). In lung cancer, a high incidence of exons absence
like the familiar deletion of WWOX exons 6 8 was reported
(23). However, it is still unclear how these somatic mutations
evolve in cancer development. Recently, a germline CNV was
found related with LOH in Chr18q22.1 in ileal carcinoid
tumor cells (25), implying that the constitutional CNV
may induce high frequency of somatic mutations and thus
be involved in cancer predisposition. Using bioinformatics
analysis, we found that there were several CNVs in WWOX
(http://projects.tcag.ca/variation/?source=hg18, date last accessed
January 6, 2013), and we hypothesized that the CNVs in WWOX
might be associated with lung (...truncated)