Nucleotide Excision Repair Gene Polymorphisms and Risk
of Advanced Colorectal Adenoma: XPC Polymorphisms
Modify Smoking-Related Risk
Wen-Yi Huang,1Sonja I. Berndt,1Daehee Kang,1,3Nilanjan Chatterjee,1Stephen J. Chanock,1,2
Meredith Yeager,4Robert Welch,4Robert S. Bresalier,5Joel L. Weissfeld,6and Richard B. Hayes1
1Division of Cancer Epidemiology and Genetics and
Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea;4Core Genotyping Facility, Advanced Technology Center,
National Cancer Institute-Frederick, Gaithersburg, Maryland;5Department of Gastrointestinal Medicine and Nutrition, M.D. Anderson Cancer
Center, Houston, Texas; and6Department of Epidemiology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania
2Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland;
Objectives: Nucleotide excision repair enzymes remove
bulky damage caused by environmental agents, including
carcinogenic polycyclic aromatic hydrocarbons found in
cigarette smoke, a risk factor for colorectal adenoma. Among
participants randomized to the screening arm of the Prostate,
Lung, Colorectal, and Ovarian Cancer Screening Trial,
we studied the risk of advanced colorectal adenoma in
relation to cigarette smoking and selected single nucleotide
polymorphisms (SNP) in the nucleotide excision repair
Methods: Cases (n = 772) were subjects with left-sided
advanced adenoma (>1 cm in size, high-grade dysplasia,
or villous characteristics). Controls (n = 777) were screen-
negative for left-sided polyps by sigmoidoscopy. DNA
was extracted from blood samples and 15 common
nonsynonymous SNPs in seven-nucleotide excision repair
genes [XPC, RAD23B
(ERCC2), CCNH, XPF (ERCC4), and XPG (ERCC5)] were
Results: None of the studied SNPs were independently
associated with advanced adenoma risk. Smoking was
related to adenoma risk and XPC polymorphisms (R492H,
A499V,K939Q) modified these effects (Pinteractionfrom 0.03-
0.003). Although the three XPC variants were in linkage
disequilibrium, a multivariate logistic regression tended to
show independent protective effects for XPC 499V(Ptrend=
0.06), a finding supported by haplotype analysis (covariate-
adjusted global permutation P = 0.03).
Conclusions: Examining a spectrum of polymorphic variants
in nucleotide excision repair genes, we found evidence that
smoking-associated risks for advanced colorectal adenoma
are modified by polymorphisms in XPC, particularly
haplotypes containing XPC 499V.
markers Prev 2006;15(2):306–11)
(Cancer Epidemiol Bio-
The recent discovery of a novel autosomal recessive form of
familial adenomatous polyposis caused by mutations in the
base excision repair gene MYH (1) and the well-documented
involvement of mismatch repair in hereditary nonpolyposis
colorectal cancer suggest the importance of DNA repair
mechanisms in colorectal carcinogenesis (2). Based on
epidemiologic, molecular, and clinical evidence, colorectal
adenomas, particularly those large in size or histologically
advanced, are recognized precursor lesions for colorectal
Cigarette smoking is a risk factor for colorectal adenoma and
likely also for colon cancer (4). Tobacco products, such as
polycyclic aromatic hydrocarbons, heterocyclic amines, nitros-
amines, and aromatic amines, reaching the colorectal mucosa,
through direct ingestion or via the circulatory system, result in
DNA adducts, leading to mutations and potentially to cancer
development (5). There is considerable interindividual varia-
tion in the response to genotoxic exposures, such as polycyclic
aromatic hydrocarbons, and genetic polymorphisms in the
DNA repair genes could influence DNA repair capacity and, in
turn, cancer susceptibility (6).
The nucleotide excision repair pathway may have particular
importance for smoking-related adenoma risk because this
by polycyclic aromatic hydrocarbons in tobacco smoke (7).
Excision repair involves global genomerepair and transcription
coupled repair, involving DNA damage recognition, DNA
unwinding, excision of the damage, synthesis of new DNA, gap
repair, and ligation (Fig. 1; ref.8). Damage recognition iscarried
out either by the XPC-hHR23B (encoded by RAD23B) protein
complex in the global genome repair pathway or by RNA
polymerase II, which recruits CSA and CSB (ERCC6) in
transcription coupled repair. In the second step, DNA is
unwound by the action of TFIIH, a nine-subunit protein
complex composed of DNA helicases, XPB and XPD, and a
kinase subunit cyclin H (CCNH). Replication protein A (RPA)
stabilizes the unwound DNA, and XPA facilitates the assembly
of DNA repair factors. The damaged DNA is then removed
by XPG (ERCC5) and the XPF (ERCC4)-ERCC1 complex, which
make 3V and 5V incisions, respectively, on either side of the
damage. Finally, with the help of several replication accessory
factors, the DNA gap is filled with new bases synthesized by
DNA polymerases y and q and a DNA ligase seals the nick.
Several polymorphisms in nucleotide excision repair
genes were found to alter DNA repair, including variants
in XPC (9-11) and XPD (ERCC2; refs. 10, 12), although
not all studies have been consistent (13-15). Despite the
potential role of nucleotide excision repair in colorectal
carcinogenesis, few epidemiologic studies of colorectal tumors
have evaluated the associations with genetic polymorphisms
in this pathway. Studies of colorectal cancer in Taiwan (16) and
the United Kingdom (17) found no overall effects for selected
Cancer Epidemiol Biomarkers Prev 2006;15(2). February 2006
Received 9/29/05; revised 11/16/05; accepted 12/15/05.
Grant support: Intramural Research Program of the NIH, National Cancer Institute, Division
of Cancer Epidemiology and Genetics.
The costs of publication of this article were defrayed in part by the payment of page charges.
This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.
Section 1734 solely to indicate this fact.
Requests for reprints: Wen-Yi Huang, Division of Cancer Epidemiology and Genetics,
National Cancer Institute, EPS 8113, MSC 7240, Bethesda, MD 20892. Phone: 301-435-4710;
Fax: 301-402-1819. E-mail: email@example.com
Copyright D 2006 American Association for Cancer Research.
on adenoma and supporting data from some functional (9-11)
and epidemiologic studies of smoking-related cancers (28-30)
suggest a critical role of XPC in repairing DNA damage (e.g.,
bulky adducts) caused by tobacco carcinogens (e.g., polycyclic
aromatic hydrocarbons, heterocyclic amines, nitrosamines, and
aromatic amines). These results for XPC variants, tobacco use,
and adenoma, along with the smoking-related adenoma risk
modifications by variants of polycyclic aromatic hydrocarbon
metabolism-related genes (e.g., EPHX1, NQO1, CYP1A1, and
GSTT1) that we have previously observed in this population
(20, 21, 32), support the importance of genetic susceptibility to
tobacco-related colorectal carcinogenesis. Although we found
no relation between other nucleotide excision repair genes and
smoking-related adenoma risk, potential effects by unidenti-
fied genetic variants cannot be ruled out. Confirmation in other
studies of colorectal tumors and investigations of other genes
and variants in this pathway and other major DNA repair
pathways are needed to clarify the underlying mechanisms of
DNA repair in the development of colorectal cancer.
We thank Drs. Christine Berg and Philip Prorok (Division of Cancer
Prevention, National Cancer Institute); the Screening Center inves-
tigators and staff or the PLCO Cancer Screening Trial; Tom Riley and
staff (Information Management Services, Inc.); Barbara O’Brien and
staff (Westat, Inc.); and Drs. Bill Kopp, Wen Shao, and staff (Science
Applications International Corporation-Frederick) for their contribu-
tions to making this study possible.
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