Huang et al, 2015
The Significant Association of CCND1 Genotypes with
Colorectal Cancer in Taiwan
Chung-Yu Huang1,3*, Chia-Wen Tsai2*, Chin-Mu Hsu2, Wen-Shin Chang2,4,
Hao-Ai Shui1 and Da-Tian Bau2,4,5
1
Graduate Institute of Medical Sciences, National Defense Medical Center,
Taipei, Taiwan, R.O.C.
2
Terry Fox Cancer Research Laboratory, China Medical University Hospital,
Taichung, Taiwan, R.O.C.
3
Taichung Armed-Forces General Hospital, Taichung, Taiwan, R.O.C.
4
Graduate Institute of Clinical Medical Science, China Medical University,
Taichung, Taiwan, R.O.C.
5
Department of Bioinformatics and Medical Engineering, Asia University,
Taichung, Taiwan, R.O.C.
* The two authors contributed equally to this work
Correspondence to: Da-Tian Bau and Hao-Ai Shui, Terry Fox Cancer
Research Lab, China Medical University Hospital, 2 Yuh-Der Road,
Taichung, 404 Taiwan, Tel: +886 422052121 Ext 7534
e-mail: artbau2@gmail.com; datian@mail.cmuh.org.tw
Running title: Huang et al: CCND1 in Colorectal Cancer
1
Huang et al, 2015
Abstract. Colorectal cancer, one million cases diagnosis worldwide
annually, is one of the most common malignant tumors and 20%
incidence caused by low penetrance susceptibility genes. Cyclin D1
(CCND1) regulating cell cycle transition may determine the susceptible
individuals to genomic instability and carcinogenesis. The study aimed at
examining the contribution of CCND1 genotypes to colorectal cancer risk
in Taiwan. The genotypes of CCND1 A870G (rs9344) and G1722C
(rs678653) were determined among 362 colorectal cancer patients and
362 age- and gender-matched cancer-free controls. Significant differences
were observed between colorectal cancer and control groups in the
distributions of genotypic (P=9.71*10-4) and allelic (P=0.0017)
frequencies at CCND1 A870G. Additionally, individuals carried AG or
GG genotype had 0.56- or 0.51-fold higher of odds ratios for developing
colorectal
cancer
than
the
AA
genotype
(95%
confidence
intervals=0.40-0.78 and 0.32-0.81, respectively). Furthermore, G allele of
CCND1 A870G performed a protective effects for non-smokers and
non-alcohol drinkers (P=0.0012 and 0.0007, respectively) on colorectal
cancer risk. These findings support the concept that the cell cycle
regulation may play a role in colorectal cancer initiation and development
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Huang et al, 2015
and CCND1 A870G genotyping maybe a feasible technology for
colorectal cancer early detection.
Key words: colorectal
cancer; cyclin D1; drinking; genotype;
polymorphism; smoking.
3
Huang et al, 2015
Introduction
Colorectal cancer (CRC) is one of the most serious public health
threatening issues. There are nearly one million cases of colorectal cancer
diagnosis worldwide each year [1, 2]. The prevalent incidence and
age-adjusted mortality of CRC has keeping on increasing in the recent
years in Taiwan. The incidence and mortality of CRC has occupied the
first and third places among the common cancers in Taiwan. The
increases in incidence and mortality have been proposed to closely
associate with dietary changes to Western food style, including a
decreased consumption of dietary fiber or grain-made foods. Etiological
studies have attributed more than 85% of CRC to several environmental
factors [1, 2], and in particular meat consumption, cigarette smoking,
exposure to carcinogenic aromatic amines, such as arylamines and
heterocyclic amines [3, 4]. About 15-20% of CRC cases are with strong
familial history of cancer, suggesting additional inherited susceptibility
factors are not yet revealed [5-7].
Cancer cells are considered to be in part as cell cycle deregulated cells,
and the cyclin D1 protein encoded by the CCND1 gene located on human
4
Huang et al, 2015
chromosome 1q31-32 is therefore a candidate gene for initiating
tumorigenesis and cancer progression. Functionally, cyclin D1 is the
critical gate-keeping protein in charge of regulating the transition through
the restriction point in the G1 phase to S phase of the cell cycle. That is to
say, cyclin D1 is the determinant commander for cell fate among survival,
proliferation and cell death [8-11]. Mechanisms such as CCND1 gene
amplification, posttranscriptional or posttranslational modifications,
rearrangements, and variant polymorphisms can result in abnormal
protein levels and impaired cyclin D1 function, leading to carcinogenesis
[4, 12-15].
In the recent years, two polymorphic sites of CCND1, A870G
(rs9344) and G1722C (rs678653) were reported to be associated with
carcinogenesis of other types of cancer, such as oral cancer [16],
nasopharyngeal carcinoma [17], esophageal squamous cell carcinoma
[18], lung cancer [19] and prostate cancer [20]. In literature, the
association of CCND1 genotypes with colorectal cancer susceptibility
was studied in many populations [21-36] but not in Taiwan, where the
prevalence of CRC is on top among the common cancers. Therefore, the
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Huang et al, 2015
specific aims of this study were to determine the feasibility of the two
SNPs of CCND1, A870G (rs9344) and G1722C (rs678653), to serve as
potential early detection biomarkers for CRC in Taiwan, and to
summarize and discuss the highlights of all related literature.
Materials and Methods
Collection of investigated populations. The study population consisted of
362 CRC patients and 362 cancer-free control volunteers. Patients
diagnosed with CRC were recruited at the outpatient clinics of general
surgery between 2002-2008 at the China Medical University Hospital,
Taichung, Taiwan, Republic of China. The clinical characteristics of
patients, including histological details, were all graded and defined by
expert surgeons [37-39]. All patients voluntarily participated, completed a
self-administered questionnaire and provided peripheral blood samples.
An equal number of non-cancer healthy volunteers were selected as
controls by matching for age, gender and some indulgences after initial
random sampling from the Health Examination Cohort of the hospital.
The exclusion criteria of the control group included previous malignancy,
metastasized cancer from other or unknown origin, and any familial or
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Huang et al, 2015
genetic diseases. This study was approved by the Institutional Review
Board of the China Medical University Hospital and written-informed
consent was obtained from all participants. The details of the
characteristics of the patients and controls were summarized in Table 1.
CCND1 genotyping conditions. Genomic DNA of each participant was
extracted from peripheral blood leucocytes, aliquot and processed
according to our previous articles [16, 17, 19]. The primers used for
CCND1 A870G (rs9344) were: forward 5’-GTG AAG TTC ATT TCC
AAT CCG C-3’, and reverse 5’-GGG ACA TCA CCC TCA CTT AC-3’;
for CCND1 G1722C (rs678653) were: forward 5’-CTC TTG GTT ACA
GTA GCG TAG C-3’, and reverse 5’-ATC GTA GGA GTG GGA CAG
GT-3’. The following cycling conditions were performed: one cycle at
94oC for 5 min; 35 cycles of 94oC for 30 s, 55oC for 30 s, and 72oC for 30
s; and a final extension at 72oC for 10 min.
Restriction fragment length polymorphism (RFLP) conditions. As for the
CCND1 rs9344, the resultant 167 bp PCR product was mixed with 2 U
Nci I and incubated for 3 h at 37C. The G form PCR products could be
7
Huang et al, 2015
further digested while the A form could not. Two fragments 145 bp and
22 bp were present if the product was digestible G form. As for the
CCND1 rs678653, the resultant 159 bp PCR product was mixed with 2 U
Hae III and incubated for 3 h at 37C. On digestion with Hae III, the PCR
product arising from the G allele was cut into fragments of 111, 26 and
22 bp, whereas C allele was cut into fragments of 137 and 22 bp. Then,
10 l of product was loaded into a 3% agarose gel containing ethidium
bromide for electrophoresis. The genotype analysis was performed by
two researchers independently and blindly and the results were 100%
concordant.
Statistical analyses. Pearson’s Chi-square test or Fisher’s exact test (when
the expected number in any cell was less than five) was used to compare
the distribution of the CCND1 genotypes between cases and controls. The
associations between the CCND1 polymorphisms and colorectal cancer
risk were estimated by computing odds ratios (ORs) and their 95%
confidence intervals (CIs) from unconditional logistic regression analysis
with the adjustment for possible confounders. P < 0.05 was considered
statistically significant, and all statistical tests were two-sided.
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Huang et al, 2015
Results
The selected characteristics of all the investigated subjects are
summarized in Table 1 and the gel electrophoresis by restriction enzyme
was shown in Fig. 1. The data showed that there was no difference in the
distribution of age (P=0.932) and gender (P=0.707) among CRC patients
and non-cancer controls (Table 1).
In Table 2, the distributions of the genetic and allelic frequencies of
the CCND1 A870G among the CRC patients and non-cancer healthy
controls were presented and analyzed. The results showed that the genetic
frequencies of CCND1 A870G was differentially distributed between the
control and cancer patient groups (P=9.71*10-4). The ORs of the heteroand homozygous variant AG and GG were 0.56 (95%CI=0.40-0.78) and
0.51 (95%CI=0.32-0.81), respectively, compared with the wild-type AA
genotype. The dominant model of the AG+GG versus AA genotype
(OR=0.55, 95%CI=0.40-0.76) also suggested that people of either AG or
GG genotypes were of lower risk of CRC than those of AA genotype
(Table 2). As for allelic frequency analysis, those who had G allele were
of lower cancer risk than those who had A allele at CCND1 A870G
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Huang et al, 2015
(OR=0.71, 95%CI=0.58-0.88). On the contrary, no any difference in the
distribution of either genetic or allelic frequency was observed between
CRC patient and control groups as for the CCND1 G1722C (Table 3).
Since personal cigarette smoking and alcohol drinking status were
reported to be the environmental risk factors for CRC, we are interested
to investigate the interaction of genotype of CCND1 A870G and personal
smoking and drinking status for CRC risk. As shown in Table 4, the
genotypic distributions of CCND1 A870G AA and AG+GG were
significantly different between CRC patient non-smokers and control
non-smokers (P=0.0005) (Table 4). The AG+GG genotypic frequency
was much lower (62.7%) among CRC non-smokers than in healthy
non-smokers
(75.5%),
and
at
lower
CRC
risk
(OR=0.55,
95%CI=0.38-0.79). There was no such differential distribution among the
smokers in CRC patients or healthy controls (P>0.05), although the OR
for this subgroup was at the similar level (OR=0.56, 95%CI=0.29-1.07)
(Table 4). By the same strategy, we analyzed the interaction of CCND1
A870G genotype and alcohol drinking status. As shown in Table 5, the
genotypic distributions of CCND1 A870G AA and AG+GG were
significantly different between CRC patient non-drinkers and control
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Huang et al, 2015
non-drinkers (P=0.0007) (Table 5). The AG+GG genotypic frequency
was much lower (62.9%) among CRC non-drinkers than in healthy
non-drinkers
(75.6%),
and
at
lower
CRC
risk
(OR=0.55,
95%CI=0.39-0.77). There was no such differential distribution among the
alcohol drinkers in CRC patients or healthy controls (P>0.05) (Table 5).
The
correlations
between
genotypes
of
CCND1
A870G
and
clinicopathological features of 362 Taiwanese CRC patients were
analyzed and presented in Table 6. No statistically significant correlation
was observed between genotypic distributions and age, gender, tumor
size or location, or lymph node metastasis (all P > 0.05) (Table 6).
Discussion
In the recent years, several potential genetic markers for CRC early
detection and prediction in Taiwan were proposed, including caveolin-1
G14713A, caveolin-1 T29107A, Ku80 G-1401T and XRCC4 G-1394T
[37-39]. Caveolin-1 is a scaffolding protein while Ku80 and XRCC4 play
an important role in the double strand repair system. However, little is
known about the contribution of personal genotypes of the cell cycle
regulation genes to Taiwan CRC risk. In this study, we investigated the
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Huang et al, 2015
association of CCND1 A870G and G1722C genotypes and CRC risk in
Taiwan with a moderate population including 362 CRC cases and 362
age- and gender-matched non-cancer controls. The findings include: 1)
subjects carrying the AG and GG genotypes were of lower risk of CRC
compared with those carrying AA genotype on CCND1 A870G (Table 2);
2) as for CCND1 A870G, there was no similar differentially genotypic or
allelic distribution found (Table 3); 3) there was a genetic-lifestyle
interaction between CCND1 A870G genotype and personal smoking and
alcohol drinking status (Tables 4 and 5); 4) no obvious correlation
between CCND1 A870G genotype and clinicopathological feature was
found (Table 6).
Since CRC is one of the most common causes of cancer related
mortality, the feasible biomarkers for early detection and prediction are
helpful to control its high incidence and mortality. Cyclin D1 is
commonly overexpressed in a various of epithelial cancers, including
colorectal carcinomas, and elevated cyclin D1 may contribute to
increased
mismatch
repair
errors
and
microsatellite
instability,
contributing to CRC progression [40, 41]. In literature, the contribution of
CCND1 A870G genotypes to CRC risk has been widely investigated and
12
Huang et al, 2015
discussed. We have collected all the epidemiological genotyping studies,
excluded those irrelevant to CRC or CCND1 genotyping, those not a
case-control study, those lacked cancer-free subjects as controls, and
those of less than 100 controls together with 100 cases, and finally
summarized the highlights of 16 studies in Table 7. Among them, seven
groups reported that allele A carriers were of higher risk than allele G
carriers [22, 23, 26, 32-35], while eight groups found no positive
association [21, 24, 25, 27-29, 31, 36]. The only one study proposed that
G allele as a risky factor for CRC with 101 controls and 254 cases in
Singapore [30], validated in 1169 controls and 300 cases with negative
association next year [28], and was a miniature of diverse
epidemiological findings with different populations observed with
various genetic background, life-style and environmental exposure. The
exact role of different CCND1 A870G genotypes to colorectal cancer
susceptibility together with their phenotypic differences remain
inconclusive; however, it is closer and closer to figure out that A allele of
CCND1 A870G genotype may serve as a risky factor for those people of
specific genetic background, lifestyle, and clinical features [42]. For
instance, it was proposed that A allele of CCND1 A870G genotype
13
Huang et al, 2015
increased the tumor risk for rectal cancer but not for colon cancer in a
meta-analysis work [43]. It is reasonable that cancers of colon and rectum
may be distinct tumors. In the future, more studies about the clinical
features, prognosis, and genetic-environmental interactions are needed.
Mechanically, it is postulated that CCND1 A870G polymorphism
was closely related to a consequential result of alternative splicing. The A
allele of CCND1 A870G was in charge of encoding a protein with an
truncated C-terminal domain via a higher expression level of mRNA than
the G allele [44, 45]. The variant cyclin D1 with altered C-terminal
domain was reported to have a longer half-life span than that of G allele,
which may bypass the G1/S cell cycle checking point and lead to
abnormal cell proliferation [46, 47].
To sum up, the current study found that CCND1 A870G genotypes,
interacted with personal cigarette smoking and alcohol drinking status,
may influence the personal susceptibility to CRC carcinogenesis in
Taiwan.
The
results
provided
evidence
supporting
that
CRC
carcinogenesis is a multiple steps that involve both inherited and
environmental factors. The A allele of CCND1 A870G may serve as a
risky marker in early detection and prediction for CRC in Taiwan.
14
Huang et al, 2015
Acknowledgement
This study was supported by research grants from Taichung Armed
Forces General Hospital (103A04 and 103A24) and in part by Taiwan
Ministry of Health and Welfare Clinical Trial and Research Center of
Excellence (MOHW103-TDU-B-212-113002). The assistance from
Mei-Due Yang and Tsai-Ping Ho in sample and questionnaire collection,
and genotyping work from Hong-Xue Ji, Chieh-Lun Hsiao, Tzu-Chia
Wang, Yun-Ru Syu, Lin-Lin Hou and Chia-En Miao were highly
appreciated by the authors.
Conflict of Interest
The authors declare that they have no conflict of interest.
Figure Legend
Fig. 1 PCR-based restriction analysis of the G1722C rs678653 (A),
A870G rs9344 (B) polymorphisms of the CCND1 gene displayed on 3%
agarose electrophoresis. M, 100 bp DNA marker.
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Huang et al, 2015
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