Cancer Genetics 222–223 (2018) 13–19

Long noncoding RNA CCAT1 polymorphisms are

associated with the risk of colorectal cancer
Yingjun Li a, Fangyuan Jing a, Ye Ding a, Qingfang He b, Yaohong Zhong a,
Chunhong Fan a,∗
a
Department of Public Health, Hangzhou Medical College, Hangzhou, Zhejiang, China; b Department of Chronic
Non-Communicable Diseases Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention,
Hangzhou, Zhejiang, China

Abstract
Colorectal cancer associated transcript 1 (CCAT1) is a novel long noncoding RNA, whose
overexpression is evident in both early phase of tumorigenesis and later disease stages in col-
orectal cancer (CRC). No study has explored the relationship between CCAT1 polymorphisms
and CRC risk. In the present study, a case-control study was conducted to investigate the asso-
ciation between CCAT1 polymorphisms and CRC risk in Chinese population. We identified that
CCAT1 rs67085638 polymorphism was associated with an increased risk of CRC (OR = 1.72,
95%CI = 1.14–2.58, P = 0.009 in heterozygote codominant model; OR = 1.67, 95%CI = 1.13–
2.47, P = 0.010 in dominant model). Moreover, CCAT1 rs7013433 polymorphism was associated
with late clinical stage (OR = 1.82, 95%CI = 1.16–2.86, P = 0.009 in heterozygote codominant
model; OR = 1.72, 95%CI = 1.13–2.63, P = 0.012 in dominant model). Our finding proposed a link
between CCAT1 polymorphisms with CRC risk as well as different clinical stages.
Keywords Long noncoding RNA, CCAT1, Polymorphism, Colorectal cancer.
© 2018 Elsevier Inc. All rights reserved.

Introduction mechanisms in pathogenesis of various diseases including

Colorectal cancer (CRC) is one the most common types of
gastrointestinal cancer and contributes to the third cancer
cause and fourth cancer death worldwide in 2012 [1]. There
are estimated to be 135,430 individuals newly CRC cases
and 50,260 newly CRC deaths in the United States in 2017
[2]. Although the etiology of CRC is complex and remains un-
known, many studies have reported the link between single
nucleotide polymorphisms (SNPs) in protein-coding genes
and functional noncoding RNAs with the risk of CRC devel-
opment [3–9].
Long noncoding RNAs (lncRNAs) are a class of noncoding
RNAs greater than 200 nucleotides in length, which has been
reported to play important roles as epigenetic regulators in
gene expression [10,11]. Increasing evidence indicates that
abnormal expression of lncRNAs is involved in the diversified
Received December 15, 2017; received in revised form January
18, 2018; accepted February 13, 2018
∗ Corresponding author.
E-mail address: 340076899@qq.com
cancer [12–17]. Polymorphisms of lncRNAs might exert vari-
ous effects on their expressions and/or functions, thus regu-
lating individual cancer susceptibility [18–20].
Colorectal cancer associated transcript 1 (CCAT1) is a
novel 11.2 kb lncRNA, whose overexpression is evident in
both early phase of tumorigenesis and later disease stages
in CRC [21]. Xiang et al. has demonstrated that CCAT1 plays
a role in MYC transcriptional regulation and promotes long-
range chromatin looping. Knockdown of CCAT1 reduces long-
range interactions between the MYC promoter and its en-
hancers [22]. MYC transcription and cell growth are tightly
correlated with the presence of CCAT1 RNA in a variety of tu-
mor types [23]. Moreover, Zhao et al. has found that oncogenic
SNP rs6983267 in the MYC enhancer region plays a role in
the regulation of CCAT1 expression and are associated with
endometrial carcinoma [24]. A meta-analysis has demon-
strated that increased expression level of CCAT1 is asso-
ciated with clinicopathological features in relevant cancers
including TNM stage [25]. Additionally, emerging evidence
has shown that CCAT1 is associated with CRC development
and prognosis. Zhao et al. has found that increased plasma

2210-7762/$ - see front matter © 2018 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.cancergen.2018.02.003
14
Fig. 1 Forest plots shows odds ratio for the association between CCAT1 rs7013433 (A), rs67085638 (B), and rs77628730 (C)
polymorphisms and the risk of colorectal cancer stratified by age, gender, BMI, and education level in codominant model.
CCAT1 could be used as a predictive biomarker for CRC
screening [26]. Ozawa et al. has found that high expression
of CCAT1 is significantly associated with poor recurrence free
survival and overall survival in CRC patients [27].
However, to the best of our knowledge, no study has ex-
plored the relationship between CCAT1 polymorphisms and
CRC risk. Therefore, a case-control study was conducted to
investigate the association between CCAT1 polymorphisms
and CRC risk in Chinese population.
Materials and methods
Study subjects
The CRC cases were recruited from our ongoing CRC study,
in which participants were from the First Affiliated Hospi-
tal of Zhejiang University and Zhejiang Provincial People’s
Hospital. Eligible cases were incident and histologically con-
firmed primary colorectal cancer, mentally competent to com-
plete the interview and with no previous diagnosis of famil-
ial adenomatous polyposis, ulcerative colitis or Crohn’s dis-
ease. The healthy controls were obtained from a community
in Hangzhou, Zhejiang Province by random sampling. The re-
search adopted the face-to-face questionnaire survey to ob-
tain the demographic characteristics and lifestyle-related fac-
tors of the selected objects. A structured questionnaire was
completed after the objects were asked to agree and signed
the informed consent. After interview, 5 ml blood of the subject
was collected for DNA isolation.
SNP selection and genotyping
Genomic DNA was isolated from peripheral blood samples
for each study subject using the modified salting-out proce-
Y. Li et al.
dure [28]. We selected tagSNPs with minor allele frequen-
cies (MAF) > 0.10 in Han Chinese Beijing according to the
1000 Genome Projects. We amplified the region to 2000 bp
upstream as promoter region. We also selected tagSNPs
from 3 UTR region as genetic variants in these regions al-
ways played functional roles in disease development [29–31].
Thus, three tagSNPs (rs7013433 A > T in promoter region,
rs67085638 C > T in 3 UTR region, and rs77628730 T > A
in 3 UTR region) were selected when linkage disequilibrium
(LD) between pair-wise SNPs was with a minimum r2 of 0.80.
Genotyping of included SNPs were conducted by using a
custom-by-design 48-Plex SNPscanTM Kit (Gensky Biotech-
nology Co., Shanghai, China) in July 2017. This kit was de-
veloped based on double ligation and multiplex fluorescence
PCR [32]. We randomly selected 5% DNA samples for re-
peated detection and the concordance rates were >99%.
Statistical analysis
The analyses were mainly carried out by SAS 9.2 software
(SAS Institute, Cary, NC, USA). Chi-square test was used to
test the differences in the distribution of selected demographic
variables and genotypes of tagSNPs. A goodness-of-fit chi-
square test was used to test the Hardy–Weinberg equilibrium
for each SNP. Unconditional logistic regression analyses with
odds ratios (ORs) and 95% confidence intervals (CIs) were
conducted to estimate the associations between each SNP
and CRC susceptibility. Estimates were calculated in crude
(Model 1), and additionally adjusted for age (≤44, 45–59,
60–74, ≥75), gender (male, female), body mass index (BMI)
(<18.5, 18.5–23.9, 24–27.9, ≥28), education level (illiterate,
primary school, middle school and above), red meat (≥4
times/week, 2–3 times/week, ≤1 time/week), root vegetable
(≥6 times/week, 4–5 times/week, ≤3 times/week) (Model 2).
Codominant and dominant genetic models were conducted to
 15

assess the significance of SNPs. A P-value of less than 0.05 Table 1 Distribution of selected characteristics among case and
for two-side was considered statistically significant. control subjects.
Variables Case Control Pa
N (%) N (%)
Result
Age (years)
A total of 1,010 subjects including 507 CRC (328 males and ≤44 31 (6.31) 31 (6.16) 0.666
179 women) and 503 healthy controls (293 males and 210 45–59 155 (30.57) 151 (30.02)
women) were included in the present study. There were no dif- 60–74 230 (45.36) 244 (48.51)
ferences in the distribution between CRC cases and healthy ≥75 91 (17.95) 77 (15.31)
controls relating age (P = 0.666), smoking (P = 0.096), alco- Gender
hol drinking (P = 0.694), tea drinking (P = 0.418), or family Male 328 (64.69) 293 (58.25) 0.035
history of cancer (P = 0.097). However, when compared with Female 179 (35.31) 210 (41.75)
healthy controls, the higher percentage of CRC cases seem to BMI
be male (P = 0.035), to have lower education level (P < 0.001), <18.5 29 (5.72) 18 (3.58) <0.001
less likely to be overweight (P < 0.001), more intake of red 18.5–23.9 294 (57.99) 223 (44.33)
meat (P < 0.001), and less intake of root vegetable (P < 0.001) 24–27.9 152 (29.98) 211 (41.95)
(Table 1). ≥28 32 (6.31) 51 (10.14)
Table 2 shows the genotype distribution of three se-
Education level
lected SNPs (i.e. rs7013433, rs67085638, and rs77628730)
Illiterate 63 (12.45) 25 (5.13) <0.001
in CCAT1 and their association with CRC risk. The genotype
Primary school 183 (36.17) 90 (18.48)
frequencies of three SNPs among controls were in accor-
Middle school and above 260 (51.38) 372 (76.39)
dance with Hardy–Weinberg equilibrium (HWE) (P = 0.254,
0.808 and 0.144, respectively). As a result, after adjusted Smoking
for age, gender, BMI, education level, red meat, and root Yes 184 (36.29) 155 (31.31) 0.096
vegetable, only rs67085638 polymorphism was found to No 323 (63.71) 340 (68.69)
be associated with an increased risk of CRC (OR = 1.72, Alcohol drinking
95%CI = 1.14–2.58, P = 0.009 in heterozygote codominant Yes 146 (28.80) 144 (29.94) 0.694
model; OR = 1.67, 95%CI = 1.13–2.47, P = 0.010 in dominant No 361 (71.20) 337 (70.06)
model). Tea drinking
In subgroup analysis, rs67085638 polymorphism was Yes 276 (54.55) 240 (51.95) 0.418
found to be associated with an increased risk of colon can- No 230 (45.45) 222 (48.05)
cer but not rectal cancer (OR = 1.83, 95%CI = 1.16–2.90,
P = 0.010 in heterozygote codominant model; OR = 1.82, Red meat
95%CI = 1.17–2.82, P = 0.008 in dominant model) in adjusted ≥4 times/week 262 (51.68) 160 (32.06) <0.001
model (Table 3). Besides, stratified analyses relating to age, 2–3 times/week 227 (44.77) 235 (47.09)
gender, BMI, and education level were conducted. More ≤1 time/week 18 (3.55) 104 (20.84)
pronounced risk effect of heterozygote variant genotype of Root vegetable
rs67085638 were found in subgroup of age <60 (CT ver- ≥6 times/week 10 (1.97) 244 (48.80) <0.001
sus CC: OR = 2.31, 95% CI = 1.22–4.35), male participants 4–5 times/week 257 (50.69) 190 (38.00)
(CT versus CC: OR = 2.20, 95% CI = 1.31–3.69), BMI ≥ 24 ≤3 times/week 240 (47.34) 66 (13.20)
(CT versus CC: OR = 2.10, 95% CI = 1.19–3.71), and primary Familial history of cancer
school and above (CT versus CC: OR = 1.78, 95% CI = 1.19– Yes 99 (20.75) 74 (25.96) 0.097
2.65) (Fig. 1). Additionally, increased CRC risk of heterozy- No 378 (79.25) 211 (74.04)
gote variant genotype of rs77628730 was found in subgroup
Tumor site
of BMI < 24 (TA versus TT: OR = 1.74, 95% CI = 1.03–2.92).
Colon 237 (46.75)
We also tried to explore the association between three se-
Rectal 270 (53.25)
lected SNPs and different CRC TMN stages. Rs7013433 poly-
morphism was found to be associated with late clinical stage TMN
(OR = 1.82, 95%CI = 1.16–2.86, P = 0.009 in heterozygote I + II 280 (55.23)
codominant model; OR = 1.72, 95%CI = 1.13–2.63, P = 0.012 III + IV 227 (44.77)
in dominant model) in adjusted model (Table 4).
BMI, body mass index; N, number.
a Differences between cases and controls were tested by two-sided

Discussion χ 2 test for categorical variables.

In the present study, we explored the association between ge-
netic variants of lncRNA CCAT1 with CRC susceptibility and
different CRC TMN stages. CCAT1 rs67085638 C > T was
associated with increased risk of CRC as well as colon can-
cer. CCAT1 rs77628730 T > A was associated with increased
CRC risk in subgroup of BMI < 24. CCAT1 rs7013433 A > T
was associated with late CRC clinical stage. To our knowl-
edge, this is the first study to investigate the link between
CCAT1 polymorphisms and CRC risk.
CCAT1 is a new identified lncRNA which has been re-
ported to be associated with the development, progression,
and treatment of various cancers. Li et al. has demonstrated
16 Y. Li et al.

Table 2 Association of the selected SNPs in CCAT1 with colorectal cancer risk.
Variable Case Control Model 1a Pa Model 2b Pb
(%) (%) OR (95% CI) OR (95% CI)
rs7013433 (PHWE = 0.254)
Codominant model
AA 135 (26.63) 129 (25.65) Ref. Ref.
AT 248 (48.92) 241 (47.91) 0.98 (0.73–1.33) 0.912 0.83 (0.55–1.26) 0.383
TT 124 (24.46) 133 (26.44) 0.89 (0.63–1.26) 0.510 0.70 (0.44–1.10) 0.124
Dominant model
AA 135 (26.63) 129 (25.65) Ref. Ref.
AT + TT 372 (73.37) 374 (74.35) 0.95 (0.72–1.26) 0.723 0.78 (0.53–1.15) 0.210
rs67085638 (PHWE = 0.808)
Codominant model
CC 324 (63.91) 346 (68.79) Ref. Ref.
CT 165 (32.54) 138 (27.44) 1.28 (0.97–1.68) 0.078 1.72 (1.14–2.58) 0.009
TT 18 (3.55) 19 (3.78) 1.01 (0.52–1.96) 0.972 1.39 (0.53–3.66) 0.506
Dominant model
CC 324 (63.91) 346 (68.79) Ref. Ref.
CT + TT 183 (36.09) 157 (31.21) 1.24 (0.96–1.62) 0.101 1.67 (1.13–2.47) 0.010
rs77628730 (PHWE = 0.144)
Codominant model
TT 260 (51.28) 259 (51.49) Ref. Ref.
TA 202 (39.84) 196 (38.97) 1.03 (0.79–1.33) 0.844 1.16 (0.80–1.69) 0.439
AA 45 (8.88) 48 (9.54) 0.93 (0.60–1.45) 0.762 0.73 (0.40–1.34) 0.309
Dominant model
TT 260 (51.28) 259 (51.49) Ref. Ref.
TA + TT 247 (48.72) 244 (48.51) 1.01 (0.79–1.29) 0.947 1.06 (0.74–1.50) 0.753
HWE, Hardy–Weinberg equilibrium.
a crude model.
b adjusted for age, gender, BMI, education level, red meat, root vegetable.

that CCAT1 could promote the tumorigenesis and progres-
sion of gastric cancer by negative-regulating miR-219-1 [33].
Chen et al. has demonstrated that CCAT1 could exert an
oncogenic role in multiple myelomaby by positively regulat-
ing HOXA1 expression through sponging miR-181a-5p [34].
Lai et al. has reported that CCAT1 down-regulation could im-
prove radiosensitivity of breast cancer cells via negatively
regulating miR-148b expression [35]. Zhang et al. has re-
ported that CCAT1 could promote the migration, invasion,
and epithelial-mesenchymal transition (EMT) activation of in-
trahepatic cholangiocarcinoma through suppressing miR-152
[36]. Cao et al. has found that CCAT1 could advance the initi-
ation and progression of epithelial ovarian cancer via CCAT1-
miR-152/miR-130b-ADAM17/WNT1/STAT3/ZEB1 regulatory
network [37]. As with CRC, famous “adenoma-carcinoma se-
quence” multi-step model proposed by Fearon and Vogel-
stein has been the paradigm of the genetic alterations in-
volved in the development of CRC [38]. Interestingly, CCAT1
is up-regulated all across the adenoma-carcinoma sequence
of CRC [21,39], which indicates CCAT1 may play crucial role
in the development and progression of CRC.
The promoter region is a DNA regulatory region, which is
located in the upstream of a gene, plays a crucial role in tran-
scriptional regulation [40]. SNPs in lncRNA promoter region
could modulate the expression and function of the lncRNA by
influencing the binding of transcription factor or the methy-
lation status of CpG islands [41,42]. For instance, genetic
variant in lncRNA IRAIN promoter region could influence the
expression of IRAIN by affecting the methylation status of
CpGs island, and is correlated with breast cancer risk [43].
Otherwise, 3 UTR region is a non-coding region of mRNA,
which is a target of miRNA. For example, miR-199a targets
lncRNA ANRIL at 3 UTR, that is, lncRNA ANRIL could pro-
mote carcinogenesis via sponging miR-199a in triple-negative
breast cancer [44]. SNPs in lncRNA 3 UTR region could af-
fect the combination and expression of related miRNA, thus
being associated with disease susceptibility [45]. As a result,
we detected the link between SNPs in promoter region and 3
UTR region with CRC risk. Rs7013433 in CCAT1 promoter re-
gion was associated with late CRC clinical stage; rs67085638
in CCAT1 3 UTR region was associated with increased CRC
risk as well as colon cancer risk.
Several limitations in our study should be considered. First,
as it is a case-control study, recall bias is inevitable. Second,
the small sample size of our case-control study results in in-
sufficient statistical power and precludes us to detect the slight
effect in the association between CCAT1 SNPs and TNM
stages with age, gender, BMI, and education level. Further-
more, no functional data was available for these SNPs, and
the impact of each variant on CCAT1 expression and function
remains largely unknown. However, this is first study to inves-
tigate the link between CCAT1 polymorphisms and CRC risk.
It may provide some insight of the crucial role of CCAT1 in the
CRC tumorigenesis.
In conclusion, we found that lncRNA CCAT1
rs67085638 C > T was associated with increased risk of
Table 3 Association of the selected SNPs in CCAT1 with colon cancer and rectal cancer.
Variable Colon cancer Rectal cancer
a a b b
Case/ Model 1 P Model 2 P Case/ Model 1a Pa Model 2b Pb
control OR (95% CI) OR (95% CI) control OR (95% CI) OR (95% CI)
rs7013433
Codominant model
AA 60/129 Ref. Ref. 75/129 Ref. Ref.
AT 119/241 1.06 (0.73–1.55) 0.756 1.18 (0.69–2.04) 0.543 129/241 0.92 (0.64–1.31) 0.649 0.86 (0.42–1.80) 0.699
TT 58/133 0.94 (0.61–1.45) 0.771 0.89 (0.48–1.66) 0.717 66/133 0.85 (0.57–1.29) 0.449 0.72 (0.31–1.65) 0.432
Dominant model
AA 60/129 Ref. Ref. 75/129 Ref. Ref.
AT + TT 177/374 1.02 (0.71–1.45) 0.924 1.07 (0.64–1.79) 0.785 195/374 0.90 (0.64–1.25) 0.522 0.81 (0.41–1.61) 0.549
rs67085638
Codominant model
CC 145/346 Ref. Ref. 179/346 Ref. Ref.
CT 84/138 1.45 (1.04–2.03) 0.028 1.83 (1.16–2.90) 0.010 81/138 1.14 (0.82–1.58) 0.451 1.44 (0.89–2.34) 0.142
TT 8/19 1.00 (0.43–2.35) 0.991 1.68 (0.57–5.00) 0.350 10/19 1.02 (0.46–2.23) 0.966 1.24 (0.37–4.17) 0.732
Dominant model
CC 145/346 Ref. Ref. 179/346 Ref. Ref.
CT + TT 92/157 1.40 (1.01–1.93) 0.041 1.82 (1.17–2.82) 0.008 91/157 1.12 (0.82–1.54) 0.480 1.42 (0.89–2.26) 0.144
rs77628730
Codominant model
TT 124/259 Ref. Ref. 136/259 Ref. Ref.
TA 93/196 0.99 (0.72–1.37) 0.957 1.07 (0.66–1.71) 0.787 109/196 1.06 (0.78–1.45) 0.719 1.36 (0.83–2.23) 0.218
AA 20/48 0.87 (0.50–1.53) 0.629 0.75 (0.35–1.63) 0.468 25/48 0.99 (0.59–1.68) 0.976 1.13 (0.49–2.62) 0.772
Dominant model
TT 124/259 Ref. Ref. 124/259 Ref. Ref.
TA + TT 113/244 0.97 (0.71–1.32) 0.833 0.99 (0.64–1.55) 0.978 134/244 1.05 (0.78–1.41) 0.766 1.25 (0.68- 2.29) 0.474
a crude model.
b adjusted for age, gender, BMI, education level, red meat, root vegetable.

17
18 Y. Li et al.

Table 4 Association of the selected SNPs in CCAT1 with TMN stage of colorectal cancer.
Variable I + II III + IV Model 1a Pa Model 2b Pb
(%) (%) OR (95% CI) OR (95% CI)
(n = 280) (n = 227)
rs7013433
Codominant model
AA 85 (30.36) 50 (22.03) Ref. Ref.
AT 126 (45.00) 122 (53.74) 1.65 (1.07–2.53) 0.023 1.82 (1.16–2.86) 0.009
TT 69 (24.64) 55 (24.23) 1.36 (0.82–2.23) 0.231 1.55 (0.92–0.92) 0.098
Dominant model
AA 85 (30.36) 50 (22.03) Ref. Ref.
AT + TT 195 (69.64) 177 (77.97) 1.54 (1.03–2.31) 0.036 1.72 (1.13–2.63) 0.012
rs67085638
Codominant model
CC 175 (62.50) 149 (65.64) Ref. Ref.
CT 94 (33.57) 71 (31.28) 0.89 (0.61–1.29) 0.534 0.85 (0.58–1.26) 0.428
TT 11 (3.93) 7 (3.08) 0.75 (0.28–1.98) 0.557 0.57 (0.20–1.63) 0.295
Dominant model
CC 175 (62.50) 149 (65.64) Ref. Ref.
CT + TT 105 (37.50) 78 (34.36) 0.87 (0.60–1.26) 0.464 0.823 (0.56–1.20) 0.316
rs77628730
Codominant model
TT 143 (51.07) 117 (51.54) Ref. Ref.
TA 106 (37.86) 96 (42.29) 1.11 (0.77–1.60) 0.589 1.11 (0.76–1.63) 0.592
AA 31 (11.07) 14 (6.17) 0.55 (0.28–1.09) 0.085 0.50 (0.25–1.01) 0.053
Dominant model
TT 143 (51.07) 117 (51.54) Ref. Ref.
TA + TT 137 (48.93) 110 (48.46) 0.98 (0.69–1.39) 0.916 0.96 (0.67–1.38) 0.843
a crude model.
b adjusted for age, gender, BMI, education level, red meat, root vegetable.

colorectal cancer as well as colon cancer; CCAT1 rs7013433
A > T was associated with late clinical stage of colorectal
cancer in Chinese population.
Acknowledgments
This study was supported by National Natural Science Foun-
dation of China (No. 81703289), Research on the Appli-
cation of Public Welfare Technology of Zhejiang Province
(No.2014C33224), and Medical Science and Technology
Project of Zhejiang Province (No.2017203626).
Conflicts of interest
The authors declared no conflicts of interest.
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