European Journal of Oncology Nursing 33 (2018) 97–101

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European Journal of Oncology Nursing

journal homepage: www.elsevier.com/locate/ejon

Susceptibility and severity of cancer-related fatigue in colorectal cancer T

patients is associated with SLC6A4 gene single nucleotide polymorphism
rs25531 A > G genotype
Xi Ouyang, Guanping Zhang, Hua Pan, Jun Huang∗
Department of Gastrointestinal Surgery, Second Affiliated Hospital of Nanchang University, Nanchang 330006, China

A R T I C L E I N F O A B S T R A C T

Keywords: Purpose: To explore the correlation between the SERT gene promoter single nucleotide polymorphisms (SNPs)
Colon and rectal cancer rs25531 and rs956304 and the cancer-related fatigue (CRF) of colon and rectal cancer, and also to analyze the
Cancer-related fatigue correlation of the interaction of genetic and non-genetic factors.
Serotonin transporter Method: A sample of 568 colon and rectal cancer patients were recruited from the Second Affiliated Hospital of
Single nucleotide polymorphism (SNP)
Nanchang University from October 2013 to December 2015. The Chinese version of the Brief Fatigue Inventory
SERT gene promoter SNP rs25531
(BFI-C) was used to evaluate the CRF. The genomic DNA was extracted from peripheral blood samples of the
AG+GG genotype
patients. Direct sequencing was used to determine the rs25531 and rs956304 genotypes.
Results: Compared with the AA genotype, the risk of suffering from CRF and the severity of CRF increased to
1.77 times (95% CI = 1.22–2.59, P = 0.003) for patients who carry with G allele (AG+GG genotype) at rs25531
locus.
Conclusions: The SERT gene promoter SNP rs25531 was associated with the CRF in patients with colon and
rectal cancer and the G genotype was an independent risk factor for CRF among individuals with colon and rectal
cancer in the study.

1. Introduction
Colon and rectal cancer is the third most commonly diagnosed
cancer in males and the second in females worldwide, with an esti-
mated 1.4 million cases and 693,900 deaths occurring every year (Torre
et al., 2015). In contrast to incidence trends, decreasing colon and
rectal cancer mortality rates have been observed in a large number of
countries worldwide (Edwards et al., 2010). With the transformation to
patient-centered medical care model, we should focus on palliation of
symptoms in addition to prevention, early detection, and management
of cancer. In other words, caregiving goals should include the im-
provement of patient's quality of life.
Fatigue is the most prevalent cancer-related symptom and has a
significant adverse impact on patients’ functional ability and quality of
life (Bennett et al., 2016; Bower, 2014). Cancer-related fatigue (CRF)
has been defined as a distressing, persistent, subjective sense of phy-
sical, emotional and/or cognitive tiredness or exhaustion related to
cancer or cancer treatment that is not proportional to recent activity
and interferes with usual functioning (Berger et al., 2015). Patients
perceive fatigue to be the most distressing symptom associated with
cancer and its treatment, more distressing even than pain or nausea and
vomiting (Spathis et al., 2015; Wang and Woodruff, 2015). It is esti-
mated that approximately 60–96% of cancer patients experience fatigue
(Berger et al., 2012; Noal et al., 2011; Seruga et al., 2008). And low
level of fatigue independently predicted longer recurrence-free and
overall survival in primary breast cancer patients (Groenvold et al.,
2007). Therefore, CRF is worthy of more attention from researchers and
clinicians.
The specific mechanisms involved in the pathophysiology of CRF
are unknown. Proposed mechanisms include hypothalamic-pituitary-
adrenal (HPA) axis dysregulation, circadian rhythm desynchronization,
pro-inflammatory cytokines, skeletal muscle wasting, and genetic dys-
regulation (Bower, 2014; Bower and Lamkin, 2013; Pachman et al.,
2012). There is increasing evidence for a role for serotonin receptors,
also known as 5-hydroxyrtyptamine receptors (5-HT) in the genesis of
central fatigue (Bozina et al., 2012; Meyer et al., 2015; Ryan et al.,
2007). The level of 5-HT in the synaptic cleft is mainly regulated by the
5-HT transporter (5-HTT). The serotonin transporter (SERT or 5-HTT) is
a protein that encoded by the SLC6A4 gene. The gene was mapped to
human chromosome 17q11.1–17q12. The SERT is a type of monoamine

∗
Corresponding author. Department of Gastrointestinal Surgery, Second Affiliated Hospital of Nanchang University, 1 Minde Road, Nanchang, Jiangxi 330006, China.
E-mail address: huangjun1996@126.com (J. Huang).

https://doi.org/10.1016/j.ejon.2018.02.003
Received 16 May 2017; Received in revised form 9 February 2018; Accepted 15 February 2018
1462-3889/ © 2018 Elsevier Ltd. All rights reserved.

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Table 1
Basic definitions of genetic terms.

Terms Basic definition

Minor allele frequency MAF refers to the frequency at which the second most common allele occurs in a given population. In other words, if there are 3 alleles, with frequencies
(MAF) of 0.50, 0.49, and 0.01, the MAF will be reported as 0.49.
Allele Humans have two sets of chromosomes, which are referred to as homologous chromosomes. The “allele” represents a gene that can occupy the same
position on homologous chromosomes and that control the same character.
Up-regulate The complementary process that involves increases of such components is called up-regulation.
A>G Wild type refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the
standard “normal” allele at a locus, in contrast to that produced by a non-standard, “mutant” allele. In the polymorphic locus rs25531, “A” represents
wild-type, and “G” represents a mutant-type. A > G represents A genotype mutation to G genotype.
(GG+AG) versus AA If both alleles at a gene on the homologous chromosomes are the same, they and the organism are homozygous with respect to that gene. If the alleles
are different, they and the organism are heterozygous with respect to that gene. AA represents wild-type homozygous, AG represents heterozygote, and
GG represents mutant homozygote. (GG + AG) versus AA indicates that the phenotype of the G allele is compared to the phenotype of the A allele

Fig. 1. Sequencing results of SNP rs25531 and rs956304 genotypes.

Table 2
Single Factor Analysis of CRF in patients with colorectal cancer.

No, Mild, Moderate, Severe, χ2 values P values

n (%) n (%) n (%) n (%)

Age ≤60 52 (17.1) 100 (32.9) 112 (36.8) 40 (13.2) 4.188 0.042
(Year) > 60 24 (9.1) 100 (37.9) 88 (33.3) 52 (19.7)
Gender Male 44 (14.1) 152 (48.7) 76 (24.4) 40 (12.8) 33.54 < 0.001
Female 32 (12.5) 48 (18.8) 124 (48.4) 52 (20.3) 0
Physical exercise state Yes 44 (21.3) 91 (44.0) 48 (23.2) 24 (11.6) 34.49 < 0.001
No 32 (8.9) 109 (30.2) 152 (42.1) 68 (18.8) 9
BMI ≤23.9 45 (13.6) 117 (35.2) 121 (36.4) 49 (14.8) 2.136 0.344
(kg/m2) 24.0–27.9 21 (11.2) 67 (35.6) 64 (34.0) 36 (19.1)
≥28.0 10 (20.8) 16 (33.3) 15 (31.3) 7 (14.6)
Smoking Yes 28 (10.9) 68 (26.6) 96 (37.5) 64 (25.0) 28.17 < 0.001
No 48 (15.4) 132 (42.3) 104 (33.3) 28 (9.0) 1
Drinking Yes 12 (9.8) 44 (35.8) 43 (35.0) 24 (19.5) 1.640 0.200
No 64 (13.4) 156 (35.1) 157 (35.3) 68 (15.3)
Tumor type Colon cancer 32 (11.0) 112 (38.4) 108 (37.0) 40 (13.7) 0.076 0.783
Rectal cancer 44 (15.9) 88 (31.9) 92 (33.3) 52 (18.8)
Tumor stage (TNM) StageⅠ 28 (31.8) 40 (45.5) 16 (18.2) 4 (4.5) 60.61 < 0.001
StageⅡ 20 (10.9) 72 (39.1) 72 (39.1) 20 (10.9) 3
StageⅢ 28 (10.3) 84 (30.9) 104 (38.2) 56 (20.6)
StageⅣ 0 (0.0) 4 (16.9) 8 (33.3) 12 (50.0)
Chemotherapy Yes 12 (5.6) 56 (25.9) 92 (42.6) 56 (25.9) 50.09 < 0.001
No 64 (18.2) 144 (40.9) 108 (30.7) 36 (10.2) 6
Radiotherapy Yes 8 (13.6) 16 (27.1) 22 (37.3) 13 (22.0) 1.567 0.211
No 68 (13.4) 184 (36.1) 178 (35.0) 79 (15.5)
rs25531 AA 64 (14.7) 170 (39.0) 140 (32.1) 62 (14.2) 27.63 < 0.001
AG 10 (8.3) 29 (24.0) 56 (46.3) 26 (21.5) 6
GG 2 (18.2) 1 (9.1) 4 (36.4) 4 (36.4)
AG+GG 12 (9.1) 30 (22.7) 60 (45.5) 30 (22.7)
rs956304 AA 65 (13.3) 166 (33.9) 173 (35.4) 85 (17.4) 2.991 0.084
AG 10 (13.5) 31 (41.9) 26 (35.1) 7 (9.5)
GG 1 (20.0) 3 (60.0) 1 (20.0) 0 (0.0)
AG+GG 11 (13.9) 34 (43.0) 27 (34.2) 7 (8.9)

98

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Table 3
Multi-ordinal regression analysis of severity of CRF in patients with colorectal cancer.

Variables β Standard error Waldχ2 values P values OR (95%CI)

Constant Intercept 1 −3.701 0.464 63.636 < 0.001 0.02 (0.01–0.06)

Intercept 2 −1.404 0.445 9.972 0.002 0.25 (0.10–0.59)
Intercept 3 0.766 0.440 3.038 0.081 2.15 (0.91–5.09)
Age (Year) ≤60 −0.240 0.170 1.997 0.158 0.79 (0.56–0.91)
> 60 01
Gender Male −0.861 0.175 24.234 < 0.001 0.42 (0.30–0.60)
Female 01
Physical exercise Yes −1.067 0.171 38.812 < 0.001 0.34 (0.25–0.48)
No 01
Smoking Yes 0.842 0.169 24.858 < 0.001 2.32 (1.67–3.23)
No 01
Tumor stage StageⅠ −2.096 0.485 18.686 < 0.001 0.12 (0.05–0.32)
StageⅡ −1.168 0.438 7.101 0.008 0.31 (0.13–0.73)
Stage Ⅲ −0.965 0.428 5.093 0.024 0.38 (0.16–0.88)
Stage Ⅳ 01
Chemotherapy Yes 0.840 0.182 21.229 < 0.001 2.32 (1.62–3.31)
No 01
rs25531 AG+GG 0.575 0.191 9.042 0.003 1.77 (1.22–2.59)
AA 01

transporter protein that carry serotonin from the synaptic cleft to the
pre-synaptic neuron which terminates the action of serotonin.
Single nucleotide polymorphisms (SNPs) are one of the most
common types of genetic variations in the human genome. For example,
at a specific base position in the human gene (such as the SLC6A4
gene), the A nucleotide may appear in most individuals, but in a min-
ority of individuals, the position is occupied by a G nucleotide. This
means that there is an SNP at this specific position, and the two possible
nucleotide variations – A or G (A > G) – are said to be alleles (Table 1)
for this position. SNPs underlie differences in human's susceptibility to
disease. SNPs are located in different regions of genes such as pro-
moters, exons and introns. Usually, the promoter region SNPs affect
gene expression by altering promoter activity. For transcription to take
place, the RNA polymerase must attach to the DNA near a gene. Pro-
moters contain specific DNA sequences that provide a initial binding
site for RNA polymerase and for proteins called transcription factors
that recruit RNA polymerase. These transcription factors have specific
activator or repressor sequences of corresponding nucleotides that at-
tach to specific promoters and regulate gene expression. Through
searching the National Center for Biotechnology Information (NCBI)
database, we found seven SNPs(rs2020932, rs956304, rs56087640,
rs25532, rs25531, rs25530, rs7210477) whose minor allele frequency
(MAF, Table 1) > 0.05 in SERT gene promoter. Only two SNPs
(rs25531and rs956304) can cause changes in transcription factors, so
we selected those two SNPs as study sites. The aim of this study was to
explore the correlation between rs25531 or rs956304 and the CRF of
colon and rectal cancer. We also analyzed the influence of genetic and
other factors (i.e., gender, age, body mass index, cigarette and alcohol
consumption, physical activity, tumor stage, chemotherapy & radio-
therapy) likely to influence CRF among individuals with colon or rectal
cancer.
2.2. Procedure
The Chinese version of the Brief Fatigue Inventory (BFI-C) was used
to measure fatigue severity and interference among participants.
Previous study has suggested that BFI-C satisfies the practical and the
psychometric properties for a good assessment tool to measure cancer-
related fatigue in the Chinese cancer population (Wang et al., 2004).
The final scores were divided as follows: no CRF (0 points), mild CRF
(1∼3points), moderate CRF (4∼6points), and severe CRF
(7–10points).
The blood samples were collected and preserved at-20 °C. Then the
genomic DNA was extracted from the blood samples using Blood
Genomic DNA Extraction Kit (Promega, Beijing) within one week of
collection. A UV spectrophotometer was used to detect the concentra-
tion of DNA.
2.3. Genotyping
PCR-direct sequencing was used to genotype single nucleotide
polymorphism sites rs25531 and rs956304 (Fig. 1). The genotype is the
part (DNA sequence) of the genetic makeup of a cell, and therefore of an
organism or individual, which determines a specific characteristic of
that cell/organism/individual. Each amplification contained 1 μL of
genomic DNA, 1 μL of the forward and reverse primers, dNTP 10 mM
1 μL, Taq Buffer 5 μL, 25 mM MgCl2 5 μL, Taq polymerase 5U/μL 0.5 μL
and water 35.5 μL. Reaction conditions began with an initial dena-
turation at 95 °C for 3 min followed by 35 cycles of 94 °C for 30 s, 60 °C
for 35 s, and 72 °C for 40 s, with a final extension step of 8 min at 72 °C.
The products were purified by using a PCR purification kit (Sangon
Biotech, Shanghai) and then analyzed by electrophoresis.

2.4. Statistical analysis

2. Patients and methods
Statistical analyses were performed using SPSS version 22. Chi-
square goodness of fit test was used to verify whether the distribution of
2.1. Patients
genotype in two loci complied with Hardy-Weinberg equilibrium. The
Hardy–Weinberg equilibrium states that the genetic variation in a po-
Participants with pathologically diagnosed colon and rectal cancer
pulation will remain constant from generation to generation in the
were recruited from the Second Affiliated Hospital of Nanchang
absence of other evolutionary influences. The Hardy-Weinberg equili-
University from October 2013 to December 2015. The study protocol
brium describes an idealized state, and genetic variations in nature can
was approved by the Institutional Ethical Committee and all partici-
be measured as changes from this equilibrium state.
pants gave written informed consents. The characteristics were re-
Kruskal-Wallis H test was used for comparison of variables with
corded for each patient.
non-normal distributions. Ordinal logistic regression modeling was
used to test associations of influential factors with CRF. Statistical

99

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X. Ouyang et al.
hypotheses were tested at alpha error rate set to 0.05.
3. Results
3.1. General characteristics
A total of 568 patients (312 males and 256 females) with colon and
rectal cancer were included in the analysis, of which 292 (51.4%) were
diagnosed colon cancer and 256 (48.6%) were diagnosed rectal cancer.
Using the BFI-C score rating, 76 (13.4%) participants had no CRF, 200
(35.2%) had mild, 200 (35.2%) had moderate, and 92 (16.2%) had
severe CRF.
3.2. Single factor analysis
The genotype frequency of rs25531and rs956304 was in accordance
with the Hardy Weinberg equilibrium (Fig. 1). Some potential factors
were analyzed by Kruskal-Wallis H test (Table 2), which was used for
comparison of variables with non-normal distributions. In the severe
CRF group, the difference was statistically significant among different
genotypes of rs25531, with AA (14.2%), AG (21.5%), GG (36.4%) and
AG+GG (22.7%) respectively (χ2 = 27.636, P < 0.001). However, the
proportions of different genotypes of rs956304 did not reveal statisti-
cally significant difference (χ2 = 2.991, P = 0.084).We also observed
that the different situations of age, gender, physical exercise state, ci-
garette consumption, tumor stage and chemotherapy were correlated
with significantly different degree of CRF(P < 0.05).
3.3. Multi-ordinal regression analysis
In consideration of the low proportion of GG genotype at rs25531
locus, we compared genotype AG+GG to genotype AA (Table 1). The
results of the analysis indicated that independent factors that influence
the severity of CRF include gender, physical exercise state, cigarette
consumption, tumor stage, chemotherapy and the genotype of rs25531
(Table 3). Compared with AA genotype, the risk of suffering from CRF
and the severity of CRF increased to 1.77 times for carriers with G allele
(AG+GG genotype) at rs25531 locus.
4. Discussion
This study is the first to identify a relationship between SERT gene
regulatory polymorphisms and CRF in colon and rectal cancer survi-
vors. Selected SNPs are located in predicted transcription factor binding
sites, regions with putative regulatory control over gene expression.
CRF was reported as the most distressing symptom associated with
cancer as it has many negative impacts on patients’ daily activities and
quality of life (LaVoy et al., 2016; Wang and Woodruff, 2015). How-
ever, there are no report describing the role of rs25531 and rs956304 in
CRF susceptibility among individuals with colon and rectal cancer. In
this study, the results indicated that rs25531 A > G genotype was
related to the susceptibility of CRF in colon and rectal cancer patients,
and G allele (AG+GG genotype) significantly increased the risk of
suffering from CRF and the severity of CRF. This finding is noteworthy
because it lend additional support for the role of genetic variation in the
development of CRF in colon and rectal cancer patients.
Despite its prevalence, the etiology of cancer-related fatigue is still
poorly understood. The 5-HT is involved in the regulation of diverse
brain functions including emotional and behavioral activities in the
central nervous system (CNS)(Homberg and Lesch, 2011). Polymorph-
isms found in the regulatory regions, such as promoters, can, in many
cases, affect in vitro expression of the gene product. The results of
several studies indicated SNP rs25531 A > G genotype may influence
physical and psychosocial functioning in young patients with chronic
fatigue syndrome (CFS)(Meyer et al., 2015), and be associated with
suicide ideation and behavior (Bozina et al., 2012). In addition, SNPs in
100
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European Journal of Oncology Nursing 33 (2018) 97–101
the SERT gene may modulate attention to threat (Klumpers et al.,
2012), anxiety, negative affect and fear (Lonsdorf et al., 2009). The
rs25531 A allele to G allele mutation could create a binding site for a
transcription factor activating enhancer-binding protein 2 (AP2)(Hu
et al., 2006). AP-2 protein mediates dimerization and DNA binding and
regulates apoptosis, cell cycle and gene expression (Bassett et al., 2012;
Eckert et al., 2005). Therefore, the G allele may lead to lower tran-
scription of the SLC6A4 gene, lower expression of serotonin transporter,
and then reduction of 5-HT reuptake in synaptic space, which results in
inhibition of brain function and cause fatigue.
The occurrence of CRF is influenced by many factors. Redeker et al.
investigated 263 cancer patients who were undergoing chemotherapy
and found that women had more anxiety and fatigue than did men
(Redeker et al., 2000). Similarly, our study also showed that female
patients were easier to suffer from CRF. Of the specific non-
pharmacologic interventions for CRF, physical activity has the strongest
evidence base for reducing the severity and occurrence of fatigue
(Abbott and Hooke, 2017; Zhang et al., 2017). We drew the same
conclusion from this study but the practical significance is limited, as
we did not control every participant's form and frequency of exercise.
Smoking is a risk factor for CRF and it may up-regulate (Table 1) cer-
ebrovascular 5-HT receptor (Cao et al., 2013). Fatigue could be a
toxicity manifestation of elevated body temperature caused by che-
motherapy (Koltyn et al., 1992). Tumor stage is another influencing
factor of CRF.
Our study suggests that SNP rs25531 A > G in SERT gene promoter
is an independent risk factor for CRF in patients with colon and rectal
cancer. The probable mechanism is the G allele may reduce the re-
uptake of 5-HT in synaptic space. If this hypothesis is valid, it will help
to develop some SERT-targeting drugs to treat CRF in patients with G
allele. However, there are still some limitations in our study. Firstly, it
was a single-center study although the sample size was large. Secondly,
other factors that may impact the final interpretation of data, such as
economic conditions, complications and treatment regimen were not
included in the analysis. The impact of this finding should be in-
vestigated in a prospective multi-center study with a larger sample size
and proved by further studies of relevant molecular mechanism.
5. Conclusion
In conclusion, we found that the occurrence of CRF is caused and
influenced by multiple factors such as female gender, physical exercise,
smoking, advanced tumor and chemotherapy. It is necessary to
strengthen the assessment and management of fatigue in patients with
colon and rectal cancer and give prompt and effective intervention such
as physical exercises. We identified for the first time that SNP rs25531
A > G (Table 1) in SERT gene promoter is an independent risk factor for
CRF in patients with colon and rectal cancer (P = 0.003). Therefore, the
SNP rs25531 A > G in SERT gene promoter shows promise for use as a
screening marker.
Conflict of interest
The authors have declared no conflicts of interest.
Acknowledgement
The project was funded by the Natural Science Foundation of
Jiangxi Province (20142BAB205047).
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