Comprehensive Analysis Of Cdca8 In Colon Adenocarcinoma Including Expression, Methylation, Mutations, and Prognostic Significance

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Vol.31 No.5 (2024): JPTCP (1748 -1759) Page | 1748
Journal of Population Therapeutics
& Clinical Pharmacology
RESEARCH ARTICLE
DOI: 10.53555/jptcp.v31i5.6419
COMPREHENSIVE ANALYSIS OF CDCA8 IN COLON
ADENOCARCINOMA INCLUDING EXPRESSION,
METHYLATION, MUTATIONS, AND PROGNOSTIC
SIGNIFICANCE
Muhammad Imran1, Imtiaz Ali Soomro2, Kiran Nazish3, Naheed Bano4, Muhammad Abbas5,
Muhammad Khizer Hayat6, Habibullah Janyaro7*, Usama Ahmed8, Hafeez Ullah9,
Muhammad Salman Hameed10
1Department Of Animal Sciences, KBCMA College Of Veterinary And Animal Sciences, Narowal ,
Pakistan
2Department Of Surgery, Peoples University Of Medical And Health Sciences Nawabshah, Pakistan
3Department Of Veterinary Epidemiology And Public Health SBBUVAS Sakrand, Pakistan
4Department Of Zoology, Wildlife & Fisheries, MNS-University Of Agriculture Multan, Pakistan
51st Affiliated Hospital Of Hebei North University Hebei Province, China
6Center For Animal Diagnostics, Chughtai Lab Lahore, Pakistan
7Department Of Veterinary Surgery, SBBUVAS, Sakrand, Pakistan
8Department Of Medicine, School Of Biomedical Engineering, Shenzhen University Medical
School, Shenzhen 518060, PR China
9Department Of Microbiology, Abasyn University Peshawar, Pakistan
10International Joint Research Center For Intelligent Biosensor Technology And Health, Central
China Normal University, Wuhan 430079, P.R. China
*Corresponding Author: Habibullah Janyaro
*Email Address: Janyaroh@Gmail.Com
ABSTRACT
In the current study, the role of cell division cycle-associated 8 (CDCA8) in colon adenocarcinoma
(COAD) was analyzed through comprehensive expression and methylation analysis, genetic mutation
inquiry, and prognostic assessment. Utilizing the UALCAN database, CDCA8 expression analysis
revealed significant overexpression in carcinogenic cells compared to normal control samples,
suggesting its involvement in COAD proliferation. Further examination of CDCA8 expression across
various clinical parameters showed significant upregulation in different cancer development stages,
racial groups, genders, and age classes within COAD patients, highlighting its critical role in cancer
proliferation. Validation using the GEPIA2.0 tool confirmed that CDCA8 was highly expressed in
COAD compared to normal controls. Additionally, analysis of CDCA8 expression across different
cancer stages revealed dysregulation in all four stages, with the highest expression in stage I and the
lowest in stage III. The study also investigated the promoter methylation level of CDCA8, finding a
significant association between COAD samples and normal controls. Analysis of promoter
methylation across various clinical parameters showed significant variations, with distinct
methylation patterns observed across cancer stages, racial groups, genders, and age groups. Overall

Comprehensive Analysis Of Cdca8 In Colon Adenocarcinoma Including Expression, Methylation, Mutations, And
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survival (OS) and disease-free survival (DFS) analyses using the KM plotter tool demonstrated that
low CDCA8 expression was associated with shorter OS compared to high CDCA8 expression. In
terms of DFS, COAD patients with higher CDCA8 expression experienced better DFS than those
with low CDCA8 expression. Further validation of CDCA8 expression against survival data indicated
that high CDCA8 expression was associated with better OS and DFS in COAD. Lastly, mutational
assessment using the cBioPortal platform showed no significant mutations in COAD samples.
Overall, these findings highlight the complex role of CDCA8 in COAD pathogenesis, underscoring
its potential as a prognostic biomarker and therapeutic target in COAD management.
Keywords: Colon adenocarcinoma, Diagnosis, Treatment, Biomarker
Introduction
Cancer remains the leading cause of mortality worldwide, presenting significant health-related and
socio-economic challenges (1, 2). Current cancer treatments include surgery, chemotherapy,
radiotherapy, and immunotherapy (3, 4). Colorectal cancer (CRC) is the third leading cause of cancer-
related mortality in both men and women, affecting over 1.4 million individuals and causing
approximately 693,900 deaths annually (5). Approximately 60% of CRC patients are diagnosed with
localized and distant metastases, categorized as stage IV, which has a 5-year survival rate ranging
from 12.5% to 70.4%, and a poor prognosis compared to over 90% for stage I (6). Recently, there has
been a trend toward younger age at diagnosis of CRC (7). Over the last decade, CRC incidence rates
increased by 22% and CRC mortality rates increased by 13% among adults under 50 years old in the
USA (8). These facts highlight the urgent need to develop early molecular biomarkers for CRC. CRC
is a heterogeneous, multifactorial disease, with approximately 35% of cases attributed to genetic
factors. Genome-wide association studies have identified around 50 associated loci (9). Additionally,
smoking, alcohol consumption, low physical activity, obesity, and environmental factors have been
linked to increased CRC risk (10). Currently, chemotherapy, including anti-cancer drugs and
compounds, is primarily used in advanced stages of the disease or as an adjuvant therapy after surgery
in cases of lymph node metastasis (11, 12). Surgery combined with chemotherapy and radiotherapy
is still considered the best approach for treating most patients at stages III and IV. However, these
treatments are often associated with severe adverse reactions and chemo-resistance (13).
The CDCA8 gene encodes the Borealin/Dasra B protein and is a crucial component of the
chromosome passenger complex (CPC) (14, 15). The CPC is a vital structure during cell division,
comprising four key parts: INCENP, Survivin, Aurora B, and Borealin/Dasra B (16). CDCA8 is
essential for localizing the CPC to the centromere, correcting kinetochore binding errors, and
stabilizing bipolar spindles (17, 18). The CPC includes the enzymatic core Aurora-B kinase, the
scaffold protein inner centromere protein, CDCA8, and two non-enzymatic surviving subunits (19,
20). Therefore, CDCA8 is a significant factor in mitosis regulation (21, 22). The eight members of
the cell division cycle-associated (CDCA) gene family (CDCA1-8) are critical regulators of cell
proliferation. Studies have shown that the abnormal expression of CDCAs can cause cancer (19, 23,
24). Specifically, CDCA8 is highly expressed in breast cancer cells, and knockdown of the CDCA8
gene can suppress the survival and growth of cancer cells. Furthermore, higher CDCA8 gene
expression is strongly associated with poor prognosis in various cancers. CDCA8 is thus a vital
mediator of estrogen-stimulated breast cancer cell growth and survival (25, 26). Research has
confirmed that CDCA8 plays a crucial role in mitosis, chromosome segregation, and cancer cell
division (27, 28). One study showed that CDCA8 was overexpressed in colorectal cancer, and that
depletion of CDCA8 hindered the growth of malignant cells and induced apoptosis (29).
In the ongoing research, our goal was to investigate CDCA8 mutations, expression levels, prognostic
implications on survival, and functional perspectives within the context of colon adenocarcinoma
(COAD) through bioinformatics analysis. Additionally, we explored the relationship between
CDCA8 expression and promoter methylation levels. To accomplish this, we utilized various

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databases including The Cancer Genome Atlas (TCGA), the UALCAN platform, the Kaplan-Meier
database, the Gene Expression Profiling Interactive Analysis (GEPIA2.0), and cBioPortal. The
primary aim of this study was to evaluate CDCA8 expression patterns in COAD and elucidate its
potential significance in cancer treatment and prognosis.
Materials and methods
GEPIA2.0 analysis
GEPIA2.0 is a powerful online tool that facilitates survival analysis in cancer research (30). The
GEPIA2.0 website allowed us to compare the expression of CDCA8 in tumor tissues versus adjacent
normal tissues and generate box plots. By utilizing information from TCGA and GTEx data sets,
GEPIA2.0 enables users to evaluate the impact of specific genes on patients' survival across various
cancer types. In the current study, GEPIA2.0 was employed to analyze the association between
CDCA8 gene expression and prognosis, including overall survival (OS) and disease-free survival
(DFS), in colon adenocarcinoma (COAD).
UALCAN analysis
UALCAN (http://ualcan.path.uab.edu/) is an integrative and interactive online resource that can be
used to analyze level 3 RNA-seq data and clinical information from 31 different tumors in The Cancer
Genome Atlas (TCGA) data set. This portal allows users to examine differences in the expression
levels of query genes between tumor and normal samples and to estimate the impact of gene
expression levels and clinicopathological characteristics on patient survival (31). In our study, we
used the UALCAN database to probe CDCA8 expression levels and promoter methylation status in
colon adenocarcinoma (COAD). Additionally, we utilized UALCAN to assess CDCA8 expression
and promoter methylation levels across various clinical parameters, including patient race, age, and
gender. This comprehensive investigation provided valuable insights into the relationship between
CDCA8 expression patterns, promoter methylation, and demographic factors in COAD patients.
Kaplan-Meier Plotter analysis
The Kaplan-Meier (KM) plotter is an essential tool in the domain of survival analysis (32). This
online platform harnesses extensive clinical data to evaluate the impact of specific genes on patient
survival across different cancer types. Researchers can easily explore the prognostic value of gene
expression, identifying potential prognostic biomarkers. KM Plotter's intuitive interface offers
Kaplan-Meier survival curves, providing insights into how gene expression correlates with patient
outcomes. In this study, the KM plotter tool was utilized to analyze the impact of CDCA8
dysregulation on the overall survival (OS) of cancer patients.
cBioPortal analsysis
cBioPortal (https://www.cbioportal.org/) (33) is a crucial platform for analyzing genetic alterations
in cancers. Utilizing large-scale genomics data, it enables researchers to investigate and interpret
genomic alterations, including mutations, copy number variations, and mRNA expression changes.
The user-friendly interface facilitates in-depth analysis of these alterations across various cancer
types, contributing to a better understanding of the molecular landscape and potential therapeutic
targets. In the current research, we utilized cBioPortal for mutational analysis of the CDCA8 gene
across COAD tumors.
Results
Expression analysis of CDCA8 in COAD based on sample types
CDCA8 expression in COAD and normal control samples was investigated using the UALCAN
database (Figure 1). Our findings reveal a significant overexpression of CDCA8 in COAD cancer
cells compared to normal control samples. This pronounced upregulation indicates a potential
association between CDCA8 expression and the proliferation of COAD cancer cells.

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Figure 1: Expression profiling of CDCA8 in COAD and normal tissue samples.
Expression analysis of CDCA8 in COAD cancer divided based on different clinical parameters
Following this, we conducted an evaluation of CDCA8 in COAD samples across various clinical
parameters, encompassing cancer stages, patient demographics including race, gender, and age (refer
to Figure 2). Initially, we examined CDCA8 expression across different stages of cancer development
and observed a significant increase in CDCA8 expression in COAD compared to normal control
samples across all stages (Figure 2A). Subsequently, we assessed CDCA8 expression in COAD
patients, revealing a substantial upregulation of CDCA8 in each of the three racial groups—
Caucasian, Asian, and African American—compared to normal controls (Figure 2B). Furthermore,
we investigated CDCA8 expression in COAD patients stratified by gender, which demonstrated a
notable elevation of CDCA8 expression in both male and female patients compared to normal
controls (Figure 2C). Lastly, we examined the correlation between CDCA8 expression and patient
age in COAD. Our findings indicated an increased expression of CDCA8 across various age groups
among COAD patients (Figure 2D).
Figure 2: Expression of CDCA8 across different clinical boundaries

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Validation of CDCA8 expression in COAD
We utilized GEPIA2 to examine CDCA8 expression in COAD cancer compared to normal tissues.
The analysis revealed a significant upregulation of CDCA8 in colon adenocarcinoma (COAD) when
compared to normal control samples (refer to Figure 3A). Additionally, we investigated the
correlation between CDCA8 expression and different pathological stages using the GEPIA2 database.
The results demonstrated a strong association between CDCA8 expression levels and the stages of
COAD patients. Notably, CDCA8 exhibited the highest expression in stage I and the lowest
expression in stage III among COAD patients (Figure 3B).
Figure 3: Validation of CDCA8 across different stages of COAD
Promoter methylation of CDCA8 in COAD and normal tissue
Therefore, we examined the differentiation in promoter methylation of CDCA8 between COAD and
normal control samples using the UALCAN dataset (refer to Figure 4). Our analysis unveiled a
significant variation, particularly hypermethylation, in the promoter methylation levels of CDCA8 in
COAD compared to normal control samples. This observation suggests potential epigenetic
dysregulation of CDCA8, underscoring its involvement in COAD pathogenesis. Such findings
contribute to our understanding of the molecular mechanisms underlying COAD development and
propose insights into the role of CDCA8 as a potential biomarker or therapeutic target in COAD
management.

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Figure 4: Promoter methylation pattern of CDCA8 in COAD and normal control samples
Promoter methylation of CDCA8 in COAD cancer divided based on different clinical
parameters
To further delve into the promoter methylation status of CDCA8 in COAD, we analyzed various
clinical parameters (refer to Figure 5). Initially, we examined CDCA8 promoter methylation across
different COAD stages in comparison to normal control samples. We observed significant variations
among stages, with stage I exhibiting hypomethylation and the remaining stages displaying noticeable
hypermethylation (Figure 5A). Subsequently, we investigated CDCA8 promoter methylation in
relation to the race of COAD patients. Our analysis revealed hypermethylation in CDCA8 promoter
regions across Caucasian and African American groups, whereas hypomethylation was observed in
the Asian race group compared to normal control samples (Figure 5B). Following this, assessment of
CDCA8 promoter methylation based on patient gender showed gender-specific differences, with both
females and males exhibiting hypermethylation (Figure 5C). Finally, we explored CDCA8 promoter
methylation with respect to patient age, revealing varying methylation levels across different age
groups (Figure 5D). These comprehensive analyses highlight the intricate relationship between
CDCA8 promoter methylation and various clinical parameters in COAD, providing insights into the
diverse mechanisms underlying CDCA8 expression regulation in COAD pathogenesis.

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Figure 5: CDCA8 promoter methylation pattern across different clinical parameters
Survival analysis of CDCA8
To further evaluate CDCA8 gene expression in COAD, we conducted an analysis for overall survival
(OS) and disease-free survival (DFS) using the KM plotter tool. Our examination revealed a
significant association between CDCA8 gene expression and patient survival outcomes in the current
study. Specifically, COAD patients with low CDCA8 expression exhibited shorter overall survival
compared to those with high CDCA8 expression levels (refer to Figure 6A). Similarly, in the
assessment of disease-free survival (DFS), COAD patients with higher CDCA8 expression
experienced better DFS relative to COAD patients with low CDCA8 expression. These findings
underscore the pivotal role of CDCA8 in influencing the survival outcomes of COAD patients,
emphasizing its potential clinical significance as a prognostic marker in COAD management.
Figure 6: KM survival curve (OS, RFS) of CDCA8 in COAD patients

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Prognostic analysis of CDCA8 in COAD
We utilized the GEPIA2.0 database to explore the prognostic significance of CDCA8 expression in
COAD cancer progression. COAD patients were stratified into low and high expression groups based
on CDCA8 expression levels. In COAD, high CDCA8 expression was correlated with improved
overall survival (OS) compared to low CDCA8 expression (refer to Figure 7A). Furthermore, we
observed that a high CDCA8 expression level was associated with favorable disease-free survival
(DFS) in COAD compared to the low CDCA8 expression group (refer to Figure 7B).
Figure 7: Survival curve (OS, RFS) of CDCA8 in COAD patients
Mutational analysis of CDCA8 in COAD
For the analysis of CDCA8 mutation features, we conducted a comprehensive mutational analysis of
CDCA8 in COAD cancer using the cBioPortal dataset. In the current review, no significant mutations
of CDCA8 were observed (refer to Figure 8).
Figure 8: Oncoplot of CDCA8 in COAD cancer
Discussion
Colorectal cancer (CRC) is widely understood to develop through a multistep process, starting from
aberrant crypt foci, progressing through benign precancerous lesions (adenomas), and eventually
culminating in malignant tumors (adenocarcinomas) over an extended period (34). While the majority
of CRC cases are sporadic, approximately 20%-30% of CRC patients carry inherited mutations (35,
36). Despite significant advancements in surgical resection for patients with localized disease, the
majority of CRC patients eventually experience recurrence and metastasis (37, 38). Current
therapeutic approaches, such as chemotherapy, are recommended for CRC treatment; however, these
non-surgical interventions have limited efficacy and are ineffective against distant metastasis (39).
Consequently, the prognosis for CRC patients remains poor, highlighting the need to focus on future
therapeutic strategies to improve clinical outcomes. Immunotherapy has recently emerged as a
treatment option for advanced CRC and holds the potential to eradicate the disease by activating
immune responses (40).
CDCA8 stands as a crucial regulatory gene in mitosis, playing a pivotal role in various cancer types
by promoting cell proliferation and invasion, thus acting as an oncogene (41, 42). Previous studies
have highlighted the heightened transcriptional activity of CDCA8 in embryos, embryonic stem cells,
and cancer cells, while it either lacks expression or shows minimal expression in normal tissues (43).
Consequently, aberrant CDCA8 expression strongly correlates with cancer pathogenesis. Li et al.
demonstrated that CDCA8 encodes the protein Borealin/Dasra B, which plays a critical role in
regulating postnatal liver development, injury-induced hepatic progenitor-like cell regeneration, and

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liver tumorigenesis in mice (44). Earlier research has indicated that upregulated CDCA8 expression
plays a significant role in cancer initiation, progression, and transformation. Yu et al. illustrated that
CDCA8 induces tamoxifen resistance and enhances cell proliferation by inhibiting apoptosis and
promoting cell cycle progression in breast cancer cells (45). Additionally, CDCA8 knockdown has
been shown to inhibit cell proliferation and promote cell differentiation in lung cancer, colorectal
cancer, and human embryonic stem cells (29, 46, 47).
As illustrated in the aforementioned studies, elevated CDCA8 expression plays a crucial role in
various types of cancer. Recently, an increasing number of studies have investigated CDCA8 as a
potential prognostic marker. Gu et al. conducted RNA-Seq data analysis and identified CDCA8 as a
prognostic gene in kidney renal clear cell carcinoma (48). Additionally, Ci et al. demonstrated that
cutaneous melanoma patients with high CDCA8 expression had significantly lower overall survival
compared to those with low expression, suggesting CDCA8 as an independent prognostic indicator
in cutaneous melanoma (41). Similar findings have been observed in gastric cancer, lung cancer,
breast cancer, and colorectal cancer (49, 50). Furthermore, high CDCA8 expression has been
associated with poor prognosis in gastric cancer. In pancreatic ductal adenocarcinoma, CDCA8
mediates the upregulation of KIF18B and promotes cancer cell proliferation (51). Depletion of
CDCA8 leads to cell cycle arrest at the G2/M stage, increased DNA damage and apoptosis, and
enhances the sensitivity of ovarian cancer cells to Cisplatin and Olaparib (52). Through the ROCK
signaling pathway, CDCA8 knockdown can inhibit cancer cell proliferation and invasion (41).
However, the significance of CDCA8 in COAD has not been fully elucidated.
In our current investigation, we utilized the UALCAN database to explore the expression of CDCA8
in COAD. Consistent analysis across different stages, cancer types, age, gender, and racial groups
revealed upregulation of CDCA8 expression. Regarding cancer progression, our study found
significantly higher CDCA8 expression levels in COAD tissues compared to normal control samples.
Furthermore, using the KM plotter tool, our evaluation indicated that COAD patients with low
CDCA8 expression experienced shorter overall survival and worse disease-free survival compared to
patients with high CDCA8 expression levels. Our analysis suggests that CDCA8 expression level in
tissue serves as an independent poor prognostic factor. Further investigations are warranted to explore
the prognostic value of CDCA8 expression in cancer development.
Conclusion
Compared to adjacent normal tissues, COAD tissues exhibited elevated expression levels of CDCA8.
Increased CDCA8 levels were associated with poor overall survival (OS), disease-free survival
(DFS), and clinical features, including promoter methylation levels and genetic mutations. Therefore,
we hypothesize that CDCA8 promotes cancer development through cell cycle regulation.
Additionally, CDCA8 may play a potential therapeutic role in COAD-related immunity.
Consequently, CDCA8 holds promise as a potential biomarker for early COAD detection and
prognostic prediction.
Conflict of interest
None
Acknowledgement
None
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