Cancer Management and Research

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Biochemical Markers of Colorectal Cancer –

Present and Future

Wojciech Jelski & Barbara Mroczko

To cite this article: Wojciech Jelski & Barbara Mroczko (2020) Biochemical Markers of
Colorectal Cancer – Present and Future, Cancer Management and Research, , 4789-4797, DOI:
10.2147/CMAR.S253369

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© 2020 Jelski and Mroczko.

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Biochemical Markers of Colorectal Cancer –

Present and Future
This article was published in the following Dove Press journal:
Cancer Management and Research

Wojciech Jelski 1 Abstract: According to a report by the National Cancer Institute, colorectal cancer (CRC) is
Barbara Mroczko 1,2 one of the most common types of cancer worldwide. CRC is often recognized too late for
1
successful therapy. Tumor markers have been sought for a number of years to detect the
Department of Biochemical Diagnostics,
Medical University of Bialystok, Bialystok, transformation of malignant cells at the earliest possible stage. They are usually proteins
Poland; 2Department of associated with a malignancy and might be clinically useful in patients with cancer. Several
Neurodegeneration Diagnostics, Medical
classical markers have been used to recognize colorectal cancer, including carcinoembryonic
University of Bialystok, Bialystok, Poland
antigen (CEA), carbohydrate antigen (CA 19.9), tissue polypeptide specific antigen (TPS)
and tumor-associated glycoprotein-72 (TAG-72). None of these tests, however, have excel-
lent diagnostic accuracy. Recent studies have been conducted on the use of hematopoietic
growth factors (HGFs) and various enzymes in the diagnosis and prognosis of colorectal
cancer. These include macrophage-colony stimulating factor (M-CSF) and granulocyte-
macrophage-colony stimulating factor (GM-CSF), interleukin-3, interleukin-6 and enzymes
(alcohol dehydrogenase and lysosomal exoglycosidases). Significantly, most cancer deaths
are not caused by the primary tumor itself but by its spread. Analysis of circulating cancer
cells (CTCs), ie, factors responsible for metastasis, may be a source of information useful in
the treatment of patients with colorectal cancer. Currently available markers have significant
limitations.
Keywords: tumor markers, colorectal cancer

Introduction
Colorectal cancer (CRC) is one of the most common cancers worldwide, with over
one million new cases per year. CRC is the second leading cause of cancer deaths in the
United States.1 In recent years, an increase in colorectal cancer incidence has occurred
in younger people (aged<50 years). Beginning in the early 1990s, incidence rates
increased among younger adults from 8.6 per 100,000 in 1992 to 12.5 per 100,000 in
2015, an overall increase of 45%.2,3 Over time, the incidence of CRC increases in
younger patients. In China, due to changes in diet and lifestyle, morbidity associated
with CRC is on the rise, and CRC has recently begun to affect younger people. One of
the primary risk factors for colorectal cancer is obesity, a condition typically assessed
using a scale known as the body mass index (BMI).4 The underlying etiology of CRC
includes both genetic variation and environmental exposure. It has been suggested that
Correspondence: Wojciech Jelski
Department of Biochemical Diagnostics, the interplay between genetic variants and environmental risk factors, known as gene–
Medical University of Bialystok, environment interaction, may also contribute to an increase of CRC risk.5 The majority
Waszyngtona 15 A, Bialystok 15–269,
Poland of cases are due to poor dietary patterns, host immunity, and lifestyle factors such as
Tel +48 85 746 8587 smoking, low physical activity levels, and obesity. Other gastrointestinal disorders,
Fax +48 85 746 8585
Email [email protected] such as inflammatory bowel disease characterized by chronic inflammation, mucosa

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Jelski and Mroczko Dovepress

disruption, and the excessive production of reactive oxygen assessment make the choice of therapeutic treatment
species, act as risk factors in the onset of cancer. In recent possible.
years, a new and remarkable factor in the development of Recent technological and analytic advances have
cancer and other related intestinal diseases has emerged; the boosted scientific biomarker research. In the near future,
gastrointestinal tract microbiota.6 Carcinogenesis is a long, the advent of novel urinary assays with high efficacy that
complex and gradual process. The prognosis for patients with would reduce CRC mortality is expected. In colorectal
colon cancer is correlated with the pathological stage at the cancer, molecular (eg mutations in the KRAS, NRAS,
time of detection and it is very important to find markers that BRAF, PIK3CA genes) and immunohistochemical mar-
would detect a malignant tumor as early as possible.7 This is kers (eg TS, P21, PTEN proteins) are used to assess
why the search for new biochemical markers in blood is predictive goals. Molecular markers in colorectal cancer
necessary. Colorectal cancer is a serious disease that is char- can be divided into somatic mutations and microsatellite
instability (MSI).
acterized by rapid progression, invasiveness and high resis-
tance to treatment. Diagnosing CRC at an early stage is not
easy, as cancer is often asymptomatic. Screening requires Classical Tumor Markers
Carcinoembryonic antigen (CEA) is a glycoprotein oncofetal
tools and methods that are both highly sensitive and specific
antigen that is expressed in many epithelial tumors. This
when diagnosing the early stages of cancer. They must be
relatively inexpensive blood test, first described by Gold and
safe, cheap and widely accepted. A tumor marker can be
Freedman in 1965, was part of most recommended surveil-
detected in a solid tumor tissue, in a lymph node, bone
lance strategies.10 CEA is a glycoprotein which is formed in
marrow, peripheral blood, or other biological materials
the cells of the large bowel. Seventy percent of patients with
(urine, ascites, and stool).8 Several markers of colorectal
CRC have high CEA levels during diagnosis, which makes it
cancer, including carcinoembryonic antigen (CEA), carbo-
a very good marker for the treatment and monitoring of the
hydrate antigen (CA 19.9), tissue polypeptide specific anti-
disease after resection. Although CEA is usually considered
gen (TPS), tumor-associated glycoprotein-72 (TAG-72), and
a cancer marker, its concentrations may also be elevated in
hematopoietic growth factors (HGF-s) have been recognized a variety of benign conditions, including hepatitis, pancreati-
and are accepted in routine clinical practice.9 The first diag- tis, obstructive pulmonary disease and inflammatory bowel
nostic examination is frequently a simple, noninvasive and disease. According to commonly accepted units of measure-
inexpensive fecal occult blood test (Figure 1). However, fecal ment values of up to 5 ng/mL are considered normal antigen
blood is a nonspecific indicator of colorectal cancer, as it can level in blood. It has been observed that these values in
not only come from cancerous lesions but also from polyps. smokers, in cases of ulcer colitis or liver cirrhosis, can be
Distal endoscopy, which is the gold standard in diagnosing increased up to 10 ng/mL11. Tan et al conducted a quantitative
CRC, allows the diagnosis of changes in real time and meta-analysis of 20 studies involving 4285 patients and inves-
enables physicians to perform a target biopsy and histopatho- tigated CEA performance characteristics when used to detect
logical analysis. Endoscopic ultrasound, computed tomogra- recurrence of colorectal cancer. Overall sensitivity was found
phy and magnetic resonance imaging (MRI) with full clinical to be 0.64 and specificity 0.90.12 The study by Chen et al in

DIAGNOSTICS
of
COLORECTAL CANCER

CIRCULATING HEMATOPOIETIC
TUMOR CELLS GROWTH FACTORS

ENZYMES TUMOR ANTIGENS

Figure 1 Division of colorectal cancer markers.

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Dovepress Jelski and Mroczko

Taiwan examined whether rising CEA was an added value in antigen occurs in about 60–80% of patients with colorectal
detecting postoperative relapses. In a study of 4841 patients, cancer.19 The survival rate was significantly lower in patients
999 had elevated CEA (defined at >5 ng/mL) and a relapse. with initially higher concentrations of TPS. Repeated deter-
About three-quarters of these patients had recurrence detected mination of TPS concentration during therapy may be of
by other means at the same time as the first increase in CEA.13 clinical importance, especially as a marker of non-response.
Patients treated for colorectal cancer should have CEA levels Therefore, TPS is superior to the commonly used CEA.18 In
monitored every 3 months. Unfortunately, an increase of CEA asymptomatic patients that require active treatment due to
concentration is only sometimes observed during the first a generally poor prognosis, changes in elevated TPS levels
stage of CRC. This mostly happens in the advanced stages appear to be useful in determining the length of treatment.20
of cancer. An increased concentration of CEA prior to opera- Tumor-associated glycoprotein-72 (TAG-72) is
tion may correlate with an adverse prognosis. a glycoprotein formed in bile duct endothelial cells, gastric
CA 19.9 (carbohydrate antigen) is a glycoprotein char- epithelium or renal pelvis cells. It is a mucin-like molecule
acterized by a high molecular weight which may be with a molar mass of over 1000 kDa. TAG-72 is found on
released to the blood. This marker is used in the diagnos- the surface of many cancer cells, including colon, ovary,
tics of pancreatic, colorectal and gastric cancers. Like breast, and pancreatic cells.7 Guadagni et al showed that
CEA, it is not specific to a particular histological type of serum concentrations of TAG-72, CEA, CA 19.9 were
carcinoma and the organ which it comes from. Vukobrat- elevated in 43%, 43% and 27% of patients with colorectal
Bijedic et al showed that CA 19.9 is less sensitive than cancer, respectively. It is advisable to determine TAG-72
CEA.14 The combined assays of CEA and CA 19.9 may together with other markers, primarily CEA. Sixty-one
increase diagnostic sensitivity in colorectal cancer detec- percent of patients had at least one marker with elevated
tion. Moreover, the determination of both of these markers levels when measuring these three markers.21
is used as a postoperative prognostic factor in the evalua- Analysis of ctDNA in peripheral blood samples, so-called
tion of the stage of the disease and survival rate.15 liquid biopsies, has the potential to discern early-stage detec-
Nakatani et al in their research from 2012 provided data tion of CRC and serve as a prognostic, monitoring and
that colon cancer located in the region of sigma had predictive tool. A number of studies describe the use of
extremely high concentrations of CEA and CA19.9.16 ctDNA methylation markers for the diagnosis and prognosis
There is no significant increase in sensitivity by combining of colorectal cancer. So far, the highest accuracy for CRC
CEA and CA 19.9 determinations. Both CA 19.9 concen- detection has been obtained by SEPT9 hypermethylation
tration and sensitivity increase with higher Dukes’ stage of analysis, especially in combined panels. The high sensitiv-
disease, but do not correlate with the tumor location and ities of up to 100% and specificities of up to 97% of SEPT9
number of positive lymph nodes. Patients with Dukes’ methylation ctDNA analysis suggest a diagnostic role for this
C tumors with preoperative CA 19.9 concentrations higher candidate marker.22 In addition, Lou et al have shown that
than 37 U/mL had a shorter disease-free survival period.17 a single ctDNA methylation marker, cg10673833, could
Tissue polypeptide specific antigen (TPS) has been yield high sensitivity (89.7%) and specificity (86.8%) for
described as a useful tumor marker in many malignant can- the detection of CRC and precancerous lesions in a high-
cers and as a response factor in monitoring chemotherapy in risk population in a prospective cohort study.23 Several stu-
different advanced gastrointestinal carcinomas.18 It is dies found that abnormal methylation of septin9 (mSEPT9)
a singular conjugated chain of polypeptide, which is pro- in the blood can be used as an early diagnostic marker for
duced in different phases of the molecular cycle (S or G2) colorectal cancer. Using the latest second-generation
and subsequently released to tissue after mitotic division. mSEPT9 assay, Zhi Yao Ma et al found a significantly higher
Tissue-polypeptide-specific antigen (TPS) is a soluble frag- sensitivity of mSEPT9 than CEA for the diagnosis of CRC
ment derived from the carboxy-terminal end of cytokeratin (73.2% vs 48.2%; P < 0.001), especially for patients with
18. High TPS concentration is a marker of tumor activity, but stage II and III cancer.24 Toth et al reported similar results,
not necessarily mass of tumor. The level of TPS in blood, with respective sensitivities of 95.6% (88/92) and 51.8% (14/
strongly associated with proliferation of cancer cells, is 27), and specificities of 84.8% and 85.2% for mSEPT9 and
a function of the cell division rate. Estimation of tissue CEA20.25 In another recent study, mSEPT9 was also shown
polypeptide specific antigen may be applicable in the early to have a higher diagnostic value than CEA for both sensi-
stages of cancers. A high level of tissue polypeptide specific tivity (61.8% vs 35.0%) and specificity (89.6% vs 62.6%).26

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Insulin-like growth-factor binding protein 2 (IGFBP-2) Proliferation

Metastasis
is an extracellular protein that binds insulin-like growth
Protection from
factor 2 (IGF-2) and, with a smaller affinity, insulin-like
the host response
growth factor 1 (IGF-1). IGFBP-2 plays an important role Hematopoietic Angiogenesis
growth factors and
in heat shock protein 27-mediated cancer progression and their receptors

metastasis. IGFBP-2 serum levels were reported to be

Migration
significantly elevated in patients with colon cancer in
three studies.27,28
Adherence of tumor cells
Recently, several inflammatory markers including pre- to endothelium
treatment neutrophil to lymphocyte ratio (NLR) have been
Communication between cancer
used as prognostic factors, since host inflammatory response
cells and non-neoplastic cells
to cancer is believed to determine disease progression.29
Dimitriou et al have found that in patients with CRC, Figure 2 The role of hematopoietic growth factors and their receptors in tumor
a pretreatment NLR above 4.7 is a poor prognostic factor development.

for disease-free survival, 5-year survival and overall survival.

The poor prognostic effect of NRL is magnified in stage II induce normal cells, such as tumor-associated macrophages
CRC patients.30 (TAM) and endothelial cells, to produce additional cytokines
The concentration of IGFBP-2 appears to be that support the malignant process. Several cell lines of
a prognostic factor that strongly correlates with overall a malignant tumor have been demonstrated to secrete large
survival.27 Heat shock protein 60 (HSP60) is a key factor amounts of CSFs. Mroczko et al found that blood concentra-
involved in inflammation, and serum HSP60 levels might tion of M-CSF and granulocyte-colony stimulating factor
also be increased in patients with inflammatory patholo- (G-CSF) were significantly higher in colorectal cancer patients
gies such as ulcerative colitis and Crohn’s disease.31 Vocka in comparison to controls.33 The level of both markers was
et al indicated that serum HSP60 could be used as an dependent on the stage of the tumor, but only M-CSF showed
effective prognostic biomarker of CRC with the same significant differences. In addition, it was found that M-CSF
sensitivity as CEA and better sensitivity than CA19-9.27 serum levels were higher in patients with lymph node or
distant metastases. The diagnostic specificity and sensitivity
Hematopoietic Growth Factors of M-CSF were 95% and 65%, respectively. All diagnostic
Colorectal cancer cells are capable of producing hematopoietic criteria such as sensitivity, specificity and area under ROC
growth factors (HGFs). Stem cell factor (SCF), macrophage- curve were lower for G-CSF than for M-CSF. Therefore,
colony stimulating factor (M-CSF) and granulocyte- M-CSF seems to be a better marker than G-CSF in the
macrophage-colony stimulating factor (GM-CSF) are diagnosis and prognosis of colorectal cancer. Other studies
members of glycoprotein cytokines called colony-stimulating showed elevated levels of several proinflammatory cytokines,
factors (CSFs) or HGFs. Hematopoietic growth factors are such as interleukin-6 (IL 6), interleukin-8 (IL 8), tumor necro-
involved in the regulation of growth and spread of cancer. sis factor-α (TNF-α) and acute-phase proteins in patients with
HGFs regulate the proliferation of hematopoietic progenitor colorectal carcinoma and other malignancies.34,35 Mroczko
cells and can also affect the proliferation of nonhematopoietic et al showed a potential role for stem cell factor and inter-
cells (Figure 2). Cell surface receptors for HGF have been leukin-3 (IL 3) as tumor markers for colorectal cancer, espe-
detected in colon cancer cell lines and the stimulation of tumor cially in combination with CEA and CA19-9.36
cells proliferations occurs via these receptors. Several studies
have shown that HGFs can also stimulate the proliferation of Enzymes
nonhematopoietic cells and the effect of these cytokines is not Newly conducted research by Jelski et al on the use of
limited to bone marrow cells.32 HGFs can act on cancer tissue enzymes as markers for colorectal cancer, including alcohol
in an autocrine manner or on supporting tissues and blood dehydrogenase (ADH), cathepsin D and lysosomal exogly-
vessels to produce an environment conducive to the develop- cosidases reported that the activity of alcohol dehydrogenase
ment of cancer. Receptors of HGFs have been detected in is significantly higher in cancerous cells than that in healthy
colorectal cancer cell lines and stimulation of CSFs receptors tissue and the activity of aldehyde dehydrogenase (ALDH) is
induced the proliferation of tumor cells. HGFs may also not different between healthy and cancer tissues. ADH

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Dovepress Jelski and Mroczko

activity seems to be disproportionally higher compared to the Circulating Tumor Cells (CTCs)
activity of ALDH in cancer tissue. This would suggest that In the case of cancer (including colorectal cancer), death is
cancer cells have a greater capability for ethanol oxidation rarely caused by the primary tumor itself but is due to
and considerably less ability to remove acetaldehyde than determination, ie the distant metastases, that may develop
healthy tissues. Acetaldehyde concentration may increase in years after the primary tumor resection. Circulating tumor
cancer tissue and intensify the carcinogenesis. Moreover, the cells (CTC) have been reported in patients with metastatic
same studies showed that only the activity of ADH I (the CRC as an independent predictor of overall and progres-
most important colon isoenzymes of alcohol dehydrogenase) sion-free survival. There are at least three advantages to
is markedly higher in colorectal cancer than in healthy colon CTCs. The first is the monitoring of the treatment efficacy
cells.37 The high activity of enzymes in cancer tissues is of CRC patients. The second is the molecular characteriza-
reflected in an increase in their level in the blood. The tion of captured CTCs for targeted treatment, and the third
serum total ADH activity has been changed in the course of is the cultivation of captured CTCs for drug sensitivity
CRC. The increase of total activity of alcohol dehydrogenase testing. All of these approaches allow researchers to recog-
was positively correlated with isoenzyme class I of ADH, so nize and respond to changes of the phenotype of cancer cells
the cause of the increase of serum total alcohol dehydrogen- during disease progression and introduce personalized med-
ase in the course of colorectal cancer is an elevation of class icine into clinical practice. Despite promising results, deci-
I ADH isoenzymes.38 Moreover, the total serum activity of sions regarding disease stage and adjuvant treatment still do
ADH and ADH I tended to be higher in colorectal cancer not include CTC results. This is largely due to the lack of
patients with more advanced stages. The diagnostic sensitiv- standardized and automated CTC detection systems, such
ity for ADH I was 76%, specificity 82%, positive and nega- as CellSearch, which currently holds a dominant position in
tive predictive values were 85% and 74%, respectively. Area the field of CTC detection devices.48 The role of CTCs as
under Receiver Operating Characteristic (ROC) curve for prognostic markers for primary colorectal cancer has been
ADH I was 0.72. These results suggest a potential role for described in many studies.49,50 Detection of CTC in the
ADH (especially ADH I) as markers for colorectal cancer, serum of patients after resection of colorectal, liver or
but further investigation and confirmation through many other metastases is associated with the prognosis of
a prospective study is necessary.39 Estimation of alcohol the disease. In 2008, the CellSearchTM system (Veridex
dehydrogenase activity may be conducted in the majority of LCC, Raritan, NJ, USA) was cleared by the US Food and
laboratories. Drug Administration (FDA) as a diagnostic tool for identi-
Development of colorectal cancer and its metastases fying and counting CTCs in blood samples in patients with
can be supported by exoglycosidases released by metastatic colon cancer. Compared with other techniques
macrophages.40,41 Szajda et al showed a marked increase such as reverse transcription-polymerase chain reaction
of N-acetyl-β-D-hexosaminidase, its isoenzymes A and (RT-PCR), the CellSearchTM system is an excellent plat-
B activity in the blood and urine of CRC patients.42 form for the detection of CTC in a clinical setting. The FDA
Waszkiewicz et al reported that the high level of cathe- approved CEllSearchTM system and two panels of antibo-
psin D is due to increased breakdown and nest restoration dies against cytokeratins: cytokeratin 8, 18, and 19 (CK8/
of glycoconjugates in colorectal adenocarcinoma.31 The 18/19) and CK8/18/19/20, were used for the detection of
lysosomal exoglycosidases are unspecific. Their activity CTCs. Cytokeratin 20 (CK20) is a well-established marker
is also high in other cancers, such as thyroid, renal, for colon epithelium. Welinder et al suggest that CK20 is
pancreatic, ovarian, as well as such diseases as idiopathic a biomarker for CTCs in patients with metastatic colorectal
arthritis hypertension, glomerulonephritis or following cancer.51 The importance of the CTC topic becomes evident
liver transplantation.43–46 in the context of the rapid integration of the evaluation of
Ornithine decarboxylase (ODC) activity is higher in K-ras mutations in the daily practice of oncologists.
colorectal cancer and increases gradually from normal, Assessment of the presence of K-ras mutations in cancer
through adenomatous, to cancerous. It has been shown cells in patients treated with epidermal growth-factor recep-
that ODC activity in microscopically normal colon tissue tor (EGFR) tyrosine kinase inhibitors (TKIs) was conducted
from patients with CRC is higher than in the normal colon by Pao et al.52 This study suggested an association between
of patients without CRC.47 K-ras mutations and an absence of response to EGFR-TKIs

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treatment. In addition to determining the status of CTC Numerous studies on colorectal cancer use animal
K-ras, assessing other genes in captured CTC may improve models.57–59 Of all animals, the mouse is the most used
predictive response to treatment. Gazzaniga et al deter- animal model in the study of carcinogenesis, and the main
mined the expression profile of multidrug resistance- model in biomedical research. By comparing the human
related proteins (MRPs) of patients with a diagnosis of genome with an animal genome, it is possible to under-
CRC in CTCs isolated from peripheral blood.53 stand the structure and function of human genes better and
apply that knowledge to studying human diseases in order
to develop new strategies and mechanisms to prevent,
K-RAS Mutations
detect, and treat CRC. The availability of recombinant
Evaluation of mutations in KRAS is an example of the
inbred mouse panels and the existence of transgenic,
application of the molecular test needed to introduce tar-
knock-out and knock-in genetic models further increase
geted therapy in a specific group of patients, in this case,
the value of animal studies. The current management of
colorectal cancer patients. Nowadays, this research is
mCRC involves various active drugs, either in combina-
necessary in order to make a decision about the treatment
tion or as single agents, but the effects of available treat-
of these patient groups. The KRAS gene codes a small
ment strategies for mCRC are often temporary, with
protein that is involved in the activation of the cascade of
resistance and disease progression developing in most
signal paths, including receptor signaling pathway for epi-
patients.60 Thus, new treatment strategies are urgently
dermal function growth factor (epidermal growth-factor
needed. Targeted therapies, based on the use of monoclo-
receptor – EGFR), which is considered fundamental in the
nal antibodies directed against the epidermal growth-factor
regulation of life, growth and cancer transformation epithe-
receptor (EGFR) and vascular endothelial growth factor
lial cells.54 The RAS protein functions as a signal transdu-
(VEGF), have been shown as promising treatments. On the
cer from activated EGFR. EGFR activation (by linking to its
basis of the presence of specific receptors for hypothala-
ligand) leads to the activation of RAS RAF/MAPK and
mic peptides on various human cancers including CRC,
PI3K/AKT, and the increased proliferation and inhibition
Engel et al developed targeted cytotoxic analogs of soma-
of cancer cell apoptosis. As a result of the mutation in RAS,
tostatin (SST) and LHRH linked to doxorubicin or
a protein encoded by the mutated gene is formed, which due
2-pyrrolinodoxorubicin.61
to difficult hydrolysis still remains in an active form (RAS-
The actual understanding of the basic biology of cancer
GTP). In the cells with a mutation in KRAS, there is
initiation and development confirmed that suppressor gene
a constant signal transduction that induces mitogenesis,
mutations and oncogenes can be identified in body fluids
regardless of whether the EGF receptor is activated.
that drain from the organs affected by the tumor. The
Analysis of mutations in KRAS allows stratification of
analysis of single markers in the recognition and prognosis
patients with metastatic colorectal cancer for therapy with
of the disease is applicable, but often associated with low
anti-EGFR mAb and mutations in KRAS are a negative
sensitivity and specificity in routine medical practice
predictor of this therapy.55 Mutations in KRAS in colorectal
(Table 1). The overall findings of multiple authors, as
cancer most often occur in codons 12, 13 of exon 2 (in
presented above, suggest the usefulness of serum HGFs,
nearly 40% of colorectal cancers), less often activating
enzymes and especially classical tumor markers in the
KRAS mutations in codons 59, 61, 117 and 146. The asso-
diagnosis and prognosis of CRC patients.
ciation of colorectal cancer location and metastasis site with
The best way seems to be to determine at least two or
the presence of mutations in KRAS was found. Patients
more markers simultaneously to increase their diagnostic
with mutations in codons 12 and 13 were more likely to
utility. Circulating tumor cells analysis could be a part of
have colorectal cancer located on the right side of the colon
an integrative medical approach of the multimodal diag-
compared to patients without the KRAS mutation.56
nostics, individual patient profiles, disease-specific bio-
marker patterns, and person-specific treatment. Recently,
Summary – CRC Diagnostics in the technological and analytic advances have boosted scienti-
Future fic biomarker research. In the near future, we expect the
The use of tumor markers in screening examinations and advent of novel urinary assays with high efficacy that
intervention in the first stages of colorectal cancer can would reduce CRC mortality. In colorectal cancer, mole-
significantly reduce mortality from colorectal cancer. cular (eg mutations in the KRAS, NRAS, BRAF, PIK3CA

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Table 1 Diagnostic Criteria for Markers of Colorectal Cancer

Group/Markers Diagnostic Sensitivity (%) Diagnostic Specificity (%) Area under ROC Curve

Tumor antigens
Carcinoembryonic antigen CEA10,22 64 90 0.7940
Carbohydrate antigen CA 19–915 34 55 0.6520
Tissue polypeptide specific antigen TPS16 95 83 0.8020
Tumor-associated glycoprotein-72 TAG-7219 40 77 No data

Hematopoietic growth factors (HGFs)

Stem cell factor (SCF)24 89 17 0.7232
Granulocyte-colony stimulating factor (G-CSF)21 31 95 0.6900
Macrophage-colony stimulating factor (M-CSF)21 65 95 0.8300
Interleukin622 72 96 0.8960
Interleukin324 55 80 0.6840

Enzymes
Alcohol dehydrogenase (ADH)27 60 70 0.6538
Isoenzyme class I of ADH27 76 82 0.7231
N-acetyl-β-D-hexosaminidase (HEX) in serum28 90 95 0.9326
N-acetyl-β-D-hexosaminidase (HEX) in urine28 86 81 0.8739
CathepsinD31 91 93 0.9137
Ornithine decarboxylase (ODC)35 82 85 No data

Circulating tumor cells

Cytokeratin 20 (CK20)39 No data No data 56 No data
Multidrug resistance-related proteins (MRPs)41 No data No data No data

genes) and immunohistochemical markers (eg TS, P21,

PTEN proteins) are used to assess predictive goals. References
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Wojciech Jelski has received consultation honoraria from
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Wiener Lab and Abbott. Barbara Mroczko has received techniques in the diagnosis, prognosis and management of patients
consultation honoraria from Wiener Lab, Roche, Cormay, with colorectal cancer: a practical approach. Human Pathol. 2012;8
(8):1157–1168. doi:10.1016/j.humpath.2012.03.003
Abbott and Biameditek. The authors report no other con- 9. Świderska M, Choromańska B, Dąbrowska E, et al. The diagnostics of
flicts of interest in this work. colorectal cancer. Contemp Oncol. 2014;18:1–6.

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