Molecular Tumor Markers as a Tool for
Diagnosis, Prognosis, Prediction and Therapy
Hussein Abd Elhay Kaoud*
Full Professor, Cairo University, Egypt
Submission: August 21, 2017; Published: November 22, 2017
*Corresponding author: Hussein Abd Elhay Kaoud, Full Professor, Cairo University, Giza, Egypt, Email: [email protected]
How to cite this article: Hussein A E K. Molecular Tumor Markers as a Tool for Diagnosis, Prognosis, Prediction and Therapy of Tumors. J Tumor Med
Prev. 2017; 2(3): 555588. DOI: 10.19080/JTMP.2017.02.555588.
Molecular tumor markers can be produced directly by tumor or non tumor cells as a response to the presence of a tumor. Most tumor markers are tumor antigens but not all tumor antigens can be used as tumor markers. Molecular markers are diagnostic, prognostic or predictive. The article discussed the Molecular tumor markers; significance of each markers and its role in diagnosis, prognosis and prediction of tumor and tests used (Figure 1).
Novel molecular markers are being developed with the increasing understanding of the molecular environment of the cancer cell and other pathological cells. Most tumor markers are tumor antigens, but not all tumor antigens can be used as tumor markers. Biomarkers can determine the appropriate dose in the early stages of a new antidepressant medication for cancer clinical development. They also help determine who to treat, how aggressively to treat and which candidates are likely to respond to a particular drug, and the dose is most effective. Theranostic, use a combination of diagnosis and therapy sessions, and can be different perception. Imaging can be used to track drug delivery within the body. However, imaging can also be used to activate the drug release from the outside, by an external stimulus. These external influences to be laser light, temperature or ultrasound, for example.
Cancer is a multigene disease (cluster of diseases) which arises as a result of mutational & this contributes to development of cancer genotype. It involves alteration of three main classes of genes:
2) Tumor suppressor genes
3) DNA repair genes.
Epigenetic changes coupled with activation of complex signaling networks. And these alterations resist the naturaluphenotype & inherent death mechanisms embedded in cells (apoptosis) coupled with deregulation of cell proliferation events. These genetic alterations include gene rearrangements, point mutations and gene amplifications leading to disturbances in molecular pathways regulating cell growth, survival and can also be used for detection. When these changes manifest in majority of patients with specific type of tumor this can be used as tumor markers (Biomarkers). Metastasis and developing
targeted therapies besides predicting responses to treatment.
Molecular markers may be diagnostic, prognostic or predictive.
A tumor biomarker should be indicative of: Tumor
susceptibility of the patient- Severity or virulence of the tumor-
Prognosis of the disease- Tumor burden (Including metastasis).
They include a broad range of biochemical entities such as:
Nucleic acids, Proteins, Sugars, Lipids, Small metabolites,
Cytogenetic and cytokinetic parameters, Whole tumor cells and
Cancer stem cells.
On the basis of their chemical nature tumor markers can
be proteins, conjugated proteins, peptides or carbohydrates.
Proteins or conjugated proteins may be enzymes, hormones or
fragments of proteins and Sequencing of genes. Tumor markers
are usually classified into three categories: prognostic, predictive,
and pharmacodynamic  (Figure 2).
a) Deviations from diploid chromosomes to hypo and hyper
diploidy as well as aneuploidy noted in malignant tumors.
b) Enhanced cell proliferation, most important hall mark
of cancer can be assessed by flow cytometric analysis of DNA
c) Gene deletions can be discovered by PCR using
microsatellite probes to various chromosomes and sites.
d) Oncogenes are derived from proto-oncogenes that may
be activated by dominant mutations, insertions, deletions,
translocations, or inversions. Most oncogenes are associated
with hematologic malignancies, such as leukaemia and to lesser
extent solid tumors.
BRCA ashkenazi Jewish mutations: BRCA1 and BRCA2
are human genes that belong to a class of genes known as
tumor suppressors. Mutation of these genes has been linked to
hereditary breast and ovarian cancer. Genetic tests are available
to check for BRCA1 and BRCA2 mutations a blood sample is
required for these tests.
B-cell gene rearrangement: The B- and T-cell rearrangement
test can detect a monoclonal population of B- and T-cells. Strongly
indicative of neoplasia. This is accomplished through the use of
BCL-2 gene rearrangement: Gene Rearrangement bcl-2;
Major Breakpoint Region (MBR); minor cluster region (mcr); t
(14:18) Translocation. Applies to Follicular B-Cell Lymphomas.
A translocation between immunoglobulin genes (heavy chain or
light chain genes) and bcl-2 results in the over expression of bcl-
2 protein and thus the expansion of B cells due to inhibition of
BCR-ABL gene rearrangement: Translocation bcr/abl; Gene
Rearrangement bcr; Philadelphia Chromosome; t (9:22) Applies
to Acute Myelogenous Leukemia (ALL); Chronic Myelogenous
BRAF gene mutation detection
c-kit mutation detection for systemic mastocytosis
KRAS gene mutation detection
Muir Torre syndrome [MTS]
PMLRAR alpha t (15;17) translocation: Breast cancer two
genomic: assays are currently in use for breast cancer: Oncotype
DX and Mamma Print. Oncotype DX looks at the activity of 21
genes, Mamma Print at 70 genes. A number of genetic alterations
and consequent metabolic changes are involved in metastatic
progression of cancer .
Alpha-fetoprotein: Alpha-fetoprotein (AFP, α-fetoprotein;
also sometimes called alpha-1-fetoprotein, alpha-fetoglobulin, or
alpha fetal protein) is a protein [3,4], that in humans is encoded
by the AFP gene . The AFP gene is located on the q arm of
chromosome 4 (4q25).
AFP is measured in pregnant women through the analysis of
maternal blood or amniotic fluid, as a screening test for a subset
of developmental abnormalities. Some of the diseases in which
AFP will be elevated in a person are listed below:
a) Hepatocellular carcinoma/hepatoma: ↑ α-fetoprotein.
b) Neural tube defects: ↑ α-fetoprotein in amniotic fluid and
Carcinogenic embryonic antigen: Borderline: 25ng\ml-
5ng\ml (testing immunoassay). Elevated} 5ng\ml. Carcinogenic
colon, pancreas, lung, breast and ovary. 75% of the patients with
recurrent colorectal cancers elevate CEA before the development of the symptoms. Gastrointestinal cancer, cervix cancer, lung
cancer, ovarian cancer, breast cancer, urinary tract cancer .
Tumor associated protein
CA15-3 (Cancer Antigen 15-3): Is a tumor marker used to
monitor certain cancers, especially breast cancer
CA 27-29: A tumor marker similar to the CA 15-3 that is
found in the blood of most breast cancer patients may be used
to check for recurrence in women previously treated for stage II
and stage III breast cancer. And can also be elevated by cancers
of the colon, stomach, kidney, lung, ovary, pancreas, uterus, and
CA19-9 (carbohydrate antigen 19-9, also called cancer
antigen 19-9 or sialylated Lewis (a) antigen)
CA-125 (cancer antigen 125, carcinoma antigen 125, or
carbohydrate antigen 125): Also known as mucin 16, has found
application as a tumor marker or biomarker that may be elevated
in the blood of some patients with specific types of cancers, or
other benign conditions.
Early Prostate Cancer Antigen (EPCA): Is a nuclear matrix
protein linked with the nuclear transformations that occur in
early prostate cancer development .
PCA3/DD3: The prostate cancer antigen 3 (PCA3 or DD3)
gene encodes a prostate-specific mRNA that is over expressed in
cancer prostate tissue .
Ki 67 antige: Is a labile, non-histone nuclear protein that
is tightly linked to the cell cycle. Ki-67 score is the most often
measured on histological sections by IHC methodology and is
defined as the percentage of stained invasive carcinoma cells
Tumor protein p53: Is involved in several critical pathways
including cell cycle arrest, apoptosis, DNA repair, and cellular
senescence. In breast cancer, approximately 30% of patients
display TP53 gene mutation, but this frequency fluctuates from
more than 80% in basal-like to less than 15% in luminal-A
Chromogranin A (CGA or GRN-A): Part of the granin family
of proteins, is an acidic protein that has been identified in all
neuroendocrine cell types, it has been examined for its diagnostic
and prognostic values as a biomarker for prostate cancer .
Carcinogenic antigen: Cancer cells may elicit the production
of antibodies against self-antigens or against neo-antigens
[13,14]. Thus, the ‘immunosignature’ is defined as the common
pattern of binding that is shared by patients with a given disease
but not with another disease or with healthy controls .
B7-H3: B7-H3 is the first immune molecule that possibly
participates in the development of prostate cancer and in
predicting the recurrence and progression of cancer
Molecular hormonal receptors (HER-2 oncogene, Ki-
67, and p53 proteins): The hormone receptors are expressed
proteins both in the epithelium and in breast stroma which bind
to circulating hormones, mediating their cellular effects .
HER-2 \neu: (Human Epidermal Growth Factor Receptor
2) is a marker for breast cancer. HER2-positive breast cancer
is a breast cancer that tests positive for a protein called human
epidermal growth factor receptor 2 (HER2), which promotes the
growth of cancer cells.
The HR: The HR best studied in breast cancer is estrogen
receptor (ER) and progesterone receptors (PR). Breast cancers
classified by positive immune-histochemistry (IHC) expression
of ER and PR has different clinical, pathological, and molecular
Calcitonin: Tumor marker for medullary carcinoma thyroid.
It is 32 amino-acids linear polypeptide hormone. Produced by
para-follicular cells of the thyroid. Normal level: male =3-26ng\
L, Female=2-17ng\L. Also elevated with other cancers, such as
lung cancers and leukemias, but not used to detect them.
a-Methylacyl Coenzyme A Racemase (AMACR): It is an, in
prostate cancer [18-20].
TMPRSS2-ERG gene fusion rearrangement: Transmembrane
protease serine 2, play a possible role in prostate
tumor metastasis through the activation of protease-activated
receptor-2 (PAR-2) .
Protein tyrosine phosphatase: Receptor type, C also known
as PTPRC is an enzyme that, in humans, is encoded by the PTPRC
gene.  PTPRC is also known as CD45 antigen (CD stands for
cluster of differentiation), which was originally called leukocyte
common antigen (LCA).
Tumor M2-PK: Can be elevated in many tumor types,
rather than being an organ-specific tumor marker such as PSA.
Increased stool (fecal) levels are being investigated as a method
of screening for colorectal tumors, and EDTA plasma levels are
undergoing testing for possible application in the follow-up of
Telomerase: One of the best markers for human cancer
associated with only malignant tumors. Telomerase enzyme
ensures the maintenance of telomere and thereby protecting
the cell from degradation and death. In cancer the Telomerase
shuttling system is impaired. TRAP (telomeric repeat
amplification protocol) assay is used for the detection of its
activity. GRN163l (drug) and GRNAV1 is a vaccine.
MicroRNAs are naturally occurring, noncoding small RNA
molecules of 21-24 nucleotides that binds partially or completely
to 3′untranslated regions (3′-UTRs) of protein-coding genes,
leading to cleavage or translational repression of targets .
The miRNA can be stably present in whole blood, serum, and
plasma, but the origin of circulating miRNA is still unclear. It has
been proposed that tumor-associated miRNAs can be released
into bloodstream when tumor cells are dying and being lysed or
through active secretion of miRNA loaded exosomes by tumor
Biomarkers for cancer have multiple effects in cancer
intervention. Reliable biomarker can be used for cancer diagnosis
and evaluation of risks and diagnostics, and to monitor the
effectiveness of treatment. More importantly, some, but not all,
biomarkers can be used as targets therapeutic. This is because
some of the biomarkers may be a mere “messengers“that do not
contribute directly to the growth of the tumor and therefore are
not ideal therapeutic targets.
a) Histone deacetylases (HDACs)
b) Mammalian target of rapamycin or FK506-binding
protein 12-rapamycin-associated protein 1.
This receptor is required for migration of breast cancer cells
from the primary site to lung, bones, and lymph nodes, which
represent organs that secrete high levels of chemokine CXCL12.
For this reason, CXCR4 has been found to be a prognostic marker
in breast cancer, among other types of cancer.
Tumor markers can be produced directly by the tumor or
by non-tumor cells as a response to the presence of a tumor.
Most tumor markers are tumor antigens, but not all tumor
antigens can be used as tumor markers. Usually classified into
three categories: prognostic, predictive, and pharmacodynamic.
A better understanding of the mechanisms behind biomarker
elevation in biological fluids may facilitate the discovery of new
tumor markers. Current cancer biomarkers suffer from low
diagnostic sensitivity and specificity and have not yet made a
major impact in reducing cancer burden. New tumor markers
must undergo rigorous validation before they are introduced
into routine clinical care. Theranostics take advantage of these
abundant molecular targets to gain specific access to tumors,
visualizing the site of disease, defining the presence or absence
of a molecular target, and delivering cytotoxic payloads directly
to tumor sites. Study of tumor markers that include current
biomarkers or examination of fluids and tissues that are in close
proximity to the tumor might also assist in identification of novel