2. CONTENT
S
I. DEFINATION
II. HISTORY OF BIOMARKERS
III. DISCOVERY OF BIOMARKERS
IV. PROPERTIES OF AN IDEA BIOMARKER
V. CLASSIFICATION
VI. COMMON BIOMARKERS FOR CANCER
VII. APPLICATIONS
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3. DEFINATION
• Biomarkers (short for biological markers) are biological measures of a
biological state. By definition, a biomarker is "a characteristic that is objectively
measured and evaluated as an indicator of normal biological processes,
pathogenic processes or pharmacological responses to a therapeutic
intervention.“
• Biomarker is any indicator that is used as an index of the intensity of a disease
or other physiological state in the organism.
• A substance that when introduced into the organism serves for the estimation
of organ function or some other form of health assessment.
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7. HISTORY OF BIOMARKERS
• The practice of uroscopy — examining a patient’s urine for signs of disease —
dates back to the 14th century when doctors would regularly examine the colour
and sediment of their patient’s urine
• In 1960, researchers discovered that some patients with chronic myelogenous
leukaemia (CML) have a specific genetic change associated with their cancer. ( i.e.
shortened version of chromosome 22)
• This abnormality, known as the Philadelphia chromosome is caused by a
translocation between chromosomes 9 and 22. The consequence of this
translocation is the creation of the BCR-ABL ‘oncogene’.
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8. • The word biomarker is a little over 30 years old, having first been used by
Karpetsky Humphrey and Levy in the April 1977 edition of the Journal of the
National Cancer Institute.
• Reported that the serum RNase level was not a biomarker either for the presence or
extent of the plasma cell tumor.
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9. Discovery of biomarker and validation
• Because of diseased tissue/tumour heterogeneity and other biases.
• it is important that the identification of biomarkers should proceed in a systematic
manner.
• In 2002, The National Cancer Institute’s ‘Early Detection Research Network’
developed a five-phase approach to systematic discovery and evaluation of
biomarkers .
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10. PHASE I
• Refers to preclinical exploratory studies.
• Biomarkers are discovered through knowledge based gene selection, gene
expression profiling or protein profiling to distinguish cancer and normal samples.
• In labs nuclear cells, blood, urine, saliva, tissues are analyzed in which the target
biomarkers are identified(genes, proteins, enzymes and other substances)
• Obtained values are compared in healthy and diseased subjects in order to
establish the extent of correlation .
• After this the very method is perfected, i.e. its reliability and sensitivity.
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11. PHASE II
• An assay is established with a clear intended clinical To document clinical
usefulness.
• Firstly, such assays need to be validated for reproducibility and shown to be
portable among different laboratories use.
• Secondly, evaluated for their clinical performance in terms of ‘sensitivity’ and
‘specificity
i.e. its ability to identify diseases compared to the gold standard, and the
reference values are determined along with intra individual variations
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12. PHASE III
• Implies retrospective epidemiological studies on screening and the predictive value
of the biomarkers
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13. PHASE IV
• includes prospective clinical studies
• investigate the correlation between biomarker levels and the onset of clinical
indicators of the disease course.
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14. PHASE V
Evaluates the overall benefits
Risks of the new diagnostic test on the screened population.
Phases IV and V are necessary to evaluate benefits and risks of the use of a biomarker in
screening and detection.
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15. PROPERTIES OF AN
IDEAL BIOMARKER
IDEAL MARKER FOR DIAGNOSIS:
Should have great sensitivity.
Specificity.
Accuracy in reflecting total disease
burden.
A tumor marker should also be
prognostic of outcome and treatment.
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16. IDEAL BIOMARKER
FOR SCREENING
1. The marker must be highly specific, minimize false
positive and negative
2. The marker must be able to clearly reflect the
different stages of the disease (early)
3.The marker must be easily detected without
complicated medical procedures. The disease
markers released to serum and urine are good
targets for application of early screening
4.The method for screening should be cost effective.
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17. CLASSIFICATION OF
BIOMARKERS
• They can be classified as
• Genomic biomarkers: based on the analysis of DNA (deoxyribonucleic acid) profiles,
especially the analysis of SNPs (single nucleotide polymorphisms), i.e. identification
of punctual variations in genomic DNA.
• Transcriptomic biomarkers: based on the analysis of RNA expression profiles.
• Proteomic or Protein biomarkers: based on the analysis of the protein profiles.
• Metabolomic biomarkers: based on the analysis of metabolites (metabolites are the
inter-mediates and products of metabolism).
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18. GENOMIC OR DNA BIOMARKERS
• A measurable DNA characteristic that is an indicator of normal biologic
processes, pathogenic processes, and/or response to therapeutic or
other interventions.
• somatic mutations form in the DNA of individual cells during a person's
life. Because these somatic mutations are only present in tumor cell
DNA, they provide an extremely specific biomarker that can be detected
and tracked.
• Mutations in oncogenes, tumour-suppressor genes, and mismatch-repair
genes can serve as DNA biomarkers.
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19. TRANSCRIPTOMIC BIOMARKERS
• The transcriptome is the set of all RNA molecules,
including mRNA, rRNA, tRNA, and other non-coding RNA produced in
one or a population of cells. It differs from the exome in that it includes
only those RNA molecules found in a specified cell population, and
usually includes the amount or concentration of each RNA molecule in
addition to the molecular identities.
• RNA-based biomarkers undergoing clinical evaluation consist of multi-
gene molecular patterns or ‘fingerprints’.
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21. PROTEOMIC BIOMARKERS
• Proteomics is the large-scale study of proteins, particularly
their structures and functions.
• Proteomics technologies are emerging as a useful tool in the discovery of
cancer biomarkers.
• These advances overcome in part the complexity and heterogeneity of the
human proteome, permitting the quantitative analysis and identification of
protein changes associated with tumor development. With the advent of new
and improved proteomic technologies, it is possible to discover new
biomarkers for the early detection and treatment of cancer.
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22. Ongoing & anticipated implications of
Proteomics biomarkers in medicine
• Proteomic-based approaches for biomarker
investigation can be employed in different
aspects of medicine, such as –
1. elucidation of pathways affected in
disease,
2. identification of individuals who are at a
high risk of developing,
3. identification of individuals who are most
likely to respond to specific therapeutic
interventions, and prediction of which
patients will develop specific side effects
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23. METABOLOMIC BIOMARKERS
• Metabolomics is the "systematic study of the unique chemical
fingerprints that specific cellular processes leave behind", the
study of their small-molecule metabolite profiles.
• Metabolomics, was introduced to refer specifically to the
analysis of metabolic responses to drugs or diseases.
• Metabolomics has become a major area of research; it is
the complex system biological study, used as a method to
identify the biomarker for various disease.
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24. In general, in most disease cases, a metabolic pathway had or has
been either activated or deactivated - this parameter can thus be
used as a marker for some diseases.
For eg., Serotonin production pathways, activated in a person who
has recently consumed alcohol for instance, can be a metabolic
marker of recent alcohol consumption.
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25. DEPENDING ON THEIR APPLICATION THEY ARE
CLASSIFIED AS FOLLOWS
1)Diagnostic biomarkers : e.g. cardiac troponins
2)Biomarkers to determine the stage of disease
:e.g. Brain natriuretic peptide
3)prognostic biomarkers : e.g. tumor markers
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27. 1.Imaging Biomarkers: (CT), (PET), (MRI).
CT, PET, MRI and nuclear imaging are already widely used Medical imaging could
have a great impact on slow progressing diseases, such as lymphoma, non-small
cell lung cancer, Alzheimer’s disease and rheumatoid arthritis.
• Help monitor drug distribution, pharmacokinetics and pharmacodynamics
essential for clinical trials.
Advantages : non-invasive, they produce intuitive, multidimensional results,
Yielding both qualitative and quantitative data
Disadvantages: Exposing to radiation, high cost.
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28. Molecular Biomarkers/non-imaging biomarkers:
• mainly used to monitor treatment, especially in molecular medicine, medical
diagnostics, disease prognosis, risk assessment.
• involves measurements in biological samples (plasma, serum, cerebrospinal
fluid and biopsy) include nucleic acids-based biomarkers such as gene
mutations or polymorphisms and quantitative gene expression molecules .
• levels on which molecular biomarkers can be identified, from formation of
protein to degraded products .
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30. 1.Type 0- Natural history marker: defined as a marker of disease severity
examples of type 0 markers as independent predictors of risk are the CD4' T-cell
count and the HIV 1 plasma RNA level.
2.Type 1- Biological activity marker: defined as one that responds to therapy.
determined in the context of early phase clinical trials. Example Triple-
drug anti retroviral combinations appeared superior to single drugs and double-drug
combinations in vitro
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31. Type 2: Surrogate marker of therapeutic efficacy: (single
or composite of several markers)
defined as one that accounts fully for the efficacy of
an agent
Ideally, type II markers represent "complete" surrogates
of clinical outcome.
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32. THEY CAN ALSO BE CLASSIFIED
AS
• DRUG RELATED BIOMRKERS
• DISEASE RELATED BIOMARKERS
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33. DRUG RELATED…….
• THEY INDICATE WHETHER A DRUG
WILL BE EFFECTIVE IN A SPECIFIC
PATIENT AND HOW A PATIENT BODY
WILL PROCESS IT.
DISEASE RELATED
• THEY GIVE AN INDICATION OF THE
PROBABLE EFFECT OF TREATMENT
ON PATIENT ( RISK INDICATOR OR
PREDICTIVE BIOMARKER)
• IF A DISEASE ALREADY EXISTS
(DIAGNOSTIC BIOMARKERS)s
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34. Types of Biomarkers Based upon application and Use in
Drug Development and Disease Management
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35. COMMON BIOMARKER FOR
CANCER
• CEA (>10 ng/ml)
• Carcinoembryonic antigen (CEA) is produced during fetal development. After birth, the
production of CEA stops and is undetectable. CEA has also been found elevated in
nonmalignant tumors such as pleural effusions. Elevation of CEA after conventional
treatment of neoplasms has been correlated with a recurrence of cancer
• AFP (>100 ng/ml)
• Alpha fetoprotein (AFP) is typically found in the developing fetus. Because of the association
of the rapid cell growth, this fetal protein is also used as a tumor marker. non cancerous liver
diseases such as cirrhosis and viral hepatitis can lead to high level AFP
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36. CA19-9 (>37 U/ml)
Carbohydrate Antigen 19-9 (CA 19-9) is present in the fetus in the epithelium of the fetal
stomach. It is primarily used as a marker for pancreatic cancer. High levels also exist in
conditions such as non-malignant liver disease and other disorders of the
gastrointestinal tract.
HCG (>10 mIU/ml )
Human Chorionic Gonadotropin-beta (HCG) is normally produced by the
placenta during pregnancy, an indicator of pregnancy. The protein can be
detected in serum or urine. Non-malignant elevations may be observed in
pregnancy, ulcers, duke’s disease, and cirrhosis. Levels of HCG are useful in
monitoring the effectiveness of treatment.
Ferr (>120 ng/ml )
Ferritin is an iron binding storage found in the liver, spleen, and bone marrow.
Elevated levels observed in non-cancerous conditions include rheumatoid
arthritis and anemia
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37. APPLICATIONS OF BIOMARKERS
• IN DIAGNOSIS
• TREATMENT
• DISEASE PROGRESSION
• SAFETY BIOMARKERS
• Forensic applications.
• Biomarkers for Personalized Prevention Strategies.
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38. DIAGNOSTIC TECHNOLOGIES.
• Screening : Screening discriminates the healthy from the asymptomatic disease
state by screening particular groups.
• Biomarkers are important for screening and early diagnosis.
• E.g. the prognosis of advanced HCC is poor, whereas smaller HCC suitable for
organ transplantation, surgical resection or radio frequency ablation have shown a
better prognosis and longer survival.
• For this reason, a surveillance program using alpha fetoprotein (AFP) and
ultrasound (US) every six months has been recommended, and is widely practiced.
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39. DISEASE PROGRESSION
• HIV INFECTION IS ASSOCIATED WITH INCREASED RISK OF
CARDIOVASCULAR COMPLICATIONS.
• PLASMA LEVELS OF COAGULATION BIOMARKER D-DIMER (DD) HAVE BEEN
CORELATED WITH INCREASED MORTALITY AND CARDIOVASCULAR EVENTS
IN HIV PATIENTS.
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40. SAFETY BIOMARKERS
• THE ISOENZYME OF LACTATE DEHYDROGENASE AND CREATININE KINASE
IN COMBINATIOM WITH MORE MORE SPECIFIC MARKERS OF CARDIAC
INJURY SUCH AS CARDIAC TROPONINS CAN PROVIDE INFORMATION ON
THE RELATIVE SEVEREITY, EXTENT OR DURATION OF MYOCARDIAL INJURY.
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41. APPLICATIONS
• BIOMARKERS CAN REFLECT ENTIRE SPECTRUM OF DISEASE FROM THE
EARLIEST MANIFESTATIONS TO THE TERMINAL STAGES.
• THEY HAVE THE POTENTIAL ABILITY TO IDENTIFY NEUROLOGICAL DISEASE
AT AN EARLY STAGE TO PROVIDE A METHOD FOR HOMOGENOUS
CLASSIFICATION OF DISEASE AND TO EXTEND OUR KNOWLEDE BASE
COVERING THE UNDERLYING DISESE PATHOGENISIS.
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42. • IN EPIDEMIOLOGICAL INVESTIGATIONS , BIOMARKERS INCREASE THE
VALIDITY WHILE REDUCING ERRORS IN THE MEASUREMENT OF EXPOSURE
FOR NEUROLOGICAL DISEASE
• MOLECULAR BIOMARKERS HAVE THE ADDITIONAL POTENTIAL TO IDENTIFY
INDIVIDUALS SUCCEPTIBLE TO DISEASE (MOLECULAR GENETICS)
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43. BIOMARKERS FOR
PERSONALIZED PREVENTION
STRATEGIES
• Medicines that target the genetic signatures of diseases are making inroads into
modern medicine. Health experts see this therapeutic approach as the beginning of
a new era in medicine.
• In the treatment of diseases especially cancer, there is a shift from the traditional
clinical practices to novel approaches.
• Traditionally, cancer patients were treated with drugs of low toxicity or of high
tolerance.
• novel approaches are intended to identify individualized patient benefits of
therapies, minimize the risk of toxicity and reduce the cost of treatment.
• The chemotherapy drug irinotecan (Camptosar) is one example of personalized
medicine,(used to treat advanced colorectal cancer)
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45. REFERENCES
Ziad j.s, Suzan m. Semaan and Qing-a, Methodology and Applications
of Disease Biomarker Identifi cation in Human Serum Florida State
University, Tallahassee.
Manoj .kand shiv .k s, Biomarkers of diseases in medicine, New Delhi,
current trends in sciences, by Indian academy of sciences.
Abdel.bh, Biomarkers in Drug Development: A Useful Tool but
Discrepant Results May Have a Major Impact, USA.
Dr. Austin.t, Application of Biomarkers in Early Phase Clinical Trials,
Almac.
Dr Richard .k, biomarker and personalised medicine, Almac uk .
Ezzatollah.f, Seyed a.m and Raheleh.f Biomarkers in Medicine: An
Overview, British Journal of Medicine & Medical Research, dec 2013.
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