Biological markers might be either present or absent; or might be increased or decreased; or might be present in a changed form.
With the increasing importance and awareness of healthcare, the quality of care and patient safety have gained global concern. In this context, the need for biomarkers cannot be denied at all.
What are biomarkers?
The term “biomarker” is a merged/blended word of “biological marker”. Biomarkers indicate the underlying biological processes/events, either normal or abnormal taking place in one’s body. Biological markers might be either present or absent; or might be increased or decreased; or might be present in a changed form. They serve as indicators of an underlying disease process, determining the risk factors associated with a disease process. They provide crucial clues about one’s current health or to future health status.
Biomarkers can be found in blood, urine, stool, tumor tissue or body fluids. They are produced by the normal cells in response to a disease process or cancer or by the cancer cells itself. Biomarkers are available for various diseases: heart diseases, neurological diseases, renal diseases, infective disorders, genetic disorders, cancers etc.
What are the characteristics of an ideal biomarker?
An ideal biomarker should have the following characteristics:
- It should be sensitive.
- It should correlate with the severity of disease/damage.
- It should express itself early in the disease progression.
- It should be measurable in blood/urine.
- It should be stable in a tissue so that it can be measured even after sometime has passed.
- It should be visible prior to the histopathological changes.
- It should give reproducible results.
- It should be portable, reliable, and immediate.
- It should be precise, sensitive and specific.
What are the types of biomarkers?
A. Molecular, histologic, radiographic or physiologic biomarkers.
B. Molecular biomarkers can be:
- DNA (genes)
C. The other type of classification is:
1. Diagnostic biomarkers: Detects/ confirms the presence /absence of a disease condition. Also helps in identifying the disease subtype and helps in differentiating between different diseases. Example: High sensitivity Troponin assay helps in diagnosing myocardial necrosis.
2. Predictive/ prognostic biomarker: Helps to indicate how a disease may develop in an individual when a disorder is already diagnosed. Also helps to determine which patients might be benefitted from a specific treatment plan. To identify the likelihood of a clinical event, disease recurrence, or disease progression in patients with a disease.
3. Monitoring biomarker: This type of biomarker can be measured serially in order to assess the status of a disease. Example: Measurement of HbA1C, LDL cholesterol levels, INR (to adjust the dose of anticoagulants) etc.
4. Susceptibility biomarker: It indicates the risk for developing a disease in an individual who is currently not having any disease.
5. Safety biomarker: It is measured before/ after an exposure to a medical intervention to indicate the likelihood, presence or extent of toxicity as an adverse event.
6. Treatment- response biomarker: Helpful to differentiate patients on the basis of their outcomes related to efficacy and side effects (responders/non-responders and patients with/without adverse drug reactions).
Macromolecules such as nucleic acids, genetic alterations, and protein molecules as well as intact cells are utilized as diagnostic biomarkers in breast cancer.
Emerging biomarkers in various fields of Pathology:
- Myeloid neoplasms biomarkers:
- Immunohistochemistry (IHC) plays an indispensable role in analyzing biomarkers that play an important role in treatment of patients with myeloid neoplasms.
- Cluster of differentiation markers or CD markers are the most commonly used leukemia biomarkers. CD marker specific antibodies are used for cell sorting, identification and leukemia diagnosis.
- Genetic abnormalities have been correlated with Chronic myeloid leukemia (CML) in the blast phase. The genes involved are as follows:
- In regulation of cell apoptosis and proliferation: Epidermal growth factor receptor (EGFR), tumor protein p53 (TP53)
- In cell adhesion: Catenin beta 1 (CTNNB1),
- Genes associated with TGF Beta: Transforming growth factor beta 1 and 2 (TGFB1, TGFB2)
- TNF-alpha pathways: Tumor necrosis factor-alpha (TNFA), Nuclear factor kappa B subunit 1 (NFKB1)
- MicroRNAs are also involved in CML: miRNA -451 nad miRNA -21
- Breast cancer biomarkers:
As we all are aware, the three most important markers for breast cancer are:
- Estrogen receptor (ER)
- Progesterone receptor (PR)
- HER 2 neu
Some of the single blood-based biomarkers in detecting breast cancer are: Human epidermal growth factor receptor 2 (HER2), Cancer Antigen 15-3 (CA 15-3), Carcinoembryonic Antigen (CEA), MUC1.
Macromolecules such as nucleic acids, genetic alterations, and protein molecules as well as intact cells are utilized as diagnostic biomarkers in breast cancer. Recently it is found that aberrant DNA methylation is linked to breast cancer. MAST1, PRDM14, ZNF177 irregular DNA methylation variants were found and verified as prospective breast cancer molecular indicators. Circulating proteins are used as screening biomarkers such as Trefoil factor TFF1, 2, 3. Micro RNA such as miR-145, 221 and 21 are found in the blood of breast cancer individuals.
- Colorectal cancers (CRC) biomarkers:
- Tumor based biomarkers: Microsatellite instability (MSI) analysis, BRAF and KRAF mutation analysis. Micro RNAs also contribute to oncogenesis in CRC.
- Stool biomarkers: Fecal blood tests (gFOBT) is based on the detection of pseudoperoxidase activity of heme in stool samples due to bleeding in adenomatous / neoplastic lesions. Stool immunohistochemical test (FIT) and detection of Vimentin methylation.
- DNA based tests: Mutations in key genes TP53 and APC
- RNA based tests: Detection of tumor mRNA transcripts such as PTGS2 and MMP7.
- Blood based biomarkers: CEA
- Endometrial cancer biomarker: K-RAS, HER2/neu, EGFR, PI3KCA, FGFR2, PTEN, p53.
- Neurodegenerative disease biomarkers: Amyloid beta, Total tau protein, Phosphorylated Tau Protein.
- Biomarkers in diabetes: HbA1C, fasting plasma glucose (FGP), Oral glucose tolerance test (OGTT). Adiponectin, C-reactive protein (CRP), ferritin and interleukin-2 receptor A.
The use of biomarkers is not only limited to cancer but has a widespread use in all the major fields of medicine and research. “The biomarkers are undoubtedly a boon to clinical practice.”
“Composed by: Dr. Shubha.H.V is a Consultant Pathologist/Lab Head, SRL Diagnostics, Fortis Hospital, Rajajinagar, Bangalore. “