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Mutant Gene Products as Cancer Biomarkers

BY: Chandra Kala | Category: Biotech-Research | Submitted: 2012-09-26 22:22:34
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Article Summary: "Biomarkers are hot topic in the area of Cancer research because of its utility in preventive diagnosis, prognosis, and therapy. Many of the cancer deaths can be avoided with early cancer diagnosis. The existing therapies such as surgeries and chemotherapies are more effective in early stages of cancer when compared to final stag.."


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Biomarkers are hot topic in the area of Cancer research because of its utility in preventive diagnosis, prognosis, and therapy. According to the studies in the United States, 25% of deaths are due to cancer. Many of the cancer deaths can be avoided with early cancer diagnosis. The existing therapies such as surgeries and chemotherapies are more effective in early stages of cancer when compared to final stages. Billions of money has been utilized for basic research for finding molecular differences with respect to cancer research for diagnostic kits for detection and progression of disease. Proteins that resulted for the somatic mutations of the genes can be considered as the biomarkers, since they are not only expressed in tumors but are responsible for tumor growth. Variant proteins resulted from somatic mutations can be identified by mass spectrometry. Current practice of detection of biomarkers is associated with proteins present in plasma, the sample which can be easily collected from the patient. Proteins of the gene products that can be considered as biomarkers, when they can be easily identified in blood plasma at some stages, irrespective of the source of cancer tissue. Plasma biomarkers are useful in early detection of cancer and should be present in concentrations which can be detectable in plasma. This throws challenges in making any rapid advance in cancer diagnostics kits.

Genome-wide analysis has shown that solid tumors contain around 20 to 100 mutated genes and proteins. A fraction of these mutations in genes and proteins are called "drivers" which initiates the tumors growth and the remaining fractions are called "passengers" which occurs with driver mutation with no definite role in tumor occurrence. The mutated proteins provide very good opportunities for biomarker development as they are produced only in tumor cells and functionally they are not only expressed but harbors driver gene mutations which are responsible for tumor occurrence and growth.

The identification of proteins encoded by mutated genes is very simple, when new stop codon occurs within the coding sequence making the protein length truncated/ shorter. The altered/ variants proteins can easily be detected with antibodies against particular domain of proteins from cell extract. The detection of mutated proteins with missense type of point mutation is very difficult as there will be one or few amino acid changes in the proteins without change in the domains structure. Also many mutations can barely distinguishable from the normal wild type proteins. Most often, the mutated proteins activity are only quantitatively detectable than qualitative. Raising antibodies to the mutant protein is time consuming and becomes expensive, which might not be possible in routine clinical applications.
FDA has approved number of biomarkers proteins that are available for different type of cancers. These includes, CEA (carcinoembryonic antigen ) for malignant pleural effusion and peritoneal cancer dissemination; Her-2/neu [ERBB2] for stage IV breast cancer; Bladder Tumor Antigen for urothelial cell carcinoma; Thyroglobulin for thyroid cancer metastasis; Alpha-fetoprotein for hepatocellular carcinoma; PSA (prostate-specific antigen) for prostate cancer; CA 125 (carbohydrate antigen 125) for non-small cell lung cancer; CA19.9 (carbohydrate antigen 19.9) for pancreatic cancer; CA 15.3 (carbohydrate antigen 15.3) for breast cancer; leptin, prolactin, osteopontin, and IGF-II [insulin-like growth factor 2 (somatomedin A) ] for ovarian cancer; CD98 (solute carrier family 3 (activators of dibasic and neutral amino acid transport), member 2), fascin, and 14-3-3 eta for lung cancer; Troponin I for myocardial infarction and B-type natriuretic peptide for Congestive heart failure.

Mass Spectrometry (MS) has been the choice to detect precisely somatic mutations at the DNA level. MS has been utilized for detection of post-translation modifications such as phosphorylation, acetylation, histone modifications, sumoylation, etc., in proteins. Advances in MS have allowed users to use of large fraction of normal and tumor cellular extracts to quantify the protein levels. MS can be utilized to characterize and quantify the amount of wild type and variant/mutated proteins in clinically important tissue samples and fluids. This technique is highly sensitive; the wild and mutant proteins can be easily detected at lower levels/ concentrations by using minimal quantity of sample. MS technology has more potential than the current practice of detection of biomarker with antibody technology and can be used with more precise in future cancer disease diagnosis and treatment.

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