Tuesday, July 2, 2013

Tumor marker : Introduction, Classification and Clinical application


The first tumor marker reported was the Bence-Jones protein (monoclonal light chains of Ig secreted by tumor plasma cells) by precipitation in acidified boiled urine and is the diagnostic marker of multiple myeloma. It was identified by H. Bence-Jones in 1846. The second era (1982-1963) was the discovery of hormones, enzymes, isoenzymes and proteins
and later on chromosomal analysis. The third era (1963-1965) was discovery of onco developmental markers e.g. AFP, CEA. The fourth era started in 1975 with the development of monoclonal antibodies and their use to detect oncofetal antigens and antigens derived from tumor cell lines like carbohydrate antigens (CA 125, 15-3, etc.). Finally advancement in molecular genetics helped to detect alteration in chromosomal level (e.g. oncogenes, suppressor genes, etc.).  

A tumor marker is a substance present in or produced by tumor itself or by the host in response to a tumor that can be used to differentiate a tumor from normal tissue or used to determine presence of tumor based on their measurement in blood or secretions

Some markers may be tumor-specific present only in the given tumor or tumor associated markers that are found with different tumors of same tissue type. They are present in higher quantities in cancer tissue or in blood from cancer patients.

Ideally tumor marker should be produced by the tumor cells and be detectable in body fluids. It should not be present in healthy people or in benign conditions. They must be highly sensitive and specific for a given tumor, should have well validated analytical method for detection, should be cheap easily available and cost effective.  

Fig. Tumor markers

These are first group of tumor markers identified. They were measured by RIA and spectrophotometric methods. 

They were used for the detection and monitoring of cancer. They were measured by RIA

Oncofetal antigens, like AFP, CEA, and PSA
They were discovered using antisera produced against fluids from cancer-bearing animal or extracts of cancer tissues. 

Cell surface markers 
E.g. CA 125, 15-3, 19-9, blood group antigens, are identified by using monoclonal antibodies prepared against tumor cell preparations. They have better clinical sensitivity and specificity than do oncofetal antigens.

Genetic markers
They have great potential for diagnosis by chromosomal analysis to detect mutations or alterations. Two types of markers are used oncogene and tumor suppressor genes. 


  • Screening in general population, e.g. PSA for prostate cancer in old age, AFP for Hepatocellular Carcinoma (HCC). Except these two no other tumor marker are validated for screening. Screening for susceptibility to breast and ovarian cancer is done by identifying germline BRCA1 and BRCA2 mutations. 
  • Differential diagnosis in symptomatic patients
  • Clinical staging of cancer
  • Estimating tumor volume
  • Prognostic indicator for disease progression
  • Evaluation of success of treatment. After treatment markers should decrease and this this decrease can be predicted by using half-life of marker. For E.g. T1/2 of PSA is 2-3 d, hCG is 12-20 h and AFP is 5 d. If the T1/2 after treatment is longer then the expected T1/2, then treatment has not been successful in removing tumor. Oestrogen and progesterone receptor and their presence or absence in breast cancer tissue determines the success of endocrine therapy. 
  • Detecting recurrence of cancer. E.g. breast cancer marker CA 27.29 has shown to detect recurrent disease before any clinical evidence in breast cancer patients receiving chemotherapy.
  • Despite of these applications tumor markers are mostly and importantly used for prognosis and monitoring effects of therapy and for targets for localization and therapy. For other applications the current usefulness is of limited value or controversial. 

Hook effect: When analyte concentrations exceed the analytical range excessively, both the capture and label antibodies can be saturated (i.e. they will be occupied) resulting in lack of sandwich formation, which results in significant decrease in signal. This can be overcome by diluting the specimen. Samples displaying hook effect will yield higher values on dilution.

(source: Tietz Textbook of clinical chemistry, 4th Edition, Marshall's Clinical Chemistry)

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