Use of Biomarkers for Early Detection of Cancer

Although plasma tumor biomarkers are widely used clinically for monitoring response to therapy and detecting cancer recurrence, only a limited number of them have been used effectively for the early detection of cancer. A review of the use of cancer biomarkers in the US shows that only PSA, cancer antigen 125 and a-fetoprotein have been clinically used for the early detection of prostate, ovarian and liver cancers, respectively (Meany et al. 2009). Few plasma tumor biomarkers have been used effectively for the early detection of cancer, mainly because of their limited sensitivity and/or specificity. Several approaches are being developed to improve the clinical performance of tumor biomarkers for the early detection of cancer.

Applications of Biomarkers for Cancer Diagnosis

Methylated DNA Sequences as Cancer Biomarkers

To identify and overcome barriers in the application of methylated genes as cancer biomarkers and to promote validation studies of these biomarkers, the NCI Early Detection Research Network (EDRN) joined forces in 2005 with the National Institute of Standards and Technology (NIST) to conduct a workshop on Standards and Metrology for Cancer Detection and Diagnostics focusing upon DNA methyla- tion. The objectives of the workshop were:

  • • To evaluate methods and standards for robust, sensitive, and preferentially, quantitative measurements of DNA methylation in clinical specimens.
  • • To evaluate demands stemming from different types of specimens (e.g. tissue versus biological fluids).
  • • To identify and evaluate variables (e.g. amount of DNA template) influencing the robustness of the particular assay.
  • • To evaluate the need, and develop recommendations, for Standard Reference Materials for the discovery and validation of methylated DNA biomarkers (including cross-validation between laboratories and platforms).
  • • To evaluate the need and make recommendations regarding the necessity to establish a common collection of data standards that can be used to transmit cancer- related clinical research data among investigators, clinicians, and regulators.

The results of the Workshop were published (Kagan et al. 2007). It was clear from this workshop that one standard cannot be developed for addressing all the applications for methylation in the basic and translational research fields as well as the clinical testing. The best technology depends on the question being asked. However, the development of standard assays will require standard specimens for clinical comparison. The most straightforward set of specimens are tumor cell lines, which can be regenerated and provide an unlimited source of DNA. Tumor tissue and adjacent tissue from a cancer that is common and always resected, such as colon cancer, could be a second valuable standard for assay validation. It also is clear that there is a pressing need for perhaps unexciting, but important, studies to determine the optimal parameters for choice, storage, and preparation of clinical specimen for DNA isolation, bisulfite modification, and technology controls. The conclusions of this workshop about the desirable characteristics of methylated DNA sequences as clinical biomarkers were as follows:

• Reproducible, preferentially quantitative measurement is important in all clinical applications.

  • • Absolute methylation measurement (% methylation at individual sites) is more amenable to precise quantitation.
  • • Individual gene methylation measurement will likely be clinically useful in cancer detection, diagnosis and prognosis and classification and possibly in risk assessment.
  • • The performance of a biomarker is highly dependent on the choice of methyla- tion detection method.

Choice of technology recommendations were:

• Bisulfite sequencing is optimal for the analysis of CpG island methylation of

new genes

  • • Pyrosequencing is optimal for quantitation of individual CpG sites.
  • • Quantitative methylation-specific PCR is optimal for sensitive detection of methylated alleles.

Standardization issues and recommendations were:

  • • Different genes used in detection assays: establish optimal gene panel by interlaboratory testing.
  • • Different area of promoter of same gene: establish optimal gene panel by interlaboratory testing.
  • • Different technology used for analysis of methylation status: establish by interlaboratory testing of aliquots from universal standard.
  • • Different reference or controls used with same technology: establish by interlaboratory testing of aliquots from universal standard.
 
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