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Biomarkers in molecular medicine: cancer detection and diagnosis
Padma Maruvada, Wendy Wang, Paul D. Wagner, Sudhir Srivastava
Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA
BioTechniques, Vol. 38, No. S4, April 2005, pp. S9–S15
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In spite of advances in diagnostics and therapeutics, cancer remains the second leading cause of death in the U.S. Successful cancer treatment depends not only on better therapies but also on improved methods to assess an individual's risk of developing cancer and to detect cancers at early stages when they can be more effectively treated. Current cancer diagnostic imaging methods are labor-intensive and expensive, especially for screening large asymptomatic populations. Effective screening strategies depend on methods that are noninvasive and detect cancers in their early stages of development. There is increasing interest and enthusiasm in molecular markers as tools for cancer detection and prognosis. It is hoped that newly discovered cancer biomarkers and advances in high-throughput technologies would revolutionize cancer therapies by improving cancer risk assessment, early detection, diagnosis, prognosis, and monitoring therapeutic response. These biomarkers will be used either as stand-alone tests or to complement existing imaging methods.


During the past three decades, there has been significant progress in both the understanding and treatment of cancer. However, cancer remains the second leading cause of death in the U.S., and the Director of the National Cancer Institute (NCI) has challenged the cancer community to eliminate suffering and death due to cancer by 2015 (1). Achieving this goal will require not only improved therapies but also improved methods to assess an individual's risk of developing cancer, to detect cancers at early stages when they can be more effectively treated, to distinguish aggressive from nonaggressive cancers, and to monitor recurrence and response to therapy. Improving methods to screen asymptomatic populations for the presence of early stage cancers is a particularly challenging problem. The American Cancer Society has recently recommended various diagnostic tests to screen populations for the early detection of many cancers of high incidence including breast, colon, and prostate (2). However, there are no viable screening methods for other common cancers, such as lung cancer.

While diagnostic, imaging methods can be used to identify individuals with cancer, many are too labor-intensive and expensive for screening large asymptomatic populations. Moreover, some have met with resistance by the general population, as they can be embarrassing or inconvenient, limiting their usefulness for screening this group. Also, diagnostic imaging methods often miss smaller lesions, with the disease not diagnosed until it is in an advanced stage when therapeutic intervention is usually less effective. In the past several years, there has been increasing interest and enthusiasm in molecular markers as tools for cancer detection and prognosis, both as stand-alone diagnostic tools and to complement existing imaging methods and technologies.

In this article, we briefly discuss molecular technologies used for biomarker discovery and analysis and provide examples of how they can potentially be used to identify at-risk individuals and early cancers.

Why are Biomarkers Useful?

Cancers arise from an accumulation of genetic and/or epigenetic changes that result in alterations of the proteins expressed in the affected cells. The levels of specific proteins can be increased or decreased or their functions and distributions altered by posttranslational modifications. These protein alterations can affect cell metabolism and physiology, cell growth and death, and secretion of molecules that signal other cells and tissues. In cancer research, molecular biomarkers refer to substances that are indicative of the presence of cancer in the body. Biomarkers include genes and genetic variations, differences in messenger RNA (mRNA) and/or protein expression, posttranslational modifications of proteins, and metabolite levels. As the molecular changes that occur during tumor progression can take place over a number of years, genomic, proteomic, and metabolomic biomarkers can all be potentially used to detect cancer, determine prognosis, and monitor disease progression and therapeutic response ((Figure 1)).

Figure 1.

Approaches for biomarker discovery for clinical application. Cancer cell signatures can serve as biomarkers in clinical cancer research for risk assessment, detection, diagnosis, and prognosis, and for determining response to treatment. These biomarkers can be analyzed by high-throughput genomic, proteomic, and metabolomic technologies.

Traditionally, biomedical research has been hypothesis-driven; investigators put forth hypotheses and design experiments to test them. Recent advances in high-throughput technologies have given rise to more technology-driven research. Rather than putting forth a hypothesis, investigators apply high-throughput methods to biological systems and look for interesting results that could lead to hypothesis generation for further testing. For example, using microarrays containing thousands of different cDNAs, it is possible to look for differences in gene expression in cancerous versus normal tissue. Both hypothesis-driven and technology-driven approaches are applicable to biomarker discovery.

Platforms for Biomarkers Analysis

Genomic Technologies

Genomic technologies allow the determination and monitoring of genetic factors that underlie carcinogenic transformation and genetic alterations caused by environmental agents. Commonly used genomic technologies include DNA microarrays, PCR-based assays, and fluorescence in situ hybridization (FISH). Advantages of these genomic approaches include the existence of a number of high-throughput robust assay methods and the ability to amplify specific DNAs and RNAs that may exist in very low concentrations in the specimens. DNA-based biomarkers include genetic mutations, loss of heterozygosity (LOH), microsatellite instability (MSA), and DNA methylation. RNA-based biomarkers are mostly mRNAs found in tissues and bodily fluids.

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