Elsevier

The Lancet Oncology

Volume 2, Issue 11, November 2001, Pages 698-704
The Lancet Oncology

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Trends in biomarker research for cancer detection

https://doi.org/10.1016/S1470-2045(01)00560-5Get rights and content

Summary

A key challenge in cancer control and prevention is detection of the disease as early as possible, enabling effective interventions and therapies to contribute to reduction in mortality and morbidity. Biomarkers are important as molecular signposts of the physiological state of a cell at a specific time. Active genes, their respective protein products, and other organic chemicals made by the cell create these signposts. As a normal cell progresses through the complex process of transformation to a cancerous state, biomarkers could prove vital for the identification of early cancer and people at risk of developing cancer. We discuss current research into the genetic and molecular signatures of cells, including microsatellite instability, hypermethylation and single-nucleotide polymorphisms. The use of genomic and proteomic high-throughput technology platforms to facilitate detection of early cancer by means of biomarkers, and issues on the analysis, validation, and predictive value of biomarkers based on these technologies are also discussed. We report on recent advances in identifying sources of biomarkers that can be accessed by noninvasive techniques, such as buccal-cell isolates, as well as traditional sources such as serum or plasma. We also focus on the work of the Early Detection Research Network at the National Cancer Institute, harnessing expertise from leading national and international institutions, to identify and validate biomarkers for the detection of precancerous and cancerous cells in assessing risk of cancer. The network also has a role in linking discovery to process development, resulting in early detection tests and clinical assessment.

Section snippets

Biomarkers of risk

Biomarkers of risk can help identify individuals who are at increased risk of developing cancer, before the biological onset of the disease. These biomarkers are based mainly on inherited or somatically acquired susceptibilities, in the form of altered genes such as MSH2 and MLH in hereditary non-polyposis colorectal cancer, PRB in hereditary retinoblastoma, and BRCA1 and BRCA2 mutated genes that predispose to breast cancer. In these cases, there is an inherent familial predisposition to the

Biomarkers for early detection

Genetic inheritance accounts for only a small percentage of cancer incidence in the general population. Biomarkers can detect the outcomes of interaction between genetic susceptibility and the environment and are therefore extremely important for early detection. Theoretically, they could provide the opportunity to intervene during the natural progression of the cancer, to cause inhibition, regression, or even elimination of the disease. After biological onset, the disease progresses through a

Genetic and molecular signatures

Genetic and molecular changes are the initial events in carcinogenesis and could be useful if detected before the onset of symptoms and morphological changes. Although not many biomarkers have been validated for early detection so far, a few of the genetic and molecular signatures that hold promise are discussed below. These markers are being extensively studied in animal models and in patients with established cancers.

Genetic instability is an integral part of carcinogenesis; it creates a

Microsatellite instability

Microsatellites are polymorphic tandem repeats of short nucleotide sequences, of less than six bases, distributed throughout the genome. They are often used as markers for genetic mapping and in linkage analysis. The high mutation rate at most microsatellite loci results in changes to repeattract length (the length of the tandem repeat sequences of nucleotides in the microsatellite locus), which is the hallmark of MSI. The inherent instability of microsatellite loci is primarily due to changes

Hypermethylation

Methylation is thought to be one of the epigenetic mechanisms used by mammalian cells to modify gene function. Epigenetics is the phenomenon of inheriting information based on the expression levels of genes.17 The process of methylation involves covalent addition of a methyl group, from S-adenosylmethionine, to the cytosine ring, mediated by the enzyme DNA methyltransferase. The resulting 5-methylcytosine is the only modified base found in vertebrates. Methylation usually occurs within the

Single-nucleotide polymorphisms

Variations or mutations of gene sequences cause genetic instability, which often gives rise to heritable phenotypes that may predispose individuals to cancer. SNPs are by far the most common variations, occurring about once every 100-300 bases. When SNPs are present in key genes they might contribute to cancer progression by creating allelic imbalances. SNPs can change rates of drug metabolism by more than 10 000 fold or affect strength of protein binding and kinetics by more than 20 fold.23, 24

High-throughput technologies

Laboratory-based techniques for detecting the molecular and genetic changes are expensive and time-consuming. Automation and cost-effectiveness have to be built into these technologies to make them viable screening tools for use in populations. In addition, minute amounts of a biomarker should be detectable with high precision. Recent advances in genomics and proteomics hold great potential for diagnostic, prognostic, and therapeutic applications.

Genomics

Genomics can be broadly defined as the measurement of gene expression from available sequence information. The expression profile represents the function and phenotype of a cell and is called a 'transcriptome'. Technological advances in biomolecular assays in a miniature format - on glass, silicon, or even beads of fibre-optic bundles27 - have accelerated the development of genomics. cDNA and oligonucleotide microarrays on chips28 and serial analysis of gene expression (SAGE) are recently

Proteomics

Proteomic methods detect the functioning units of expressed genes34, through biochemical analysis of cellular proteins, to provide a protein fingerprint.35 The proteome reflects both the intrinsic genetic programme of the cell and the impact of its immediate environment and is therefore valuable in biomarker discovery. Distinct changes that occur at the protein level during the transformation of a normal cell into a neoplastic cell include altered expression, differential protein modification,

Non-invasive detection

Biomarkers, such as those described above can easily be used in population screening for early detection, when the tests are non-invasive. Advances in molecular biology techniques have facilitated detection of biomarkers, both from traditional sources, such as blood and body fluids, and nontraditional sources, such as exfoliated cells, stools, and urine. Mutations in the P53 gene have been observed in plasma DNA of patients with breast cancer, small-cell lung cancer, and colon cancer.39 DNA

Validation

The sensitivity, specificity, and predictive value of biomarkers have to be determined through the use of body fluids, paired tumours, and surrounding tissue from a wide variety of cancers before they can be used in populations. Many samples from individuals with known characteristics should be processed, to minimise the problems of confounding and to avoid spurious associations. Before field testing it should be established that the biomarker is truly in the path of pathogenesis and not merely

Search strategy and selection criteria

MEDLINE and CANCERLIT databases were searched for published data. Searches were limited to articles published in English from 1980 onwards. Relevant references from articles found were also used. The following books were also used as research material for this review.

Cancer prevention and control. Greenwald P, Barnett S, Kramer BS, Weed DL (Eds). New York, NY: Marcel Dekker Inc, 1995.

Molecular pathology of cancer. Srivastava S, Hanson DE, Gazdar A (Eds). Amsterdam, Netherlands: IOS Press,

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