Translating insights from the cancer genome into clinical practice

Abstract

Cancer cells have diverse biological capabilities that are conferred by numerous genetic aberrations and epigenetic modifications. Today's powerful technologies are enabling these changes to the genome to be catalogued in detail. Tomorrow is likely to bring a complete atlas of the reversible and irreversible alterations that occur in individual cancers. The challenge now is to work out which molecular abnormalities contribute to cancer and which are simply 'noise' at the genomic and epigenomic levels. Distinguishing between these will aid in understanding how the aberrations in a cancer cell collaborate to drive pathophysiology. Past successes in converting information from genomic discoveries into clinical tools provide valuable lessons to guide the translation of emerging insights from the genome into clinical end points that can affect the practice of cancer medicine.A human 'cancer genome', or oncogenome, harbours numerous alterations at the level of the chromosomes, the chromatin (the fibres that constitute the chromosomes) and the nucleotides. These alterations include irreversible aberrations in the DNA sequence or structure and in the number of particular sequences, genes or chromosomes (that is, the copy number of the DNA). They also include potentially reversible changes, known as epigenetic modifications to the DNA and/or to the histone proteins, which are closely associated with the DNA in chromatin (Fig. 1). These reversible and irreversible changes can affect hundreds to thousands of genes and/or regulatory transcripts. Collectively, they result in the activation or inhibition of various biological events, thereby causing aspects of cancer pathophysiology, including angiogenesis, immune evasion, metastasis, and altered cell growth, death and metabolism 1 .Mining the cancer genome and epigenome for aberrations that control these processes has become a major activity in cancer research, because it is widely understood that these aberrations provide clues to the mechanisms of disease pathogenesis. These studies can inform efforts to identify molecular events that can be targeted for therapy and to discover molecular biomarkers (biological indicators) that aid in early detection, diagnosis, prognosis (that is, prediction of clinical outcome) and the prediction of responses to therapies.

Patient-centric trials for therapeutic development in precision oncology

“…Insights into the molecular pathology of disease are creating opportunities for more durable clinical benefit, but are also challenging the existing paradigm of therapeutic development and clinical care [1][2][3] . Large international consortia such as the International Cancer Genome Consortium 4,5 are mapping thousands of cancer genomes to identify opportunities for prevention, early detection and treatment 6 .…”

Methylated genes as new cancer biomarkers

“…Currently, multiple approaches are available for measuring gene methylation in research laboratories. 6,[87][88][89] Some of the most commonly used methodologies, together with their advantages and disadvantages are listed in Table 4. According to the recent National Cancer Institute workshop on the clinical application of methylated DNA sequences as cancer biomarkers, bisulphite sequencing is optimal for the detection of CpG island methylation of new genes, pyrosequencing is best for quantitation of individual CpG sites while quantitative methylation-specific PCR is best for sensitive detection of methylated alleles.…”

“…3,4 Specific genes with such abnormalities have been suggested as potential new tumour biomarkers. 5,6 Compared with other molecular structures such as mRNA, miRNA and certain proteins, the use of DNA for the measurement of tumour marker has a number of attractive features. 7 Firstly, DNA molecules are very stable and in contrast to mRNA and many proteins, can survive harsh conditions for long periods of time.…”

Data Integration and Knowledge Discovery in Life Sciences

“…Oncology is the field of research where biomarker discovery is most advanced. Various types of biomarkers have been identified for use in prognostic and eventually provide patients with personalized treatment [21,22]. Emerging themes in cancer research include i) the exploitation of panels of biomarkers for successful translation of discoveries into clinical applications [23] and ii) the understanding of cancer at the pathway-level [24].…”