The goals of oncogenomics and proteomics are to improve diagnosis, therapy, and cure rates for cancer patients.
A patient’s genomic signature of a cancer may serve as the basis for choosing the most effective therapy for the individ- ual patient to improve their chances of recovery and their quality of life. Oncogenomics and proteomics have pro- gressed from molecular profiling to model systems, cancer pharmacology, and clinical trials. Although it is unlikely that a single biomarker accurately detects the presence of HNSCC, analyses that can detect multiple markers may have improved predictive value when used in combination. Imperfect bio- markers may still be clinically useful for serial testing of single individuals because acute changes in biomarker levels may signal the need for an aggressive search for the cause.
An important challenge for biomarker validation is the con- siderable molecular heterogeneity of individual cancers and the low overall incidence of the disease in general popula- tion, making it difficult to validate the true prognostic poten- tial of a biomarker or panel of biomarkers. Nonconcordance of predictive gene lists is common in many microarray stud- ies using different platforms and data mining tools and may represent differences in experimental design or data analy- ses, but also may represent true differences in biology based on different subsites or other unknown factors.
Furthermore, although current oncogenomic and pro- teomic approaches may yield valuable information in the identification of novel diagnostic markers, gene- and protein- expression profiles may not be able to provide an alternative method of diagnosis on their own. It may become necessary to include other technologies, such as metabolomics, pepti- domics, glycomics, and lipidomics for better isolation and identification of molecular targets. In order to obtain reliable prognostic markers, these technologies will need to be com- bined with advanced bioinformatics tools to integrate and mine the data from basic and clinical research. Once molecular signatures are successfully validated, it will also Key Advantages and Limitations of Proteomic
Approaches:
Advantages:
Provide insight into fluctuations in transcribed and
−
translated gene products as well as posttranslational modifications.
Capable of using a variety of tissue sources with
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minimal processing to analyze variations.
Increasingly offering high-throughput technologies.
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Limitations:
High abundance proteins may obscure data.
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Generally, only analyze a minority of proteins
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within the entire sample.
Difficult to correlate individual spectral peaks/sig-
−
natures with actual proteins.
be important to perform long-term clinical studies to deter- mine the validity of using these signatures in independent cohorts of patients for the prediction of patient response to therapeutic options.
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J. Bernier (ed.), Head and Neck Cancer: Multimodality Management, 93
DOI 10.1007/978-1-4419-9464-6_5, © Springer Science+Business Media, LLC 2011
Abstract Cancer is caused by a multi-step progression of genetic and epigenetic aberrations resulting in a clonal expansion of cells. These cells have a selective growth advantage characterised as the “hallmarks of cancer” includ- ing loss of control of the cell cycle, genomic instability, inhibition of apoptosis, insensitivity to growth signals and promotion of angiogenesis. A greatly increased understand- ing of the pathogenesis of the various underlying genetic and epigenetic lesions has accompanied the recent explosion of knowledge, coined the “omics” revolution. In a variety of cancer sites, we are already able to explain and classify much of the heterogeneity of tumour behaviour in terms of the underlying molecular lesions responsible. This capac- ity will increase with the scope of technologies becoming available, and being able to offer a corresponding tailored approach to therapy remains the ultimate goal.
Keywords Genetics • Epigenetics • Mutations • Carcinogenesis
• Tumour suppressor genes • Oncogenes • DNA methylation • Histones
Introduction
Despite the many innovations in cancer management, it is increasingly apparent that new advances in cancer therapy will rely on a greater understanding of treatment at a molecu- lar level. A new “omics” language has developed with genomics, proteomics and metabolomics, all fields of trans- lational research and terms used to bridge together traditional pure and applied science into the clinical setting. The clinical behaviour of HNSCC varies greatly from patient to patient, site to site and even within individual sub-sites, and its intrin- sic heterogeneity in biological properties, which is common
in solid tumours, is reflected in the diversity of outcomes.
These differences in tumour properties are a consequence of differing genetic and epigenetic changes as well as differing host responses. A better understanding of the genetic mecha- nisms of carcinogenesis will help to target therapies to specific characteristics of a patient’s tumour, central to the modern concept of personalised medicine. One example with clear and clinically exploitable differences in genetic mechanism is that of Human Papilloma Virus (HPV) medi- ated HNSCC, although this will not further discussed here as it is covered specifically in Chapter 10. Much of what follows is essentially a discussion of HPV negative HNSCC.
Cancer results from the accumulation of molecular lesions which occur, and might be investigated, at the genetic, epige- netic, messenger RNA or protein level. The importance of genetic changes and frequency of the resultant disease have led to cancer being labelled the commonest human genetic disease. Often when we consider genetic diseases, we imme- diately think of inherited diseases. Fortunately inherited head and neck cancer syndromes are relatively uncommon, but there are several such entities predisposing to HNSCC which offer a valuable window on the events also critical to spo- radic cancers. The great majority of sporadic cancers occur due to exposure to environmental mutagens. These mutagens cause genetic lesions that have a huge range of scale, from a single nucleotide to an entire chromosomal region being lost or gained. These genetic abnormalities occur more or less randomly rather than as an ordered sequence, and it is appar- ent that while some may be critical “drivers” to carcinogen- esis, others are “bystander” events. Our ability to explore this disordered cancer genome is dependent on, and limited by, the availability of representative tumour models, high-quality tissue resource and the capacity of available technologies.
Fortunately, there has been great progress in both areas in recent years and it is likely that this will significantly contrib- ute to our understanding of cancer biology. Since the com- pletion of the 15-year human genome project in 2003, the capability of the available “next-generation” sequencing techniques is such that an entire genome can be re-sequenced using a fraction of the resources previously required. It is now feasible to re-sequence individual tumours in attempt to
R.J. Shaw (*)
Head and Neck Surgery, Oral & Maxillofacial Surgery, University Hospital Aintree, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK
e-mail: [email protected]