From cancer genomes to cancer models: bridging the gaps

Abstract

Cancer genome projects are now being expanded in an attempt to provide complete landscapes of the mutations that exist in tumours. Although the importance of cataloguing genome variations is well recognized, there are obvious difficulties in bridging the gaps between high-throughput resequencing information and the molecular mechanisms of cancer evolution. Here, we describe the current status of the high-throughput genomic technologies, and the current limitations of the associated computational analysis and experimental validation of cancer genetic variants. We emphasize how the current cancer-evolution models will be influenced by the high-throughput approaches, in particular through efforts devoted to monitoring tumour progression, and how, in turn, the integration of data and models will be translated into mechanistic knowledge and clinical applications.

Figure 1

Driver or passenger? Multilevel strategies used to classify mutations and genes as either ‘drivers' or ‘passengers' at the level of (A) mutations, (B) genes or (C) processes. NS, non-synonymous; S, synonymous.

Figure 2

Modelling cancer evolution. Using the available technologies, the modelling of cancer evolution should provide insights into its development and progression.

Figure 3

Models of cancer evolution. (A) The ‘clonal selection model' (blue arrows) is the prevailing view to explain the successive steps of mutation and selection from normal tissue to primary tumour and metastasis. However, metastasis-generating cells can emerge relatively early in the tumorigenic process and ‘seed' distant tissues, thereby evolving in parallel with the primary tumour and delineating the ‘parallel evolution' model (red arrows). Finally, these two models can occur simultaneously and metastatic deposits can act as sites from which additional metastases can be generated, therefore leading to an integrated model of cancer evolution (green arrows). (B) Microphotographs provide a histological snapshot of normal skin tissue (a), primary tumour (superficial b₁ and deep b₂, macroscopic appearance inset in b), subcutaneous metastasis (c), metastasis in the lymph node (d) and metastasis in the lung (e), and are shown in correspondence with the cancer-evolution models. This melanoma—which originates from the transformation of pigmented skin cells—provides a visual example of the modelling paradigms, illustrating the gap between ideal models and actual observations.

Francisco X. Real, José M. G. Izarzugaza, Alfonso Valencia & Anaïs Baudot