Cancer genome sequencing--an interim analysis - PubMed (original) (raw)

Cancer genome sequencing--an interim analysis

Edward J Fox et al. Cancer Res. 2009.

Abstract

With the publishing of the first complete whole genome of a human cancer and its paired normal, we have passed a key milestone in the cancer genome sequencing strategy. The generation of such data will, thanks to technical advances, soon become commonplace. As a significant number of proof-of-concept studies have been published, it is important to analyze now the likely implications of these data and how this information might frame cancer research in the near future. The diversity of genes mutated within individual tumor types, the most striking feature of all studies reported to date, challenges gene-centric models of tumorigenesis. Although cancer genome sequencing will revolutionize certain aspects of personalized care, the value of these studies in facilitating the development of new therapies, their primary goal, seems less promising. Most significantly, however, the cancer genome sequencing strategy, as currently applied, fails to characterize the most relevant genomic features of cancer-the mutational heterogeneity within individual tumors.

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Figures

Figure 1

Figure 1. The Mutational Landscape of the Cancer Genome

(a) The cancer genome landscape of colorectal cancer as proposed by Wood et al. (9) demonstrates the mutational heterogeneity between individual tumors. The height of each violet peak represents the percentage of colorectal tumors found to carry a clonal mutation in a particular gene. The landscape comprises a small number of “mountains”, genes which are mutated in a large number of cancers [e.g. TP53 (23)], and a significantly larger number of “hills”–genes mutated in only a small number of individual tumors. While there may be 50 or more genes clonally mutated in a given tumor, any given gene is rarely mutated in more than a few tumors. (b) The mutational heterogeneity within individual tumors not detected by the cancer genome sequencing studies. The mutational landscape of three tumors are shown; each tumor is represented by a set of differently colored peaks (blue, red and yellow). The height of each peak reflects the number of cells within a single tumor that have a particular mutated gene. Split colored peaks represent the small number of mutated genes shared in common between more than one tumor. Within an individual neoplasm, a few mutations are present throughout the population (tall peaks), a greater number are present in minority subclones (short peaks) and the majority are found in only one or a few cells (invisibly distributed throughout the green background.)

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