Genome sequencing and cancer

Abstract

New technologies for DNA sequencing, coupled with advanced analytical approaches, are now providing unprecedented speed and precision in decoding human genomes. This combination of technology and analysis, when applied to the study of cancer genomes, is revealing specific and novel information about the fundamental genetic mechanisms that underlie cancer's development and progression. This review outlines the history of the past several years of development in this realm, and discusses the current and future applications that will further elucidate cancer's genomic causes.

Figure 1

A Kaplan-Meier curve illustrating the current cytogenetics and pathology-based stratification of acute myeloid leukemia patient risk. High risk cases are classified by complex cytogenetics that do not conform to known translocations, whereas low risk patients have straightforward cytogenetics that include known translocations (t15;17, t8;12, inv16) and for which well-defined therapeutics define the standard of care. Most patients are classified by normal/diploid cytogenetics as intermediate risk cases. Because the cytogenetic profiles of these patients are not prognostic for risk, genome sequencing has been pursued in an effort to identify genes that are frequently altered in the tumor and for which correlations to outcome can be made. (Figure from J.C. Byrd et al., Blood 2002. 100: 4325–36).

Figure 2

Model of the clonal progression process that occurs between the initial (de novo) and relapse presentation in AML patients. At diagnosis, this patient has an oligoclonal disease characterized by four different subclones, each present at a specific proportion in the tumor cell population and with a specific mutational profile. Chemotherapy used to induce the patient into remission decreases clonal heterogeneity but a single subclone persists, acquires new mutations, and again proliferates in the bone marrow as a relapse-specific subclone.

Figure 3

Diagrammatic representation of the cryptic insertion identified in an acute promyelocytic patient genome. In this event, a 77kb portion of chromosome 15 containing the PML first three exons and a portion of the LoxL1 gene was inserted into chromosome 17, between exons 3 and 4 of the RARa gene. The resulting sequences of chromosomes 15 and 17 are shown at the bottom of the figure.