Coping with complexity

Abstract

Human cancers are characterized by chromosomal aberrations, and an increasing number of specific balanced rearrangements have been found among malignant hematologic disorders. Most solid tumors, however, exhibit a much more complex cytogenetic pattern. Although these chromosome changes show a nonrandom distribution, tumor-specific aberrations are uncommon, and the solid tumors often contain a large number of abnormalities and also display extensive cytogenetic variability. The high level of karyotypic complexity has made a systematic characterization of the chromosomal patterns difficult. In order to better understand the biological relevance of highly abnormal karyotypes in tumor cell populations, novel statistical strategies are needed. We have developed and adapted several methods that may be useful for the evaluation of general patterns of karyotypic complexity, including distribution analysis of cytogenetic imbalances, temporal analysis for time of occurrence of aberrations, and principal component analysis for reconstructing karyotypic pathways. By applying these methods on the chromosomal changes presently known, distinct subgroups have been identified among breast, kidney, bladder, colon, and brain tumors.

Introduction

Most human cancers are characterized by chromosomal aberrations and cytogenetic analysis has proved a fruitful approach to detect pathogenetically important genetic changes. In particular, the cytogenetic investigations of hematological malignancies have been rewarding in that an increasing number of disease-specific balanced rearrangements, most often translocations, have been found, which all exert their action at the molecular level through one of two alternative mechanisms: deregulation, usually overexpression, of a seemingly normal gene is one of the breakpoints, or the creation of a hybrid gene through fusion of parts of two genes, one in each breakpoint 1, 2. However, many solid tumors exhibit a much more complex pattern of aberrations. Although these chromosome changes invariably show a nonrandom distribution over the chromosome complement, tumor-specific aberrations are uncommon. Solid tumors also tend to contain a higher number of aberrations than leukemias and often exhibit extensive variability in the pattern of aberrations, even within the same histopathological entity [1]. It has been suggested that this variability reflects a multistep pathogenetic process, resulting in both loss of tumor suppressor gene function and oncogene activation [3]. The high level of karyotypic complexity in these tumor types has made a systematic characterization of the cytogenetic evolution patterns difficult and dependent upon a large body of cytogenetic information. Obviously, novel strategies are needed to understand the biological relevance of these highly abnormal karyotypes. This article presents a set of statistical methods for describing and analyzing cytogenetic data from tumor cell populations, taking both complexity and heterogeneity into account.