Chromosomes and Cancer, Boveri Revisited

Already in the late 19th century, the link between chromosomal aberrations and the pathogenesis of cancer was described by von Hanssemann [9]. Moreover, as early as the first decade of the 20th century the German zoologist Theodor Boveri developed a genetic theory of cancer based on these chromosomal aberrations [3]. Until quite recently, these ideas have received only limited attention and focus in cancer genetics has been mainly on the role of individual oncogenes and tumor suppressor genes. Yet, there is striking contrast between the complex genomic alterations we find in most human cancers and the simplicity of model systems used to explain their biology. While in certain instances these models are informative, on multiple occasions this is not the case. Indeed multiple knockout mice have been generated that don't have a disease phenotype. The limited attention for chromosomal instability in cancer research nicely illustrates the influence of observer bias on science. Most of the time, you only find what you are looking for. In this case, the observer bias largely has a technical background. For a long time we have been devoid of tools to evaluate the biological complexity of cancer in high enough detail. In addition , we did not have convenient methods available to study chromosomal aberrations in large series of tumor samples. Banding techniques for karyotyping became available in nineteen seventy but this required cell culturing and cytogenetic skills [5]. Alternatively, fluorescence in situ hybridization, even today necessarily is restricted to a limited number of genomic probes [10,29]. One of the most popular methods for studying genomic alterations in cancer was LOH analysis, which only allowed to detected genomic losses. As a consequence, the scientific community for a substantial period of time was focused on explaining the biology of cancer mainly by the role of tumor suppressor genes. The publication of comparative genomic hybridization in the early nineteen nineties meant a large step forward and opened up new opportunities for studying chromosomal copy number changes in large tumor series [13]. Over the last decade indeed numerous studies in this field have demonstrated the presence of specific chromosomal aberrations in many different types of cancer, while in fact, not so long before that, such genomic alterations were easily regarded to be ge-nomic noise, secondary to a cancer phenotype caused by the alteration of a few tumor suppressor genes and oncogenes [11]. Of the non-random cancer associated chromosomal …