The multitude of molecular analyses in cancer: the opening of Pandora’s box

Abstract

The availability of large amounts of molecular data of unprecedented depth and width has instigated new paths of interdisciplinary activity in cancer research. Translation of such information to allow its optimal use in cancer therapy will require molecular biologists to embrace statistical and computational concepts and models. Progress in science has been and should be driven by our innate curiosity. This is the human quality that led Pandora to open the forbidden box, and like her, we do not know the nature or consequences of the output resulting from our actions. Throughout history, ground-breaking scientific achievements have been closely linked to advances in technology. The microscope and the telescope are examples of inventions that profoundly increased the amount of observable features that further led to paradigmatic shifts in our understanding of life and the Universe. In cell biology, the microscope revealed details of different types of tissue and their cellular composition; it revealed cells, their structures and their ability to divide, develop and die. Further, the molecular compositions of individual cell types were revealed gradually by generations of scientists. For each level of insight gained, new mathematical and statistical descriptive and analytical tools were needed (Figure 1a). The integration of knowledge of ever-increasing depth and width in order to develop useful therapies that can prevent and cure diseases such as cancer will continue to require the joint effort of scientists in biology, medicine, statistics, mathematics and computation. Here, we discuss some major challenges that lie ahead of us and why we believe that a deeper integration of biology and medicine with mathematics and statistics is required to gain the most from the diverse and extensive body of data now being generated. We also argue that to take full advantage of current technological opportunities, we must explore biomarkers using clinical studies that are optimally designed for this purpose. The need for a tight interdisciplinary collaboration has never been stronger.

Figure 1

Multiple levels of data integration. (a) Major inventions resulting in extreme numbers of novel observations in cancer biology: the microscope, microarray analyses and massive parallel sequencing technology. (b) The gap between current breast cancer treatment and available molecular data. Most treatment guidelines are based on studies that analyzed a small number of measurements reflecting clinical information (red) and histopathological features (blue). By contrast, an almost unlimited number of measurements can be obtained in multilevel molecular analyses using, for example, microarray-based technologies or massive parallel sequencing technologies where millions of data points can be observed simultaneously (green). miRNA, microRNA. (c) Inter-tumor heterogeneity is illustrated by these microscopic images of two tumors, one having tumor cells with luminal differentiation and abundant stromal tissue (left) and the other having less differentiated tumor cells and scarcely any stromal tissue (right). (d) The cellular composition of tumors shows great variation, as do the tumors themselves. Immunohistochemistry with an antibody against the membrane protein CD44 shows both positive and negative stained tumor cells. In addition, lymphocytes in the stromal environment are positive for this antibody.