Is cancer cytogenetics reducible to the molecular genetics of cancer cells?

Abstract

Whether cancer cytogenetics can be reduced to the molecular genetics of cancer cells is a question that must be addressed in three domains, focusing on its ontological, methodological, and epistemological dimensions. The possibility of ontological reduction hinges on whether chromosomes have other important constituents than molecules. Although this must obviously be answered in the negative, it should be emphasized that both cytogenetic and recombinant DNA investigations provide us with very selective pictures of genomic organization. This is of concern because the higher order packing of DNA and its joining with other molecules to form chromosomal structures give rise to emergent properties, functional features that become manifest only at higher levels of complexity and that may not be deducible from the base pair composition of the DNA. A position of extreme methodological reductionism would in our context be that the best research strategy is always to investigate the genetic changes of tumor cells at the highest possible resolution level, as alterations of genes and, ultimately, as changes in DNA primary structure. There are two fundamental differences between cytogenetic and molecular genetic techniques that make this stance untenable. First, whereas cytogenetic investigations are open-framed (all chromosome aberrations are revealed), molecular genetic analyses are highly specific (only those aberrations are revealed that one tests for). Second, whereas the molecular approach determines the genotypic constitution of an idealized, average tumor cell, cytogenetic analysis is of real, individual cells. These may not necessarily be representative of the main population of the tumor, but at least whatever karyotypic differences exist between them are detected. Heterogeneity and clonal evolution within the tumor can thereby be assessed. This second dissimilarity is of a less principled nature than the first and should be surmountable if isolation of single cells, followed by their analysis with PCR-based or equivalent techniques, become generally feasible methods in the molecular genetic investigation of cancers. Epistemological reduction of cancer cytogenetics to the molecular level would imply that all karyotypic findings and conclusions could be described and explained in terms of gene or, better still, DNA primary structure changes. But even in the best-studied examples of oncogene activation through chromosomal rearrangement, heterogeneities arise in both the chromosomal and molecular domains when one focuses “up” or “down” through the various resolution levels, away from the ones providing the most explanatory and predictive power, the best fit between neoplastic phenotype and genotype. Besides this “many-to-many” problem, one should also be open to the possibility that the pathogenetic consequences of at least some balanced translocations and losses of chromosomal segments might be more complex than an in principle straightforward activation of oncogenes or loss of antioncogenes. Other common karyotypic anomalies, such as those involving gain of chromosome material, especially polysomies and ploidy level changes, at present have no satisfactory explanation at the gene level. It follows that in neither the methodological nor the epistemological domain has a reduction occurred, nor does one seem imminent. Both molecular-level and chromosome-level investigations are, and most likely will remain, indispensable for an optimal approach to the analysis of neoplastic cells. In the synthetic phase of the scientific process, the regularities and causal connections that we perceive will continue to involve descriptions both in the language of cytogenetics and in the language of molecular biology. The choices we make when shifting back and forth between the two resolution levels will depend on utilitarian, instrumentalist considerations, not on any metaphysically motivated reductionist conviction.