Cancer cells strive to survive and multiply; therefore they do not like chemotherapeutic agents (or irradiation) to prevent this from happening. Thus, we have an interesting ‘gene-environment interactions’ dilemma: how can the cancer cell help prevent itself from being destroyed? Duplication of chromosomes (changes in ploidy) is always seen in cancer cells. Tetraploidization (i.e. doubling of a complete set of diploid chromosomes) is one class of ploidy abnormality that results from whole-genome doubling (WGD). WGD has been studied in both prokaryotic (organisms having a single set of chromosomes) and eukaryotic (organisms having chromosome pairs) species. WGD is seen as an evolutionary mechamism by which eukaryotic organisms give themselves a survival advantage so that they might “out-compete” their diploid progenitors. In normal human development, WGD is rare, except in germ cells (sperm, ova) during meiosis (a type of cell division resulting in four daughter cells, each with half the number of chromosomes of the parent cell).
WGD has often been seen in previous studies of cancer in lab animal models. It is believed: to arise from underlying errors in cell division; to propagate due to a defective G1 checkpoint in the cell cycle; and to result in a multitude of malignant phenotypes (traits). In human tumors, WGD has been identified incidentally as part of previous large-scale studies of DNA copy-number alterations or analyses defining the phylogenetics of disease evolution. One challenge, in studying WGD in solid tumors, has been distinguishing a singular WGD event from what may be multiple successive and independent copy-number alterations. This challenge is compounded by the fact that WGD might be permissive of subsequent chromosomal aberrations and genomic instability. Another challenge has been delineating the mutational correlates of WGD in a cohort of diverse cancer types of sufficient population size to draw robust inferences. Finally, due to limited clinical outcome data available for most large-scale genomic cohorts, little is known about the broader clinical significance of WGD –– beyond targeted cancer-type-specific studies. WGD is therefore a common, but still mysterious, event in human cancers, the evolution and clinical impact of which has not yet been broadly defined in both common and rare cancers.
Authors [see attached study] identified WGD in tumors of nearly 30% of 9,692 prospectively sequenced advanced cancer patients. WGD varied by tumor lineage and molecular subtype, and arose early in carcinogenesis –– after an earlier transforming driver mutation. While associated with TP53 gene mutations, 46% of all WGD arose in TP53-wild-type tumors and, in such cases, was associated with an E2F-mediated G1 arrest defect, although neither aberration was required for WGD to have occurred in the tumor. Variability of WGD across cancer types can be explained in part by cancer cell proliferation rates. WGD was associated with increased morbidity across cancer types –– including KRAS-mutant colorectal cancers and estrogen receptor-positive breast cancers –– independently of established clinical prognostic factors. Authors conclude that WGD is highly common in cancer and is a macro-evolutionary event correlated with poor prognosis across many cancer types.
Nature Genet Aug 2o18; 50: 1189–1195