Most cancer cells exhibit gross chromosomal aberrations, for instance, gains or losses of whole chromosomes or parts of chromosomes.
This striking feature of many cancers is called aneuploidy and is often accompanied by chromosomal instability (CIN), an increased rate of gain and loss of chromosomes or chromosome fractions. Aneuploidy in cancer cells was first observed 100 years ago by the German biologist Theodor Bovery.
To this day, scientists do not fully understand how cancer cells can cope with such a seemingly chaotic disposition, sometimes even enhancing their proliferation potential.
Increased levels of CIN worsens the prognosis in Estrogen-receptor-positive (or ER+) breast cancer, which comprises about 75% of all breast cancers. This conundrum motivated two teams lead by the Biomathematician Maik Kschischo (University of Applied Sciences Koblenz, Germany) and the Oncologist Charles Swanton (Cancer Research UK, London) to ask, how CIN modulates the activity of other genes and what the phenotypic consequences are.
The scientists designed a computational workflow to filter out core regulator genes whose DNA copy number in high CIN tumours affects the RNA expression of many other genes. Intriguingly, for two of these core regulator genes, TPX2 and UBE2C, they found their DNA copy number to be highly correlated with gene expression biomarkers used for forecasting clinical outcome and response to chemotherapy. In addition, these genes were also associated with markers for cellular proliferation.
These results shed a new light on two open questions: In recent years, various gene expression signatures were approved and marketed to predict the clinical outcome and the response to chemotherapy for woman suffering from ER+ breast cancer.
These signatures help doctors to decide on the optimal treatment strategies for individual patients. What puzzled scientists was, that these signatures have so few genes in common and that no obvious biological process or function could be identified which explains the prognostic power of these signatures. The teams of Kschischo and Swanton show, that a good part of the signal in these signatures is related to CIN and the CIN core regulators UBE2C and TPX2.
Secondly, these results support the view that CIN and aneuploidy are not just byproducts of the cancerous state, but are essential for the evolutionary processes involved in cancer development. By means of natural selection, cancer cells acquire DNA copy aberrations of core regulator genes which enable adaptation to CIN and aneuploidy and also modulation of their proliferative potential.
We still have no consistent picture about the evolutionary forces involved in cancer development and progression. However, recent progress reported here and by others and future work combining computational analysis of larger and larger data sets with targeted experimentation will help to better understand what really drives cancer.
Innovative therapeutic and diagnostic approaches will greatly profit from taking the heterogeneity and adaptability of cancer cells promoted by CIN and aneuploidy into account.
Chromosomal instability selects gene copy number variants encoding core regulators of proliferation in ER+ breast cancer.
Cancer Res 2014 Jun 26. Epub 2014 Jun 26.
David Endesfelder, Rebecca A. Burrell, Nnennaya Kanu, Nicholas McGranahan, Mike Howell, Peter J Parker, Julian Downward, Charles Swanton, Maik Kschischo
Melanie Dargel-Feils | idw - Informationsdienst Wissenschaft
Pathogenic bacteria hitchhiking to North and Baltic Seas?
22.07.2016 | Alfred-Wegener-Institut, Helmholtz-Zentrum für Polar- und Meeresforschung
Unconventional quasiparticles predicted in conventional crystals
22.07.2016 | Max-Planck-Institut für Chemische Physik fester Stoffe
Munich Physicists have developed a novel electron microscope that can visualize electromagnetic fields oscillating at frequencies of billions of cycles per second.
Temporally varying electromagnetic fields are the driving force behind the whole of electronics. Their polarities can change at mind-bogglingly fast rates, and...
Breakup of continents with two speed: Continents initially stretch very slowly along the future splitting zone, but then move apart very quickly before the onset of rupture. The final speed can be up to 20 times faster than in the first, slow extension phase.phases
Present-day continents were shaped hundreds of millions of years ago as the supercontinent Pangaea broke apart. Derived from Pangaea’s main fragments Gondwana...
Scaffolding and specialised workers help with the delivery – Heidelberg biochemists gain new insights into biogenesis
A type of scaffolding on which specialised workers ply their trade helps in the manufacturing process of the two subunits from which the ribosome – the protein...
Scientists at the Helmholtz Zentrum München have developed a new mass spectrometry imaging method which, for the first time, makes it possible to analyze hundreds of metabolites in fixed tissue samples. Their findings, published in the journal Nature Protocols, explain the new access to metabolic information, which will offer previously unexploited potential for tissue-based research and molecular diagnostics.
In biomedical research, working with tissue samples is indispensable because it permits insights into the biological reality of patients, for example, in...
Chemists at the University of Basel have succeeded in using computer simulations to elucidate transient structures in proteins. In the journal Angewandte Chemie, the researchers set out how computer simulations of details at the atomic level can be used to understand proteins’ modes of action.
Using computational chemistry, it is possible to characterize the motion of individual atoms of a molecule. Today, the latest simulation techniques allow...
15.07.2016 | Event News
15.07.2016 | Event News
11.07.2016 | Event News
22.07.2016 | Information Technology
22.07.2016 | Physics and Astronomy
22.07.2016 | Life Sciences