12 Dec Some Anti-Tumor Drugs May Promote Delayed Aggressive Cancers
Alexandra Avgustinova PhD
Postdoctoral fellow at the Institute for Research in Biomedicine (IRBBarcelona)
MedicalResearch.com: What is the background for this study?
Response: The basis of this study was the strong association between closed chromatin and high mutation rate reported several years ago. We were surprised to see this observation being widely interpreted as a causal association, as it was largely based on correlative studies without experimental backing. Therefore we decided to experimentally test for the first time whether indeed altering chromatin opening would affect mutation rate or distribution within tumours.
MedicalResearch.com: What are the main findings?
Response: We found that, despite significantly increasing chromatin opening, loss of the histone methyltransferase G9a did not have any major influence on the mutation rate or distribution within cutaneous squamous cell carcinomas. These results demonstrate that chromatin opening does not play a major role in determining the mutation rate within tumours, and we speculate that other, confounded factors (e.g. replication timing or H3K36me3 levels) are likely causal for the observed association. This, however, remains to be proven experimentally.
Another major conclusion of our study was that although tumour initiation was delayed and tumour burden decreased in the absence of G9a, the tumours that did develop were highly aggressive due to selection for more aggressive tumour clones. This finding was contrary to many published reports suggesting G9a as a good candidate for clinical targeting, highlighting the need for long-term follow-up in pre-clinical studies.
MedicalResearch.com: What should readers take away from your report?
Response: One important message is that correlation does not mean causation. Specifically, we show the common assumption that chromatin opening is a strong causal determinant of mutation rates to be incorrect. This specific finding is important for the fields of oncology and cancer genomics, but the general message applies for scientific reports in general – associations cannot be assumed to be causal until experimentally proven to be so. It is our responsibility as scientists to clearly state the limitations of our data, but also practice caution when(over-)interpreting published reports.
The second take home message is that long-term follow up is absolutely critical in pre-clinical studies. Had we terminated our tumourigenesis experiment after we observed thatloss of G9a delayed tumour onset and decreased tumour burden, our conclusions would have been fundamentally different. Like many other studies we would have concluded that G9a is an epigenetic modifier whose clinical targeting could benefit patients. Without the long-term follow-up we performed, we would have completely missed out on a major and clinically relevant finding: the tumours that do form following loss of G9a are more aggressive than those carrying functional G9a. Hence, clinical inhibition of G9a may actually select for more aggressive disease. Therefore we recommend pre-clinical trials to include along-term follow-up period as standard.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Epigenetic modifiers are multifaceted in their roles and hence can have hugely pleiotropic effects on cell biology. Therefore their clinical inhibition can have unforeseen consequences on tumour biology (as is the case in our study). Thus we urge for caution when assessing the suitability of epigenetic modifiers for clinical intervention: pre-clinical studies have to take into account potential effects on e.g. DNA integrity, repair, mutation rates, cell survival and many more.
Further, we demonstrate that including long-term follow-up studies is critical. As detailed above, had we not included a long-term follow-up period in our tumourigenesis study, we would have concluded (like many others) that clinically targeting G9a would likely be beneficial for patients. Long-term follow-up demonstrated that, contrary to expectations, loss of G9a ultimately selected for more aggressive disease. We would in fact not recommend the blanket use of G9a inhibitors in a clinical setting.
MedicalResearch.com: Is there anything else you would like to add?
Response: The field of cancer genomics has boomed in recent years with the advent of more advanced and affordable sequencing technologies. Fast progress has been driven by many exciting, and sometimes unexpected discoveries. However, we believe there is a growing need for studies at the intersection of cancer genomics and experimental cancer research to realize the full potential of both fields. Tightly intertwining computational methods with experimental validation presents and opportunity for unprecedented investigative power in a growing scientific field.
Alexandra Avgustinova, Aikaterini Symeonidi, Andrés Castellanos, Uxue Urdiroz-Urricelqui, Llorenç Solé, Mercè Martín, Ivan Pérez-Rodríguez, Neus Prats, Ben Lehner, Fran Supek and Salvador Aznar Benitah
Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours.
Nature Cell Biology (2018).DOI: 10.1038/s41556-018-0233-x
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