The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research. Previously known as our Top 10 Cancer Research Publications, it is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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Drews, R.M., Hernando, B., Tarabichi, M. et al. Nature 606, 976–983 (2022).
doi: 10.1038/s41586-022-04789-9.
Summary of findings
Chromosomal instability (CIN) is an umbrella term used to describe the accumulation of large-scale losses, gains and rearrangements of DNA. The broad genomic complexity caused by CIN is a hallmark of cancer; however, until now there has been no systematic framework to measure different types of CIN and their effect on clinical phenotypes across different cancer types. In our publication we evaluated the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We presented a compendium of 17 copy number signatures that characterised specific types of CIN, with putative aetiologies supported by multiple independent data sources. Labelled CX1 to CX17 according to pan-cancer prevalence, the signatures measure the four main drivers of CIN in human cancers: errors during mitosis (CX1, CX6, CX14), failures in DNA repair (CX2, CX3, CX5, CX10), replication stress (CX8, CX9, CX11, CX13) and tolerance of whole-genome duplication (CX4). We showed the signatures to be predictive of drug response and able to identify new drug targets, reporting 44 potential drug response biomarkers and 49 new drug targets. Of particular therapeutic importance are three signatures indicative of problems with homologous recombination repair (CX2, CX3, CX5), which allowed us to define different levels of impaired homologous recombination (IHR). In its extreme form, IHR becomes clinically relevant as well-known homologous recombination deficiency (HRD), but we found that less severe forms of IHR also leave their telltale marks in many other cancers. This extension to the classical HRD model allowed us to predict response to platinum-based chemotherapies by dividing patients into non-clinically-relevant IHR and clinically-relevant IHR. Taken together, our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.
