The EACR’s Top 10 Cancer Research Publications is a regular summary of the most interesting and impactful recent papers in cancer research. 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.
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M. Mina, A. Iyer, D. Tavernari. et al. Nat Genet 52, 1198–1207 (2020)
“This study delves into the functional relationships among genomic alterations observed in human tumors.” Elisa Oricchio, EACR Board Member
Summary of the findings
The development and progression of human tumors is driven by the continuous emergence of new alterations, such as DNA mutations. Cancer cells can harbor dozens, sometimes hundreds of alterations, a small fraction of which are believed to confer a fitness advantage. The functional effect of a given alteration can vary however in different tumors: a mutation can boost tumor cells only if originating in a specific tissue or only if another alteration is present (or absent). As a result, cancer alterations are often “paired”: some frequently observed together, while others rarely or never found in the same tumor. We termed these pairings evolutionary dependencies. Although, evolutionary dependencies exist among several cancer alterations, their effect on tumor growth and treatment is largely unknown.
Here, we designed a computational framework to integrate molecular profiles of >9,000 cancer patients with large-scale genetic screenings, which inactivate one gene at a time across multiple cancer cell lines. These analyses allowed us to infer and validate a set of functional alterations and test the effect of inactivating a gene when it is mutated alone or with specific others. Results showed that alteration pairs that we predicted to act synergistically increased the effect of single gene knock-out (Figure 1A). Conversely, alterations that we predicted to be redundant rescued the phenotype of single gene knock-out (Figure 1B). Similarly, we show that the effectiveness of a drug inactivating a specific gene does not only depend on whether or not that gene is activated in the tumor, but also by which other alterations are present.
Future impact of the findings
Precision medicine approaches in cancer are based on the principle that tumors exhibiting mutations activating specific cancer-associated genes will benefit from drugs that inactivate those genes. However, the success of these approaches is often inconsistent across patients. We argue that tumor phenotypes and response to treatment are not determined by individual and independent mutations, but by the concerted action of multiple alterations. Our study provides a framework combining computational predictions, experimental evidence and clinical data to understand the combinatorial functional effect of cancer genomic alterations.
