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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Z. Hu et al., Nature Genetics volume 51, pages 1113–1122(2019)
Summary of the findings
Hu et al. described a novel theoretical and analytical framework to enable quantitative in vivo measurement of the timing of metastasis from exome sequencing of paired primary colorectal cancers and distant metastases. By applying this evolutionary framework to patients with liver or brain metastases, they demonstrate that metastatic seeding commonly occurs early (17/21 patients), when the cancer is clinically undetectable (~104-108 cells or 0.0001-1 cm3), irrespective of the site of metastasis. These data suggest that some colorectal cancers are born to be bad, wherein their invasive and metastatic potential is specified early.
In order to define molecular features associated with metastasis, they further analyzed an independent cohort of 2,751 colorectal cancers with targeted sequencing data. The authors found that specific combinations of mutations (many of which arise early) that collectively promote niche independence were associated with metastasis. Since many of these mutations overlap with drivers of initiation, these data may help to explain why relatively few drivers of metastasis have been identified to date.
Implications and future outlook
This study demonstrates that human colorectal cancers can disseminate and seed distant metastases before the primary tumor is clinically detectable. Moreover, this effort identifies specific combinations of early driver mutations that are associated with metastasis. These findings challenge the long-held view that metastasis is a late event in the evolution of a cancer. Moreover, they highlight opportunities for improved patient stratification and the earlier detection of aggressive disease — for example by profiling circulating cell free DNA. Clearly not all colorectal cancers will metastasize and it will be important to identify determinants of favorable prognosis and the role of immune surveillance during disease progression.
