Abstract
The large majority of driver mutations were shared within all metastases from each patient.
Major finding: The large majority of driver mutations were shared within all metastases from each patient.
Approach: Cancer phylogenies were inferred from 76 treatment-naïve metastases from 20 patients with diverse tumors.
Impact: A single biopsy may be sufficient to guide therapeutic selection in patients with widespread metastases.
In primary tumors, genomic heterogeneity is associated with relapse. However, heterogeneity has not been comprehensively evaluated in treatment-naïve metastases, even though most cancer-related deaths are caused by metastases. The evolutionary dynamics of metastases remain poorly understood, and it is not clear if the same driver gene mutations that are found in primary tumors are also present in metastases. If these mutations are heterogeneous, precision approaches would be more challenging and would require multiple biopsies from distinct sites. To determine the extent of driver gene mutation heterogeneity in metastases, Reiter, Makohon-Moore, Gerold, and colleagues analyzed sequencing data from 76 treatment-naïve metastases from 20 patients with cancer, including patients with breast, colorectal, endometrial, gastric, lung, pancreatic, and prostate cancers and melanoma. Two patients with hypermutated tumors were excluded from further analyses. Nonsynonymous mutations were divided into putative driver gene mutations and passenger gene mutations. Cancer phylogenies were inferred, with mutations present in all metastases termed the “trunk” and those present in a subset termed “branches.” The trunks were enriched for driver gene mutations, although in 12 of 18 patients there were some driver mutations not present in all metastases. However, despite the heterogeneity, the large majority of driver gene mutations were present in all metastases of each individual patient, and the driver mutations not present in all of a patient's metastases were predicted not to have functional consequences. Mathematical modeling of tumor evolution and the development of metastasis suggested that the majority of metastases were driven by the same mutation as the primary tumor. These findings provide insight into the development of metastases and suggest that a single biopsy may provide information to guide therapeutic selection in patients with widespread metastatic disease.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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