Abstract
In lung cancer, brain metastasis was associated with somatic amplification of MYC, YAP1, or MMP13.
Major Finding: In lung cancer, brain metastasis was associated with somatic amplification of MYC, YAP1, or MMP13.
Concept: Overexpression of any of these genes in mouse xenograft models increased brain metastasis.
Impact: This work identified metastasis contributors using methods that could be applied to other cancers.
Somatic mutations are known to contribute to the formation of primary tumors, but whether they are involved in the development of brain metastases, a major cause of mortality in lung adenocarcinoma, is not known. To investigate this, Shih, Nayyar, and colleagues used a case–control approach, evaluating somatic copy-number alterations in patients with brain-metastatic lung adenocarcinoma versus those with primary lung adenocarcinoma. Analysis of whole-exome sequencing data from the two patient cohorts revealed evidence of positive selection for homozygous deletion of a genomic region containing CDKN2A/B as well as amplification of multiple regions—including one containing the proto-oncogene MYC and another containing the Hippo-pathway gene YAP1 and the metalloproteinase-encoding gene MMP13—in the cohort with brain-metastatic disease. Interestingly, YAP1 amplification was not observed in cases harboring oncogenic KRAS mutations, providing further evidence supporting the prior finding that YAP1 overexpression can replace KRAS activity in KRAS-dependent lung cancer cells. Sequencing of matched primary tumors and brain metastases supplied further confirmation of the contribution of positive selection for amplification of the candidate drivers MYC, YAP1, and MMP13 to brain metastasis. Finally, in xenograft mouse models of lung adenocarcinoma metastasis, overexpression of MYC, YAP1, or MMP13 substantially increased the incidence of brain metastasis without increasing total tumor burden, indicating the functional relevance of the amplification of these genes observed in patients with brain-metastatic disease. Together, these results nominate MYC, YAP1, and MMP13 amplifications as drivers of brain metastasis in lung adenocarcinoma, providing the basis for further research on the prevention and treatment of this often fatal complication. Additionally, this study demonstrates that large-scale genomic analysis is a useful strategy to uncover contributors to metastasis.
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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