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Novel Drivers of Brain Metastasis from Lung Tumors Identified

Key findings

  • This research involved whole-exome sequencing of 73 brain metastases from lung adenocarcinoma and comparison of the results with 503 primary lung tumors sequenced by The Cancer Genome Atlas
  • This approach nominated several novel candidate metastatic drivers: amplification of MYC, YAP1 and MMP13 and deletion of CDKN2A/B
  • MYC, YAP1 and MMP13 were also amplified in an independent validation cohort of 105 lung adenocarcinoma brain metastases
  • Overexpression of these three genes promoted brain metastases in patient-derived xenograft mouse models
  • The four novel drivers of brain metastasis represent potential therapeutic targets

Up to 40% of deaths from lung cancer are attributable to metastasis, and the brain is the most common metastatic site. There is an urgent need to identify treatment targets for brain metastases.

In previous work, reported in Cancer DiscoveryMassachusetts General Hospital researchers explored how brain metastases genetically evolve from diverse types of primary tumors. They performed whole-exome sequencing of 86 matched primary tumors and brain metastases, finding in 53% of cases that metastatic sites had new mutations not detectable in the primary tumor.

Priscilla K. Brastianos, MD, Naema Nayyar, Scott L. Carter, PhD, David J. H. Shih, PhD, and colleagues have now extended this research to concentrate on lung cancer. They published their findings in Nature Genetics.

Four Novel Drivers

The team performed whole-exome sequencing on 73 brain metastases from lung adenocarcinoma and compared the results with 503 primary lung tumors sequenced by The Cancer Genome Atlas. The frequency of certain alterations in known cancer genes was higher in brain metastases than primary tumors:

  • Amplification of MYC and deletion of CDKN2A/B, frequently observed in the prior sequencing study of brain metastases
  • Amplification of YAP1, which encodes the downstream transcriptional effector of the Hippo pathway and is implicated in cellular proliferation and other tumorigenic processes
  • Amplication of MMP13, which like other matrix metalloproteinases is associated with cancer-cell invasion and metastasis, including brain metastases

In a validation cohort of 105 lung adenocarcinoma brain metastases, YAP1/MMP13 was amplified in 9% of cases and MYC in 21%.

Functional Validation

Patient-derived cells overexpressing MYC, YAP1, MMP13 or a control gene were injected into the hearts of immunodeficient mice. The mice injected with cells expressing the control gene did not develop measurable brain metastases, but the incidence of brain metastasis increased in 22%–24% of the other mice.

Therapeutic Implications

The candidate drivers of brain metastasis identified in this study represent potential therapeutic targets. FDA-approved drugs that target the CDK pathway, including palbociclib and abemaciclib, are already being investigated in patients with brain metastases. Hippo pathway inhibitors are under development and might treat brain metastases harboring YAP1 amplifications.

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