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Lung Cancer Brain Metastasis Genomes Marked by Recurrent Amplifications, Deletions

NEW YORK – A team of researchers from the Dana-Farber Cancer Institute, the Broad Institute, and other centers in the US, South Korea, and Austria has tracked down recurrent driver gene mutations coinciding with brain metastases in individuals with a form of lung cancer called lung adenocarcinoma.

"These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers," co-senior author Priscilla Brastianos, a researcher affiliated with the Broad Institute and Massachusetts General Hospital, and Scott Carter, from Dana-Farber, Harvard, and the Broad Institute, and their colleagues wrote.

As they reported in Nature Genetics on Monday, the researchers sequenced the exomes of dozens of brain metastases samples from individuals with lung adenocarcinoma, comparing the data to those from more than 500 primary lung adenocarcinoma exomes profiled for the Caner Genome Atlas project. Their results revealed a handful of copy number changes that were more common in the brain metastases, including MYC, YAP1, and MMP13 amplifications and CDKN2A/B deletions.

The team went on to validate those results with fluorescence in situ hybridization (FISH) data for another 105 metastatic brain tumor samples, and in mouse xenograft tumor models with higher-than-usual MYC, YAP1, and MMP13 levels.

"The candidate drivers we identified represent potential therapeutic targets for brain metastases," the authors wrote, noting that "brain metastases harboring YAP1 amplifications might represent candidates for Hippo pathway inhibitors, which are under active development."

Around half of individuals diagnosed with lung adenocarcinoma develop brain metastases, the team noted, which are particularly difficult to treat. Consequently, the group set out to find potentially targetable copy number changes that might prompt metastasis to the brain.

"The evolution of [brain metastases from lung adenocarcinoma] is a complex multistep process," the authors wrote. "Although somatic genetic alterations have been firmly established as driving primary tumor formation, it is not known whether additional genetic changes contribute to the development of brain metastasis."

For their study, the researchers dug into this process by sequencing protein-coding portions of the genome in brain metastasis samples from 73 individuals with lung adenocarcinoma, which they set alongside exome sequences from 503 TCGA primary lung adenocarcinoma tumor samples. For a subset 464 patients, they were able to set primary and matched brain metastasis samples side by side.

Compared to the primary tumors, the brain metastases were marked by a significant uptick in amplifications involving parts of the genome containing the MYC, YAP1, and MMP13 genes, along with CDKN2A/B deletions.

The same amplifications and deletions turned up in the researchers' subsequent FISH analyses of 105 metastatic tumor samples. In 98 profiled for YAP1 and MMP13 amplifications, for example, they saw nine samples that had them. MYC amplifications were even more common, turning up in 20 of 94 samples tested.

The team's subsequent experiments using mouse xenografts designed to overexpress MYC, YAP1, and MMP13 supported the notion that amplifications involving those genes could bump up the odds of lung tumor metastasis to the brain.

The authors noted that "metastasis-driving DNA alterations may not be necessary for brain metastasis formation," though results from the mouse xenograft experiments "indicate that these alterations can promote brain metastasis formation."

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