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Researchers Identify Possible Methylation Signature for Brain Metastases of Lung Cancer

BARCELONA – Researchers from the Zhejiang Cancer Hospital in Hangzhou, China have found what they believe could be a DNA methylation signature predictive of central nervous system metastases in patients with advanced non-small cell lung cancer (NSCLC).

In a presentation at the annual meeting of the European Society for Medical Oncology in Barcelona on Friday, Zheijang researcher Yanjun Xu reported her group's work in analyzing DNA mutations and methylation to find possible biomarkers of lung cancer metastasis to the brain or the leptomeninges.

The group performed capture-based targeted sequencing to look for somatic mutations in 60 treatment-naïve advanced NSCLC patients using a panel of 520 cancer-related genes, as well as DNA methylation analyses using a methylation panel consisting of 100,000 CpG sites. The patients were split into three groups: one with brain metastases, one with leptomeningeal metastases, and the third with no metastases.

Collectively, the researchers identified 370 mutations in the lung primary lesions and 574 mutations in the brain metastases. Among them, 242 mutations were shared — of these, 128 were lung primary-specific and 332 were brain-specific. Among the mutations specific to the brain metastases, 82 percent of them were copy number variations (CNVs), which was significantly higher than the CNVs found in the primary tumors. Only 16 percent of the CNVs were found in both the lungs and the brain. The researchers also performed a pathway analysis of the genes that were only mutated in the brain and found an enrichment of genes in the PI3K-AKT and focal adhesion pathways.

In the leptomeningeal metastasis group, the researchers found a significant concordance between the driver mutations in primary lung tissue and the metastases in cerebrospinal fluid. These metastases, however, did not have a significantly larger number of CNVs than the primary tumors, Xu said.

As the researchers found that the list of mutated genes was comparable in all three patient cohorts, they next turned to DNA methylation analysis to see if they could find any markers indicating a higher likelihood of developing metastasis.

The methylation analysis revealed distinct patterns, with 268 methylation blocks being significantly differentially methylated between primary lung lesions and brain metastases. Among those, 211 blocks were hypermethylated in the brain and the remaining 57 blocks were hypermethylated in lung lesions.

When they compared methylation markers between the group with brain metastases and the group with no metastases, the researchers found 56 blocks that were differentially methylated, Xu said. When they compared the leptomeningeal metastases to the non-metastatic patients, they found 323 blocks that were differentially methylated, she added. Of these, the brain and leptomeningeal metastasis groups shared 15 methylation blocks that the researchers believe may be prognostic of central nervous system metastasis. Through a stepwise regression analysis, the team was able to narrow the signature further to six methylation blocks.

In a discussion of the Zheijang team's work, Maastricht University researcher Lizza Hendriks noted that up to 25 percent of stage IV NSCLC patients develop brain metastases, and that the key to treating these patients lies in finding a way to predict the occurrence of such metastases, and finding the molecular differences between patients who develop metastases in the brain and those who develop metastases elsewhere in the body.

She noted that because most NSCLC patients with central nervous system metastases generally don't develop other metastases, the methylation signature discovered by the Zheijang group would seem to be limited to these types of metastases, as opposed to metastasis in general. Although a larger analysis is needed, Hendriks added, this signature may be able to help predict the occurrence of metastasis before one actually forms.

She also said that the role of liquid biopsy in this population should be studied in order to determine whether tumor heterogeneity has any effect on the methylation signature, and that future studies should focus on the prevention of brain metastasis development.

Finally, Hendriks pointed to the Zheijang group's finding that brain metastases had a higher number of CNVs than the primary lung tumors, but that the leptomeningeal metastases did not. Although driver mutations didn't seem to be a significant molecular differentiator between patients with brain metastases and those without, CNVs are one way to molecularly differentiate between the two groups.