Genomic markers of brain metastasis risk identified in NSCLC
medwireNews: Researchers have identified key genomic alterations in brain metastases matched to primary non-small-cell lung cancer (NSCLC) that could serve as prognostic markers and potential therapeutic targets.
Likun Chen, from Sun Yat-Sen University Cancer Center in Guangzhou, China, and colleagues used next-generation sequencing to target 416 cancer-relevant genes in lung and brain metastasis samples from 61 Chinese patients with primary NSCLC.
They found that mutations in major driver genes, including EGFR, KRAS, and TP53, were highly concordant between the primary NSCLC and matched brain metastases, with rates of 92%, 82%, and 83%, respectively.
In 48% of the patients all the mutations identified in the primary NSCLC were also found in the matched brain metastases samples, with the exact same mutation profile in the primary and metastases samples found in 11 (18%) of 61 participants.
Eighteen (30%) patients had unique mutations in brain metastases in addition to those shared with the primary lung tumor, while eight (13%) patients had additional mutations found only in the lung. A further 17 (28%) patients had unique mutations to both the primary and brain metastases as well as the shared mutations, whereas seven (11%) patients had unique mutational profiles in their lung and brain lesions with no shared mutations.
“NSCLC [brain metastases] demonstrated an increased tumor mutation burden in comparison with primary NSCLC,” say the researchers, “and the observed genetic divergence reflects the distinct genetic evolution of [brain metastases] and provides evidence for the need to identify clinically relevant targets and therapeutic interventions for NSCLC metastatic brain tumors.”
Copy number variations were also significantly more common in brain metastases, with a median proportion of 0.135 versus 0.03 in the lung.
“Together, these data are consistent with the hypothesis that genome instability drives tumor progression and metastasis,” comment the researchers in Cancer.
Chen and colleagues also found that changes in genes encoding cell-cycle regulators, including cyclin-dependent kinases (CDKs), CDKN2A/2B, and retinoblastoma 1, were significantly more common in brain metastases than primary tumors.
Similarly, components and negative regulators of phosphoinositide 3-kinase (PI3K) signaling were significantly altered in brain metastases versus primary tumors, and regression analyses corrected for baseline clinicopathologic parameters found that patients with an activated PI3K pathway were alive and free from brain metastases for a significantly shorter time than those with wildtype PI3K, with a hazard ratio of 8.49.
These data “reinforce the association of the PI3K signaling pathway with increased [brain metastases] risk and highlight potential druggable mutations in NSCLC [brain metastases],” say the researchers.
“[O]ur findings have yielded detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched [brain metastases],” they conclude.
By Catherine Booth
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