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Sequencing Study Sees Frequent RAS-MAPK Mutations at Neuroblastoma Relapse

NEW YORK (GenomeWeb) – In Nature Genetics, an international team led by investigators in the US, Netherlands, and France pinpointed a role for the RAS-MAPK signaling pathway in neuroblastoma relapse.

The researchers analyzed whole-genome sequencing data on diagnostic tumors, relapse tumors, and normal samples from nearly two-dozen individuals with neuroblastoma — a peripheral sympathetic nervous system cancer involving tumors in the abdomen, chest, or elsewhere.

By comparing mutation patterns at relapse with those in each patient's original tumor, the team followed the evolution of diagnostic clones and tracked down new somatic mutations at recurrence. In nearly 80 percent of the relapse tumor, it turned out, these recurrence-related mutations were predicted to activate the RAS-MAPK pathway.

Some RAS-MAPK pathway mutations turned up in diagnostic tumors and neuroblastoma cell lines, too, the study's authors explained, albeit to a lesser extent. Such findings hint that at least a subset of neuroblastoma tumors may respond to treatments targeting the RAS-MAPK pathway, such as MEK inhibitors.

"Our preclinical findings strongly suggest that MEK inhibitors may directly benefit relapsed patients who have mutations on the RAS-MAPK pathway," co-corresponding author John Maris, an oncology and childhood cancer researcher affiliated with the Children's Hospital of Philadelphia and the University of Pennsylvania's Perelman School of Medicine, said in a statement.

"Patients who relapse would need to have their tumors biopsied and sequenced to determine if they qualify for this type of personalized therapy," Maris explained, arguing that the data "hold the potential to provide the documentation necessary to recommend tumor biopsies at the time of disease relapse, in order to determine evidence-based next steps."

Although most neuroblastomas typically respond to treatment — or even regress spontaneously — the disease reappears in as many as 60 percent of patients, often in a far more treatment-resistant form, the researchers explained.

Past studies suggest that certain genetic glitches in the tumor can herald more aggressive forms of disease and poorer patient outcomes, particularly MYCN amplifications, glitches at the ALK gene locus, deletions affecting portions of chromosomes 1 or 11, or gains that involve a region on chromosome 17.

In an effort to begin documenting alterations associated with relapse, Maris and colleagues used the Illumina HiSeq 2500 or Complete Genomics sequencing platforms to tackle matched diagnostic tumor, relapse tumor, and normal lymphocyte samples from 23 neuroblastoma patients, including 21 who'd been treated with chemotherapy and eight who'd received radiation.

Some 28 percent of mutations found in primary tumors were also present in relapse tumors from the same individual, the researchers reported, noting that mutations from more prevalent diagnostic tumor sub-clones tended to persist to recurrence. The relapsed tumors harbored new mutations, too — a median of 14 deleterious single-base mutations or splice site changes apiece.

In 15 of the 23 relapse tumors, the team uncovered somatic mutations affecting RAS-MAPK pathway regulators or components such as ALK, NF1, PTPN11, or BRAF. Three more relapse tumors contained structural abnormalities expected to activate the pathway.

Seven of the relapse tumors appeared to have newly acquired RAS-MAPK glitches not present in the patient's initial tumor, the researchers reported, while diagnostic tumors contained RAS-MAPK-related mutations in 11 cases.

The study's authors found similar RAS-MAPK pathway glitches in 11 of 18 neuroblastoma cell lines. Their attempts to treat these cells lines with MEK inhibitors hinted that RAS or BRAF mutation-containing tumors were particularly vulnerable to such targeted treatment — findings they followed up with cell line-derived mouse xenograft experiments.

They cautioned that "[a] prospective clinical trial in which biopsy and next-generation sequencing are used for the selection of a targeted therapy will be required to determine the clinical implication of this newly defined genetic landscape of relapsed neuroblastoma."