ALK MUTATIONS IN NEUROBLASTOMA

NEW YORK (Reuters Health) - Deep-sequencing techniques can identify ALK mutations in neuroblastoma patients that conventional sequencing may miss, new findings show.

"Our findings provide proof of principle that the systematic application of new, more sensitive deep sequencing techniques in neuroblastoma is of clinical interest and should be considered on diagnostic samples," Dr. Gudrun Schleiermacher of the Institut Curie in Paris and her colleagues write in the Journal of Clinical Oncology, online July 28.

Point mutations in the tyrosine kinase domain of ALK are the most common mutations in neuroblastoma, and ALK inhibitors are under investigation for treating the disease, the researchers note.

While ALK mutations are found in 8% to 10% of neuroblastoma patients at diagnosis, they add, their frequency at relapse has not been studied. "Recently a relapse-specific ALK mutation has been described, correlating with unresponsiveness to therapy and indicating that the determination of the ALK status at progression is critical," Dr. Schleiermacher and her colleagues write.

To investigate the frequency of ALK mutations at relapse, the researchers looked at 54 paired diagnosis-relapse samples from patients with neuroblastoma. Using Sanger sequencing, they searched for ALK mutations, and if they identified an ALK mutation in one sample, the researchers used more than 100,000X deep sequencing to search the area in the other sample.

Nine patients had ALK mutations at diagnosis, all of whom had the same mutation at relapse. Five additional patients had ALK mutations identified only in the relapse samples with Sanger sequencing. In four of these patients, the researchers probed the corresponding diagnostic sample with deep sequencing, which revealed no ALK mutation in two patients. One of the patients had an ALK mutation that was identified at the subclonal level, while the other had a different ALK mutation at diagnosis from the one found at relapse, but both mutations resulted in the same amino acid changes.

"ALK mutations should be searched for not only at diagnosis but also at relapse when considering ALK-targeted therapies," Dr. Schleiermacher and her team state. "Thus, although clinicians historically have been reluctant to prescribe invasive procedures for relapse in high-risk neuroblastoma, our findings implicate a change of medical practice in favor of tumor sampling even at relapse, and repeated tumor sampling should become a new standard of care."

SOURCE: http://bit.ly/1kWg7g2

J Clin Oncol 2014.