Genetic Link Found in Familial Neuroblastoma

WEDNESDAY, Aug. 27 (HealthDay News) -- Heritable mutations of the anaplastic lymphoma kinase (ALK) gene appear to be the main cause of familial neuroblastoma, a finding that may offer a therapeutic target for the disease, according to research published online Aug. 24 in Nature.

Yael P. Mosse, M.D., of the University of Pennsylvania School of Medicine in Philadelphia, and colleagues performed a genome-wide scan for linkage at roughly 6,000 single nucleotide polymorphisms in 20 families with neuroblastoma, which led them to a region on chromosome 2. Resequencing candidate genes identified three germline missense mutations in the tyrosine kinase domain of ALK that were found in eight families with the disease.

Further analysis of 194 tumor samples and neuroblastoma-derived cell lines from high-risk patients found single-base substitutions indicative of activating mutations in 12.4 percent. Knockdown of ALK messenger RNA in cells with ALK mutation or amplification resulted in marked inhibition of growth. These findings point to the likely importance of screening in unaffected children with ALK mutations, the authors write.

"The data presented here clearly establish ALK as a critical neuroblastoma oncogene and should increase efforts to identify the ligand for this receptor and to determine whether ALK-mediated signaling can be activated by mechanisms other than direct mutation and/or amplification of ALK alleles. Furthermore, receptor tyrosine kinases provide tractable targets for pharmacological inhibition, and this work should provide the impetus for developing therapeutic strategies aimed at inhibiting ALK-mediated signaling," the authors conclude.

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