Trial Information

Characterizing the Frequency and Spectrum of ALK Mutations in Neuroblastoma

OBJECTIVES:

Primary

- To comprehensively identify and characterize the spectrum and frequency of mutations in
ALK across all neuroblastoma disease subsets using methodologies that will be resource
neutral to the Children's Oncology Group Neuroblastoma Nucleic Acids Bank.

Secondary

- To formulate genetic screening recommendations for newly diagnosed patients with or
without a family history of neuroblastoma.

- To identify the functionally relevant ALK mutations that can be pharmacologically
inhibited.

- To test for the prognostic capability of ALK alterations.

- To determine the clinical significance of ALK mutations and/or genomic rearrangements
by combining ALK mutation, amplification, and translocation data overall and within
each neuroblastoma risk group and correlating this information with clinical phenotype
(i.e., age, International Neuroblastoma Staging System stage, and International
Neuroblastoma Pathology Classification); genetic factors (i.e., ploidy, MYCN status);
and patient outcome.

OUTLINE: Tumor DNA samples are examined by mutation analysis for germline and somatic
mutations in the ALK tyrosine kinase domain. Samples are analyzed by whole genome
amplification using polymerase chain reaction and then sequenced for DNA alterations in the
entire ALK coding sequence. Samples are also examined for single nucleotide polymorphisms
(SNPs) by polymorphism analysis. Exploratory multivariable analysis is performed to test for
the prognostic ability of ALK mutations in the presence of other known prognostic variables
(i.e., age, International Neuroblastoma Staging System stage, MYCN status, International
Neuroblastoma Pathology Classification, and diploidy).

A subset of tumor DNA samples from high-risk patients will be resequenced for DNA
alterations to determine whether or not additional regions in ALK, outside of the tyrosine
kinase domain, are prone to mutations and should be sequenced in a larger panel.