It has long been recognized that cancer is a genetic disease that arises when a cell develops mutations in key genes that govern cell behavior. The discovery of such cancer-causing mutations has provided tremendous insight into the process of carcinogenesis and led to numerous important diagnostic, prognostic, and therapeutic applications.
But the search for cancer-causing mutations has been hampered by substantial technologic barriers. For decades investigators have had the tools to search cancer cells for gross genomic aberrations, such as chromosome translocations and gene amplifications, or search them selectively for mutations in a handful of genes of interest. The ability to assess the entire cancer genome at the sequence level has been absent.
Advancements in sequencing technologies, facilitated by the completion of the reference human genome, have led to a new era in cancer investigation in which entire cancer genomes are searched for cancer-causing mutations. Although this remains a costly endeavor, the potential benefit may change the landscape of cancer care in the near future. To date, a near-complete cancer genome sequencing focused on the coding sequences of all known human genes has been achieved for a handful of adult malignancies (breast, colon, glioblastoma).
Currently, additional adult cancers are being sequenced using "next-generation sequencing" that also includes noncoding genomic regions. These studies are beginning to yield catalogues of somatic mutations for individual cancers, identify the principal biopathways disrupted, and provide insight into the mechanisms of mutagenesis for these cancers.
Pediatric cancers have not been included in the sequencing pipeline even though they are a major cause of death during childhood. But pediatric cancer is far less common than adult cancer, so fewer resources are available to study them. The genetic aberrations and preferred signaling pathways involved in pediatric cancers are likely to differ from adult carcinomas, so it has become imperative that global genomic sequencing be applied.
The global sequencing project for neuroblastoma is a collaboration between the Children's Oncology Group (COG) and investigators at the Children's Hospital of Philadelphia (CHOP), Johns Hopkins University in Baltimore, and Texas Tech University Health Sciences Center in Lubbock. I will serve as the principal investigator for this project. The first phase of this study is supported with a $500,000 grant from St. Baldrick's Foundation (see Did You Know box).
The mysteries of neuroblastoma
Neuroblastoma is a common solid tumor that arises in the developing peripheral nervous system. Although some children have localized tumors that are curable with surgery and/or outpatient chemotherapy, the majority present with locally invasive or metastatic tumors that behave aggressively. Despite intensive treatments that include chemoradiotherapy, stem cell rescue, and bioimmunotherapy, the prognosis for such children remains dismal, with the majority dying from tumor progression.
Studies of the gross genomic aberrations that occur in neuroblastoma led to the discovery of amplification of the MYCN oncogene in the early 1980s. This anomaly is found in 20% to 25% of all neuroblastomas and is highly correlated with an aggressive tumor and poor treatment outcome.
Further work by investigators worldwide has established other genomic hallmarks of high-risk neuroblastoma, including segmental chromosomal aberrations involving chromosome arms 1p, 3p, 11q, 17q, and others. Despite the recognition that distinct patterns of genomic aberrations correlate with diverse tumor behavior, no causal cancer genes or treatment targets other than MYCN have emerged from these studies.
Instead, a candidate gene approach, informed by linkage studies with rare neuroblastoma-prone families, led to the recent discovery of the ALK kinase as a neuroblastoma oncogene. Germline ALK mutations are responsible for the majority of familial neuroblastomas, while somatic mutations or gene amplifications arise in up to 20% of sporadic tumors. The finding of a potential therapeutic target such as ALK among the fewer than 200 genes sequenced in neuroblastoma to date offers hope that many other cancer genes and potential therapy targets will be discovered from the more than 20,000 genes not yet investigated.