NcXHF

MOLECULAR GENETIC PROFILING IN PEDIATRIC ONCOLOGY
State of the Art Discovery with Tumor Profiling in
Pediatric Oncology
William L. Carroll, MD, Elizabeth Raetz, MD, and Julia Meyer, PhD
OVERVIEW
It is an exciting era in pediatric oncology with the advent of new technologies to comprehensively characterize cancer genomes in
childhood tumors. Defining the genetic landscape of pediatric tumors has not only provided critical insight into tumor evolution, but
it has also offered promise for more effective treatment in some cases, such as Philadelphia chromosome-positive acute lymphoblastic
leukemia (ALL) and anaplastic lymphoma kinase (ALK)-mutated tumors. However, several challenges remain as the field of genomic
tumor profiling emerges. This new technology is costly, and the overall impact on survival has yet to be determined. Tumor
heterogeneity and clonal evolution have also presented challenges in the development of targeted therapy. In this article, we review
breakthroughs in gene sequencing methodology and discuss examples where genomic discoveries have resulted in the recognition of
tumor susceptibility as well as incorporation of targeted therapy. We also discuss how broad scale comprehensive tumor analyses have
demonstrated the convergence of individual genetic alterations on common relevant pathways. Although the impact of tumor profiling
is best studied within the context of rigorously designed clinical trials, there is promise that there will be growing opportunities for
the adaption of precision medicine in pediatric oncology in the future.
The Human Genome Project and technical breakthroughs
in gene sequencing methodologies have ushered in unprecedented
discoveries into the origins of human cancer.
More than 10,000 human tumors have been profıled at the
genetic and epigenetic level, and this information has been
translated into remarkable improvements in therapy for a
minority of cancers where the underlying genetic lesion/
pathway can be targeted with specifıc agents. Most of these
examples come from adult cancers, most notably in BRAFmutated
melanoma that can be treated with inhibitors like
vemurafenib and, more recently, for the small percentage of
adults with non-small cell lung cancer that contain ALK rearrangements
that can be targeted with crizotinib (originally
designed as a C-MET inhibitor). However, even before application
of high-throughput sequencing, the promise of personalized
or precision medicine was realized in the treatment
of pediatric Philadelphia chromosome-positive (Ph) acute
lymphoblastic leukemia (ALL) with the tyrosine kinase inhibitor
imatinib. 1
Currently, precision medicine has the potential to improve
outcome and decrease side effects for already curable pediatric
cancers, either in conjunction with chemotherapy or by
replacing some conventional agents (e.g., most ALLs, lymphomas,
and low-/intermediate-risk solid tumors) and may
fınally lead to better outcomes for children with high-risk tumors
where progress has been either slow or stalled (e.g.,
metastatic solid tumors, advanced neuroblastoma, many
brain tumors, acute myeloid leukemia and relapsed disease).
Although there is no doubt that there has been a great success
in terms of basic science discovery, there are many practical
biologic, technical, and fınancial hurdles that are likely
to interfere with successful full-scale deployment of this
strategy for routine treatment of pediatric patients with cancer.
2,3 This review will highlight biologic discoveries in pediatric
cancers in the context of changing treatment. The focus
will be on current opportunities as well as those on the horizon.
This review will specifıcally focus on targeted therapy in
the context of pharmacologic inhibition of a somatically altered
gene product or downstream pathway.
NEXT-GENERATION PLATFORMS AND THE COST OF
SEQUENCING INDIVIDUAL CANCER GENOMES
Current platforms are capable of performing a variety of sequencing
approaches including whole genome (single nucleotide
variations and copy number differences in all DNA
base pairs), whole exome (mutations and copy number differences
in transcribed exons—protein coding, miRNAs, and
other RNA species), RNA sequencing (gene expression,
splicing changes, fusion transcripts), as well as epigenetic differences
using Methyl sequencing (methylation differences
in DNA, likely to affect expression) and Chromatin Immu-
From the Division of Pediatric Hematology/Oncology, Department of Pediatrics, NYU Langone Medical Center, New York, NY; Perlmutter Cancer Center, NYU Langone Medical Center, New York,
NY; Department of Pediatrics, University of Utah, Salt Lake City, UT; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: William L. Carroll, MD, NYU Cancer Institute, Smilow 1207, 522 First Ave., New York, NY 10016; email: william.carroll@nyumc.org.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e601