NcXHF

MOLECULAR GENETIC PROFILING IN PEDIATRIC ONCOLOGY
FIGURE 1. Clonal Evolution of Relapsed Disease in ALL
A pre-leukemic stem cell (LSC; light blue) gives rise to frank ALL (dark blue cells).
Intrinsically, drug-resistant clones (red) may be present and detected at diagnosis at low
levels in approximately 34% of cases. However, relapse might emerge from an ancestral
clone or LSC (52% of cases). LSCs and other subclones may survive initial treatment and
may acquire additional lesions that result in acquired drug resistance and relapsed disease
(52% of cases). Rarely, relapse clones are genetically distinct from that at diagnosis
(second malignancy; 6% of cases). 33,45 .
resistant subclones either through gatekeeper mutations that
interfere with drug-target interaction or off-target resistance
through activation of biologic pathways that bypass the
mechanism of therapeutic targeting. Based on analysis of
samples at relapse, the development of next-generation
agents that accommodate gatekeeper mutations and dual
pathway inhibitors have shown greater effıcacy, yet the enormous
repertoire of tumor subclones is likely to be an ongoing
issue. In this regard, the nonspecifıcity of conventional
agents may prove to be an advantage when given with targeted
agents.
CURRENT CLINICAL EXPERIENCE WITH PEDIATRIC
TUMOR SEQUENCING
NGS is now being rapidly incorporated into clinical laboratory
settings, 35 which have resulted in the fast growing fıeld of
genomic medicine. More often WES is being performed as
approximately 85% of disease-causing mutations reside in
coding regions of the human genome. 36 This has led to multiple
recent studies that reported on the implementation of
these tests as well as the evaluation of the clinical utility that
exome data can provide in pediatric oncology populations. In
a study that examined obtaining informed consent for clinical
WES in newly diagnosed solid tumors, 83% of eligible
families choose to participate, allowing analysis of both tumor
and germ line DNA. 37 No signifıcant differences in enrollment
were seen based on race, ethnicity, use of
interpreters, or language of consent forms. Additionally, no
difference in enrollment was seen based on tumor type or
availability of specimens. Of those families that chose to decline,
the most commonly stated reason was being overwhelmed
by the new diagnosis. Furthermore, of the 83% of
patients that consented to the study, clinically relevant mutations
were identifıed in 28% of tumor cases (22 of 80
cases). 38 Similar data were obtained by another group profıling
high-risk and refractory pediatric solid tumors. 39 Using
targeted NGS, Sequenom assay or array comparative
genomic hybridization individualized cancer therapy recommendations
were made in 30% of cases based on profıling
results.
In addition to WES, targeted NGS panels are currently being
developed that are specifıcally tailored to capture cancerrelated
genes and introns of genes commonly rearranged in
pediatric tumors. The hybridization capture assay currently
offered by Foundation Medicine, which can be completed in
14 to 17 days, surveys 236 genes and 47 introns of genes commonly
involved in chromosome translocations. Recent analysis
of 400 cases profıled by this method, consisting of both
solid and hematopoietic tumors, showed 60% of samples obtained
at least one alteration associated with a FDA-approved
or experimental therapy in an open clinical trial. 40 Although
these studies show that sequencing can lead to therapeutic
decisions, additional research is still needed to determine the
effect NGS has on overall survival and outcome.
Although most WES studies have focused on somatic variants,
germ line data is also routinely profıled in pediatric tumors
in tandem to provide an analysis of pathogenic mutations in
cancer susceptibility genes as well as mutations present in
nononcogenic-related diseases. In a large study surveying 565
genes in 1,120 pediatric cancers, 8.6% of patients were found to
have a pathologic or likely pathologic germ line variant. 41 Likewise,
14% of cases harbored a predisposing pathogenic mutation
in the germ line DNA in 80 solid tumor cases mentioned
previously. 38 This demonstrates that the number of pediatric
cancers caused in part by inherited variation may be much
higher than anticipated previously, and in many of these cases a
family history was not suggestive of a predisposition. Additionally,
the discovery of unanticipated incidental germline fındings
raises a considerable debate about the return of such information
to patients. 38 Early recommendations included mandatory
return of germ line results on 56 genes associated with 24 inherited
conditions, but an early revision of this policy is that patients
may opt out from receiving such information. 42
CLINICAL TRIALS OF PRECISION MEDICINE:
PEDIATRIC IMPACT
Given all the challenges discussed, the true effect of precision
medicine on patient outcome remains uncertain. It is noteworthy
that from 2002 to 2014, 71 agents were approved for use in
adult solid tumors, with many qualifying as targeted agents. Although
there were striking exceptions, the median improvement
in progression-free survival and overall survival was 2.5
months and 2.1 months, respectively. 43 In this context, careful
clinical trials that rigorously incorporate NGS would seem to be
essential before routine adaptation of this approach at individual
centers that treat pediatric oncology patients. Although
N-of-1 protocols and molecular tumor boards may add value,
the true effect of precision medicine is best measured when bio-
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