Genetic changes play an important role in the development of childhood tumors. There are three main categories of genes affected: proto-oncogenes, tumor suppressor genes, and DNA repair genes. Mutations in tumor suppressor genes like RB1 and TP53 can lead to cancers due to a loss of control of cell proliferation. Activation of proto-oncogenes also contributes to childhood cancers like leukemias and solid tumors. Molecular diagnostic techniques can identify genetic alterations that provide prognostic and therapeutic insights for managing childhood cancers.

1. Presented by-
Dr. Jheelam Biswas
Intern doctor
Department of pediatrics surgery
ShSMCH

2. An important development in cancer research
over the past 2 decades has been the
recognition that genetic changes drive the
pathogenesis of tumors of both adulthood
and childhood. These changes can be
inherited or somatic. However genetics plays
an important role in the development of
different types of tumors in childhood.

3. In the pathogenesis of childhood tumors 3
principal categories of genes are mainly
affected. They are:
1. Proto-oncogenes,
2. Tumor suppressor genes,
3. DNA repair mechanism

4.  Inactivation of tumor suppressor genes, whose
products normally provide negative control of
cell proliferation, contributes to malignant
transformation in various cell types. For
example-
 In the inherited form of retinoblastoma, the first
mutation of RB1 is present in the germline; an
early onset and a high

5. frequency of bilateral disease characterize these
cases.
•For another example, TP53 gene blocks cell
division at the G1 phase of the cell cycle to allow
DNA repair. But germline mutation in this gene
leads to development of various types of cancers
like sarcomas, breast cancer, brain tumors,
adrenocortical cell carcinoma, and acute
leukemia.

6.  Activation of proto-oncogenes is a common
theme in childhood leukemias and solid tumors.
Transcription factors (proteins that bind to the
regulatory sequences of target genes) compose
the largest class of oncogenes identified in
pediatric tumors.
 In B-progenitor acute lymphoblastic leukemia
(ALL), acute myeloid leukemia

7. (AML), and non-Hodgkin lymphoma (NHL),
and certain solid tumors, translocations fuse
discrete portions of 2 different genes to create
chimeric transcription factors with oncogenic
properties.
Alternatively, in T-cell and B-cell acute leukemia,
transcription factor genes are dysregulated by
their juxtaposition with transcriptionally active T-
cell receptor (TCR) or immunoglobulin (IG)
genes.

8. Effective clinical management of childhood solid
tumors depends on the clinical diagnosis and
effective diagnostic investigations. Recently,
molecular diagnostic techniques have had an
important role in ensuring diagnostic
accuracy. The identification of molecular
alterations has important prognostic and
therapeutic implications.

9.  Rahabdomyosarcomas are the tumor
originated from skeletal muscle cells. They
mostly contain 1 of 2 recurring translocations,
namely, the common t(2;13)(q35;q14) or the
rare t(1;13)(p36;q14). Both translocations
disrupt the FKHR gene, which encodes a
widely expressed transcription factor.
 The t(2;13) fuses part of the PAX3
transcription factor gene to FKHR

10.  encoding a Pax3-Fkhr chimeric protein,
whereas the t(1;13) creates a Pax7-Fkhr
protein. they enhance activation of target
genes that include antiapoptotic Bcl-xl and
suppress expression of TGFa2, FTI1, PDGF,
and IGF1 receptors.
 Reverse transcriptase–polymerase chain
reaction (RT-PCR) assays have been
developed to detect the chimeric transcripts
resulting from these fusion events.

11.  Such tests are both specific and sensitive,
enabling the detection of transcripts in as few
as one tumor cell per 100,000 normal cells
and identifying transcripts in cases that are
not amenable to standard cytogenetic
analysis.
 Clinically, tumors expressing Pax7-Fkhr are
associated with favorable features, and the
prognosis for patients with patients with these
tumors is better than that of patients with
Pax3-Fkhr –positive tumors.

12.  More than 90% of Ewing tumors are
characterized by the EWS-FLI1 fusion gene
formed by the t(11;22) or by variant EWS
fusions caused by the t(21;22) or the t(7;22).
The t(11;22) produces a chimeric transcription
factor that includes the transcriptional
transactivation domain of EWS fused to the
DNA binding domain FLI1; this factor is
presumed to function by the aberrant
activation of target genes.

13.  RT-PCR and fluorescence in situ hybridization
assays for this fusion have been useful in
distinguishing Ewing sarcoma from other
small round cell tumors.
 The precise t(11;22) breakpoint location has
recently been demonstrated to have possible
prognostic significance. Two studies suggest
that the more common type of breakpoint
(designated type I) is associated with a
favorable outcome.

14.  Neuroblastoma is characterized by gene
amplification, tumor suppressor inactivation, and
alterations in gene expression. The identification
of genetic alterations in this disease greatly
improves risk assessment.
Amplification of the MYCN oncogene, located on
chromosome 2, band p24, occurs in about one
fourth of tumors and is associated with advanced
stage and rapid disease progression.

15. In addition, MYCN amplification is a powerful
predictor of outcome independent of stage
and age and is therefore a factor used to
assign patients to more intensive
therapies. Loss of heterozygosity of the
short arm of chromosome 1 is also
associated with an unfavorable outcome, a
finding suggesting that a tumor suppressor
gene may be located in this region. Gain of
all or part of chromosome 17 is the most
common

16. molecular finding although only unbalanced
gains results in poor prognosis.
 Finally, expression of neurotrophin receptors
is highly correlated with both biologic and
genetic features. For example, high TRKA
expression is correlated with a lack of myc
amplification and a favorable outcome.
 Correlation of both clinical and genetic factors
provides the appropriate intensity of therapy
for each group of patients.

17.  Osteosarcomas arise from primitinve bone
forming cells. inactivation of tumor
suppressor genes likely plays a role in the
development of this tumor. Patients with
germline mutations of either TP53 or RB1
are at increased risk of developing
osteosarcoma, and loss of heterozygosity
(LOH) at the sites of these genes (17p and
13q) is a frequent finding in tumors.

18.  Recently, increased expression of the growth
factor HER2 has been associated with a poor
response to chemotherapy and a worse
outcome in osteosarcoma, providing both a
prognostic marker and potential therapeutic
target.

19.  Various tumor suppressor genes are implicated
in the development of childhood brain tumors,
including TP53 in brainstem gliomas and the
PTEN gene in glioblastoma multiforme.
 The following are suggested prognostic
indicators of glioblastomas and other
gliomatous subtypes: p53 mutation and
expression, overexpression or

20. amplification of EGFR, CDKN2A alterations
and deletion, and MDM2 amplifications.
MDM2 is the key to maintaining proliferation
and apoptosis. LOH of 10q leads to a shorter
survival in glioblastoma multiforme and LOH
of 1p and 19q may afford more favorable
prognosis.

21.  Wilm’s tumors originates from the nephroblast
cells. Although more than 95% of Wilms tumor
cases are sporadic, this disease can also occur
in the context of congenital anomalies or as part
of a familial predisposition syndrome. Patients
with congenital anomalies or a family history
often have bilateral tumors and are diagnosed
at an earlier age, indicating the germline loss of
a tumor suppressor gene in these children.

22.  Cytogenetic studies of patients with Wilms
tumor demonstrated the importance of the
11p13 band in the development of it. This led
to the cloning of the WT1 tumor suppressor
gene. WT1 encodes a transcription factor that
is important in normal kidney development
and functions as a classic tumor suppressor.
 Mutations of WT1 are detected in minority of
Wilms tumor cases, suggesting that other
genes are involved.

23.  Aberrant expression of genes located at 11p15,
such as H19, IGF2, and p57, as well as other
loci, are also likely involved in tumorigenesis. In
addition, a large number of anaplastic histology
Wilms tumors contain p53 mutations.
 A significant correlation of WT1 mutations and B
catenen mutations (a cellular adhesion protein)
has been noted. Loss of heterozygosity for 16q,
1p, and 22q are associated with adverse
outcomes.

24.  Syndromes associated with Wilms tumor
include Beckwith-Wiedemann syndrome
(BWS) (prenatal and post natal gigantism,
microglosia, abdominal wall defect, and
hemihypertrophy) Denys-Drash syndrome
of renal failure and genitourinary (GU)
anomalies, and WAGR syndrome (Wilms
tumor, aniridia, GU anomalies, and mental
retardation).

25.  Imprinting studies suggest that increased
expression of paternally derived growth-
promoting genes(potentially IGF2) or
decreased expression of maternally derived
suppressor genes (possibly H19 or p57) lead
to this condition.

26.  Characterization of the genes situated at
translocation breakpoints in childhood tumors
has provided new insights into the
mechanisms of malignant transformation.
These observations have also allowed the
development of molecular diagnostic assays,
which have had a tremendous impact on the
treatment of childhood cancer. Even these
techniques have their limitations, and full
characterization of the complex genetic

27. changes in cancer cells requires novel methods,
such as DNA microarray technology. They will
likely to lead to refinements of current
classification schemes and to help to
characterize the downstream targets of
oncogenic transcription factors. In the future,
these methods may also lead to the
development of novel therapies,including drugs
that block chimeric transcripts or that interfere
with the modulation of gene expression by
these proteins.