1. Cancer in Children
Denise Sheer
Centre for Genomics & Child Health
Blizard Institute

2. Overview
1. Outline the common malignancies in children
2. Describe the clinical presentation, cellular origins, molecular
pathology and treatment of the embryonal tumours:
a. Wilms tumour
b. Retinoblastoma
c. Neuroblastoma
d. Medulloblastoma
3. Describe the high-risk groups for developing cancer in childhood

3. 1. Outline the common malignancies in children
Background
• Childhood cancer is rare among childhood diseases
• Leading cause of death in children
• Distinct spectrum of malignancies at different ages
• Certain childhood cancers (“Embryonal”) reflect abnormal
processes of embryonic development
• No consistent environmental factors identified
• Can be predisposed by certain genetic disorders
• This lecture – Childhood Solid Tumours

4. Surveillance, Epidemiology, and End Results Program, National Cancer Institute, USA

5. National Registry of Childhood Tumours, Progress Report 2010
Improvements in Cancer Survival

6. Adapted from Robison & Hudson (2014)
Growth
&
Development
• Skeletal
matura+on
• Linear
growth
• Emo+onal
&
social
matura+on
• Intellectual
func+on
• Sexual
development
Psychosocial
• Mental
health
• Educa+on
• Employment
• Health
insurance
• Chronic
symptoms
• Physical/body
image
Cancer
• Recurrent
primary
cancer
• Subsequent
neoplasms
Fer8lity
and
reproduc8on
• Fer+lity
• Health
of
offspring
• Sexual
func+oning
Organ
func8on
• Cardiac
• Endocrine
• GI
&
hepa+c
• Genitourinary
• Musculoskeletal
• Neurological
• Pulmonary
Childhood
and
adolescent
cancer
Health and quality-of-life issues faced by cancer survivors

7. • Heterogeneous group of rare cancers
• Usually diagnosed in children before 5 years of age
• Originate in developing tissues and organ systems
• Examples
• Wilms’ tumour
• Retinoblastoma
• Neuroblastoma
• Medulloblastoma
• Hepatoblastoma
• Rhabdomyosarcoma
• Germ Cell Tumours
Embryonal tumours
This lecture

8. Possible explanations:
• Childhood tumours arise in cells that are naturally undergoing rapid developmental
growth, with fewer brakes on their proliferation than cells in adults.
• Tumour precursor cells are negotiating crucial developmental checkpoints that are
susceptible to corruption, leading to incomplete or abnormal cellular maturation
Low mutation frequency in children’s cancer
Strachan et al.
Genetics & Genomics
in Medicine (2015)

9. 2a. Wilms’ tumour
Clinical presentation
• Tumour of the kidney, also called Nephroblastoma
• Affects 1/10,000 children
• Most often in children under 5 years,
• Usually presents as asymptomatic abdominal mass without metastasis
• Spreads by growth, or via lymphatics or blood stream
• Heritable in ~5% of patients, often bilateral; can be associated with
predisposition syndromes, e.g.
- Wilms’ tumour, Aniridia, Genito-urinary abnormalities, mental Retardation
(WAGR)
- Beckwith-Wiedeman syndrome (BWS)

10. Wilms’ tumour
Cellular Origins
• Arises from pluripotent embryonic renal precursors
• Classically contains the three cell types present in the embryonic
kidney: blastema, epithelia, stroma
• Closely resembles developing nephrogenic mesenchyme
• Expresses markers of early kidney development

11. Rivera & Haber (2005)
Histological similarity between the developing kidney and Wilms’ Tumour
Embryonic kidney Wilms’ Tumour
B: Blastema
F: Mesenchyme
E: Epithelium
M: Condensing
mesenchyme
C: Comma-shaped
body
S: S-shaped body
G: Glomerulus

12. Wilms’ tumour
Molecular pathology
• Somatic activating mutations in CTNNB1; inactivating mutations in WT1,
WTX, TP53; epigenetic abnormalities at H19/IGF2 locus
• Congenital malformations associated with germline deletions or mutations
in the WT1 gene, including WAGR syndrome, in ~6% of cases
• Congenital malformations associated with germline deletions or mutations
in the H19/IGF2 locus, including BWS syndrome, in ~4% of cases
WT1 has a key role in ureteric branching; WT1 and the WNT pathway (which
is activated by β-catenin, CTNNB1) have key roles in epithelial induction of
the metanephric mesenchyme
Rivera & Haber (2005)

13. The WT1 gene in the developing kidney and Wilms’ Tumour
Scotting et al (2005)

14. Wilms’ tumour
Treatment
• Stage,
histology
and
age
at
diagnosis
are
prognos+c
factors
• Treatment
–
surgery
then
chemotherapy
(USA),
chemotherapy
then
surgery
(Europe)
• Use
of
radiotherapy
is
decreasing
• Combina+on
chemotherapy
shows
promising
results
• Counselling
is
essen+al
if
gene+c
predisposi+on
is
suspected
Gleason
et
al
(2014)

15. National Registry of Childhood Tumours, Progress Report 2012
Improvements in survival of Wilms’ tumour patients

16. Clinical presentation
• Tumour of the retina
• Usually occurs in children under 5 years, and accounts for ~5% of tumours in
this age group
• Appears to be more prevalent in sub-Saharan Africa than rest of world
• Heritable in ~30% of cases:
- positive family history
- bilateral or multifocal
- germline mutation of RB1 gene
- usually present at a younger age
• Symptoms include leukocoria (“white pupil” when light shone into it), eye pain
or redness, vision problems
• Metastatic disease in 10-15% of patients
2b. Retinoblastoma

17. Presentation of Retinoblastoma
Leukocoria Image of fundus showing tumour
Abramson (2014)

18. Cellular origins
• Originates from cone precursor cells in which signalling pathways
suppress cell death and promote cell survival after loss of RB1
Retinoblastoma
Xu
et
al
(2014)

19. Molecular Pathology
• Whole genome sequencing shows very few genetic changes
• Loss of RB1 – key role in cell cycle regulation
• MYCN activation
• MDM2 or MDM4 amplification - leads to inactivation of p53 pathway
• SYK overexpression – required for tumour cell survival
Retinoblastoma
Zhang
et
al
(2012)

20. Treatment
• Treatment options consider both cure and preservation of sight
- Small tumours – cryotherapy, laser therapy or thermotherapy
- More advanced tumours or distant disease – chemotherapy, surgery &/or
radiation
- Systemic or intraocular chemotherapy can be used to shrink tumours before
cryotherapy or laser therapy
- Identification of SYK overexpression suggests targeted therapy approach
• Germline mutation of RB1 have increased risk of second cancer, especially if
receive radiation therapy
• Late effects include visual impairment and increased risk of secondary
malignancies, including bone and soft tissue sarcomas, and melanoma
Retinoblastoma
Abramson (2014)

21. National Registry of Childhood Tumours, Progress Report 2012
Improvements in survival of Retinoblastoma patients

22. Clinical presentation
• Tumour of the sympathetic nervous system, usually arising in the adrenal
gland or sympathetic ganglia
• Most common cancer in the first year of life
• Family history in 1-2% cases
• Metastatic disease in >50% cases at diagnosis; spreads via lymphatics
and blood stream
• Highly heterogeneous disease – extremes of risk
• Prognostic factors: stage, age, MYCN amplification, DNA ploidy,
histopathology
• Neuroblastoma 4S presents in infants, specific pattern of metastatic
disease to liver and skin, spontaneous maturation and regression without
cytotoxic therapy
2c. Neuroblastoma
Cheung & Dyer (2013)

23. Cellular origins
• Derived from the sympatho-adrenal lineage of the neural crest during
development
• The cell of origin is believed to be an incompletely committed precursor cell
The neural crest gives rise to diverse cell types including peripheral neurons,
enteric neurons and glia, melanocytes, Schwann cells, and cells of the
craniofacial skeleton and adrenal medulla
Neuroblastoma

24. Development of the sympatho-adrenal lineage of the neural crest
Cheung
&
Dyer
(2013)

25. Molecular Pathology
• High-risk
- MYCN amplification; ATRX, ALK mutations
- Near-diploid/near-tetraploid karyotype, complex chromosome aberrations
- Deletions in 1p and 11q
• Low-risk, intermediate-risk and stage 4S
- Numerical chromosome gains
• Hereditary
- Germline ALK mutations
Neuroblastoma
Multiple copies of MYCN

26. Treatment
• Surgery, chemotherapy, radiation therapy
• High risk disease – high-dose chemotherapy and stem cell
transplantation
• Chemotherapy-related complications include hearing loss,
infertility, cardiac toxicity, & second malignancies
• Targeted therapy – crizotinib against ALK mutations
• Immunotherapy
Neuroblastoma

27. National Registry of Childhood Tumours, Progress Report 2012
Improvements in survival of Neuroblastoma patients

28. Clinical presentation
• Most common malignant brain tumour in children
• More prevalent in children under 10 years than older children
• Highly invasive embryonal tumour that arises in the cerebellum
• Early dissemination throughout the CNS
2d. Medulloblastoma

29. Molecular Pathology
• WHO Classification 2007 based on histology:
- Classic – intermediate risk
- Desmoplastic/Nodular – more favourable
- Large cell/Anaplastic – very poor outcome
• Molecular subtypes involving key developmental signalling pathways:
- WNT (Wingless) – most favourable
- SHH (Sonic hedgehog) – intermediate risk
- Group 3 – worst outcome
- Group 4 – intermediate risk
Medulloblastoma
Northcott et al (2012)

30. Medulloblastoma: WHO Classification 2007
LCAClassic
Nodulardesmoplastic

31. Cellular origins
• Genetic predisposition syndromes, gene expression profiling, and
mouse models have been crucial in identifying molecular and cellular
origins
• SHH subtype originates in cerebellar granule neuron precursor cells
via aberrant activation of the Sonic Hedgehog pathway
• WNT subtype originates in lower rhombic lip cells of the dorsal
brainstem via aberrant activation of β-catenin (CTNNB1)
• Group 3 appears to originate in cerebellar granule neuron precursor
cells &/or cerebellar neural stem cells via aberrant activation of MYC
• Origin of Group 4 is unknown
Medulloblastoma
Northcott et al (2012)

32. Cerebellar development and the origins of WNT & SHH Medulloblastoma
Adapted
from
Marshall
(2014)

33. Northcott et al (2012)
WNT SHH Group 3 Group 4
Age
Distribution
Metastasis
at diagnosis
Overall
survival (5 yrs)
Proposed
origin
Driver genes
~5-10%
~95%
Lower rhombic
lip progenitor
cells
CTNNB1
DDX3X
SMARCA4
MLL2
TP53
~15-20%
~75%
CGNPs of the
EGL & cochlear
nucleus; neural
stem cells of the
SVZ
PTCH1
TP53
MLL2
DDX3X
MYCN
~40-45%
~50%
Prominin 1+,
lineage- neural
stem cells;
CGNPs of the
EGL
MYC
PVT1
SMARCA4
OTX2
CTDNEP
~35-40%
~75%
unknown
KDM6A
SNCAIP
MYCN
MLL3
CDK6
Molecular subtypes in Medulloblastoma
CGNP: Cerebellar granule neuron precursor EGL: External granule cell layer SVZ: Sub-ventricular zone

34. Treatment
• Standard treatment – surgery, cranio-spinal radiotherapy (> 3 yrs),
chemotherapy
• Long-term side effects, including developmental, neurological,
neuroendocrine, psychosocial
• Targeted treatments for molecular subgroups
Medulloblastoma

35. Development of targeted treatment in Medulloblastoma
MacDonald et al (2014)

36. National Registry of Childhood Tumours, Progress Report 2012
Improvements in survival of Medulloblastoma patients

37. 3. High-risk groups for developing cancer in childhood
Genetic predisposition to childhood cancer
• Any tumour diagnosed in the perinatal period suggests a genetic
predisposition syndrome, also tumours with certain features in older children
• Bilateral or multifocal disease, associated with congenital malformations
• Cancer in close relatives
• Same rare tumour in more than one family member,
e.g. familial Retinoblastoma
• Different types of tumours occuring in family members,
e.g. Li-Fraumeni syndrome
• Genetic counselling is essential

38. Examples of genetic predisposition syndromes for childhood cancer
Syndrome
Gene/chromosome
Tumours
Developmental
defects
WAGR
11p13
dele+on
Wilms’
tumour
Aniridia,
genitourinary
abnormali+es,
mental
retarda+on
Beckwith-­‐Wiedeman
11p15:
H19/IGF2
locus-­‐
abnormal
imprin+ng
Hepatoblastoma,
adrenocor+cal
carcinoma,
Wilms’
tumour
Overgrowth
syndrome,
macroglossia,
omphalocele,
hemihypertrophy
Mul+ple
endocrine
neoplasia,
type
2B
RET
Medullary
thyroid
carcinoma,
Phaeochromocytoma
Mucosal
neuroma,
marfanoid
habitus
Basal-­‐cell
nevus
PTCH1
Medulloblastoma;
basal-­‐cell
carcinoma,
ovarian
fibromas
Macrocephaly,
hypertelorism,
palmar
or
plantar
pits,
rib
abnormali+es,
ectopic
calcifica+on
of
the
falx
cerebri
Li-­‐Fraumeni
TP53
Brain
tumour,
bone
or
so]-­‐
+ssue
sarcoma,
adenocor+cal
carcinoma;
breast
cancer,
leukaemia
-­‐
Fam
Re+noblastoma
RB1
Re+noblastoma,
sarcoma,
melanoma;
glioma,
carcinoma
-­‐
Fam
Neuroblastoma
ALK
Neuroblastoma
-­‐
Medulloblastoma
SUFU
Medulloblastoma
-­‐

39. D.H. Abramson (2014) Retinoblastoma: saving life with vision. Ann Rev Medicine 65:171-84
N-K.V. Cheung & M. Dyer (2013) Neuroblastoma: developmental biology, cancer genomics and immunotherapy.
Nat Rev Cancer 13:397-411
J.M. Gleason et al (2014) Innovations in the management of Wilms’ tumor. Ther Adv Urol. 6:165-176
T.J. MacDonald et al (2014) The rationale for targeted therapies in medulloblastoma. Neuro-Oncology 16:9-20
G.M. Marshall et al (2014) The prenatal origins of cancer. Nat Rev Cancer 14:277-289
P.A. Northcott et al (2012) Medulloblastomics: the end of the beginning. Nat Rev Canc 12:818-834
M.N. Rivera & D.A.Haber (2005) Wilms’ tumour: Connecting tumorigenesis and organ development in the kidney.
Nat Rev Cancer 5:699-712
L.L. Robison & M.M. Hudson (2012) Survivors of childhood and adolescent cancer: life-long risks and
responsibilities. Nat Rev Cancer 14:61-70
P.J.Scotting et al (2005) Childhood solid tumours: a developmental disorder. Nat Rev Canc 5:481-488
J. Zhang et al (2012) A novel retinoblastoma therapy from genomic and epigenetic analysis. Nature 481: 329-334
X.L. Xu et al (2014) Rb suppresses human cone-precursor-derived retinoblastoma tumours. Nature 514: 385-388
If you would like more information, here are some interesting resources

40. Please contact me if you have any questions
d.sheer@qmul.ac.uk