cancer in children - denise sheer
TRANSCRIPT
Cancer in Children Denise Sheer
Centre for Genomics & Child Health Blizard Institute
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
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
Surveillance, Epidemiology, and End Results Program, National Cancer Institute, USA
National Registry of Childhood Tumours, Progress Report 2010
Improvements in Cancer Survival
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
• 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
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)
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)
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
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
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)
The WT1 gene in the developing kidney and Wilms’ Tumour
Scotting et al (2005)
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)
National Registry of Childhood Tumours, Progress Report 2012
Improvements in survival of Wilms’ tumour patients
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
Presentation of Retinoblastoma
Leukocoria Image of fundus showing tumour
Abramson (2014)
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)
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)
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)
National Registry of Childhood Tumours, Progress Report 2012
Improvements in survival of Retinoblastoma patients
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)
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
Development of the sympatho-adrenal lineage of the neural crest
Cheung & Dyer (2013)
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
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
National Registry of Childhood Tumours, Progress Report 2012
Improvements in survival of Neuroblastoma patients
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
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)
Medulloblastoma: WHO Classification 2007 LC
A C
lass
ic
Nod
ular
des
mop
last
ic
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)
Cerebellar development and the origins of WNT & SHH Medulloblastoma
Adapted from Marshall (2014)
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
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
Development of targeted treatment in Medulloblastoma
MacDonald et al (2014)
National Registry of Childhood Tumours, Progress Report 2012
Improvements in survival of Medulloblastoma patients
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
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 -‐
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
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