Cancer in children Flashcards
How many children <15 are affected by cancer in the UK?
1 in 500
What are the 3 most common types of cancer in 0-14 year olds?
- leukaemia
- CNS
- lymphoma
What are the 3 most common types of cancer in 15-19 year olds?
- lymphoma
- carcinomas + melanomas
- CNS
What kind of health and quality of life issues are faced by cancer survivors in terms of:
a. growth + development
b. psychosocial
c. organ function
d. fertility + reproduction
e. cancer
Growth + development:
- sexual development
- intellectual function
- emotional + social maturation
- skeletal maturation
- linear growth
Psychosocial:
- employment
- education
- health insurance
- chronic symptoms
- physical /body images
- mental health
Organ function:
- cardiac
- endocrine
- GI + hepatic
- genitourinary
- musculoskeletal
- neurological
- pulmonary
Fertility + reproduction:
- fertility
- health of offspring
- sexual functioning
Cancer:
- subsequent neoplasms
- recurrent primary cancer
Describe how oncogenes work, how they are activated, and give examples.
Oncogenes act by a gain of function They are dominant, therefore activation of one allele is sufficient to cause cancer Activated by: - mutation - chromosome translocation - gene amplification - retroviral insertion examples: CTNNB1, MYCN, MDM2, ALK etc etc
Describe how tumour suppressor genes work, how they are inactivated, and give examples.
Act by loss of function they are recessive (inactivation of both alleles is necessary) inactivated by: - mutations - deletions - DNA methylation (epigenetics)
Cause a predisposition to cancer
examples: RB, WT1, TP53 PTCH1, BRCA1/2
Describe Knudson’s two-hit model.
deletion or inactivation of both copies of a gene = tumorigenesis first allele is either deleted/mutated = inherited or somatic loss of function of 2nd allele via: - loss of allele - loss + duplication - chromosome deletion - mutation - recombination
What is a Wilm’s tumour? How many children does it affect? What is its usual presentation + mode of spread?
It is a tumour of the kidney (nephroblastoma)
Affects 1/10,000 children (usually under 5)
Usually presents as asymptomatic abdominal mass
Spread via lymphatics/bloodstream
What somatic genetic alterations are involved in the molecular pathology of Wilm’s tumour?
- inactivated WT1, wTX, TP53 genes
- activated CTNNB1 (beta-catenin gene)
- epigenetic alterations at IGF2/H19 locus
What germline genetic alterations are involved in the molecular pathology of Wilm’s tumour?
WT1 gene (WAGR = Wilm’s tumour, Aniridia, Genito-urinary abnormalities, mental Retardation) IGF2/H19 locus (BWS = Beckwith-Wiedeman Syndrome)
What are the cellular origins of Wilm’s tumour?
Arises from pluripotent embryonic renal precursors
Usually contains 3 cell types: blastema, epithelia, stroma
What does a bilateral Wilm’s tumour indicate?
hereditary predisposition
Why can absence of WT1 result in a Wilm’s tumour?
Prevents differentiation and maintains cells in an immature state - can lead to tumour formation
What is a retinoblastoma? What % of cases are heritable? What are the symptoms?
Tumour of the retina
Heritable in ~30% of cases (+ve family history; bilateral or multifocal; germline mutation of RB1 gene)
Symptoms = leukocoria (white pupil), eye pain, redness, vision problems
What are the cellular origins of retinoblastoma?
cone precursor cells
signalling pathways promote cell survival after loss of RB1
How does a loss of RB1 affect a cell’s cycle?
Normal cells: Phosphorylation of RB1 will release E2F which will induce G1-S transition, allowing cells to move through the cell cycle
Cancer cells without RB1: e2F will be free to induce G1-S transition
What role do MYCN and MDM2 play in the development pot retinoblastoma?
MYCN - when activated allows abnormal proliferation of cone precursors
MDM2 - when over expressed/amplified will suppress p53 = cell precursors are unable to become apoptotic
What is a neuroblastoma? What % of cases have metastasised by the time of diagnosis?
Tumour of the sympathetic nervous system - usually arising in the adrenal gland or sympathetic ganglia
> 50% of cases have metastasised at the time of diagnosis
What is significant about neuroblastoma 4S?
Metastatic disease to the liver and skin
Often shows spontaneous maturation and regression
What is the cellular origin of neuroblastoma?
Sympathy-adrenal lineage of the neural crest cells during development
What are the key genes involved int he development of a neuroblastoma?
MYCN (high risk)
ALK (high risk + hereditary)
PHOX28
Medium/intermediate risk = numerical chromosome gains
What targeted therapy is there for neuroblastoma?
Crizotinib = for ALK mutations
What is the usual clinical presentation of Acute Lymphoblastic Leukaemia (ALL)?
- Most common malignancy in children
- Most frequent cause of death from cancer <20 yr age group
Symptoms:
- bruising/bleeding
- pallor or fatigue due to anaemia
- infection due to neutropenia
- due to clonal expansion of immature lymphocytes (lymphoblast/blast cells)
What is the cellular origin of ALL?
Can be traced back to haematopoiesis
Pro-B: CD19+ on the cell surface
- this is ALL with a MLL translocation (most common)
Pre-B: CD19+ and CD10+
- this is ALL with high hyperploidy or TEL-AML1 translocation
What are some high risk groups for developing cancer in children?
- genetic predisposition = will likely develop tumour in the perinatal period
- congenital malformations = will result in a bilateral or multifocal tumour formation
- cancer is close relatives
- same rare tumour in >1 family member (e.g. familial retinoblastoma)
- different types of tumours occurring in family members (e.g. Li-Fraumeni syndrome)
