Cancer Flashcards
When a proto-oncogene mutates or there are too many copies of it, it can become pathologically turned on at which point it’s now called an oncogene. What is an oncogene? Give examples
proto-oncogenes include; growth factors (signalling proteins), receptors (tyrosine kinase receptors), intracellular signalling proteins e.g. kinases, transcription factors, anti-apoptotic proteins
When any of these mutate/ get activated (by mutation, chromosome translocation, gene amplification or retroviral insertion) they get a ‘gain in function’ ( enhanced kinase activity leading to uncontrolled signalling) and become oncogenes. Oncogenes are dominant (activation of one allele sufficient).
Examples: MYCN, MDM2, ALK, ABL1, HRAS, KRAS, NRAS, BRAF
What is a tumour suppressor gene? Give examples
A tumour suppressor gene gets mutated and acts by loss of function. The mutation is recessive (inactivation of both alleles necessary).
Tumour suppressor genes are inactivated by mutations, deletions, DNA methylation (epigenetic) and they cause a predisposition to cancer
Examples: RB (Rb protein), WT1, TP53, BRCA1,BRCA2, PTCH1, APC, NF1
Explain the clinical presentation, molecular pathology, predisposition syndromes and treatment of Wilms tumour (aka nephroblastoma) seen in children
Wilms tumour (aka Nephroblastoma) is a tumour of the kidney
clinical presentation:
- children under 5 usually
- asymptomatic abdominal mass
- spreads by growth via lymphatics or bloodstream
associated w predisposition syndromes:
- WAGR: Wilms tumour, Aniridia, Genito-urinary abnormalities, mental Retardation
- Beckwith-Wiedeman Syndrome (BWS)
molecular pathology:
somatic gene alterations:
- inactivated / loss of both alleles of WT1, WTX, TP53
- activated CTNNB1 (beta-catenin) gene
treatment:
- surgery, chemotherapy
- use of radiotherapy decreasing
-combination chemotherapy is promising
- counselling is essential if genetic predisposition is suspected
Explain the clinical presentation, cellular origins and molecular pathology of Retinoblastoma seen in children
clinical presentation:
Retinoblastoma (tumour of retina)
- usually occurs in children under 5
- 30% heritable; germline mutation of RB1 (tumour suppressor gene)
- tumour grows in vitreous humor of eye
- present with leukocoria
cellular origin:
- originates from cone precursor cells
- signalling pathways promote cell survival after loss of RB1
molecular pathology of retinoblastoma:
In normal cells, phosphorylation of RB1 releases E2F, inducing G1-S; whereas in cancer cells E2F is free to induce G1-S transition
-u need both alleles of RB1 lost= MYCN activation= MDM2 or MDM4 (oncogenes) over-expression= inactivates TP53 (tumour suppressor)
treatment:
-small tumour= cryotherapy
- chemotherapy, surgery or radiation
N.B. patients w germline mutation of RB1 have increased risk of second cancer, esp. if they receive radiation therapy
Explain the clinical presentation, cellular origins and molecular pathology of Neuroblastoma seen in children
Neuroblastoma is the most common cancer in first year of life
clinical presentation:
tumour of SNS, usually arises from adrenal gland or sympathetic ganglia, family history (1-2%)
cellular origins:
-derived from sympatho-adrenal lineage of the neural crest during development
-key genes implicated: MYCN, ALK, PHOX2B
molecular pathology:
- MYCN amplification
- germline ALK mutations
treatment:
-surgery, chemotherapy, radiation therapy
- stem cell transplantation
- crizotinib against ALK mutations
Explain the clinical presentation, cellular origins and molecular pathology of Acute lymphoblastic leukaemia seen in children
Acute lymphoblastic leukaemia (ALL) is the most common malignancy in children
clinical presentation:
- bruising or bleeding due to thrombocytopaenia
- pallor + fatigue due to anaemia
- infection due to neutropenia
cellular origins
-clonal expansion of immature lymphocytes
-B and T cell leukaemias
treatment:
- induction (vincristine, corticosteroid)
- consolidation; CNS-directed treatment (Methotrexate, Dexamethasone)
- maintenance (methotrexate)
- bone marrow transplantation
define monogenic
monogenic= controlled by a single gene
define aniridia
Aniridia= congenital condition where part or all of the iris missing
What is Beckwith-Wiedeman Syndrome (BWS)
Beckwith-Wiedemann Syndrome (BWS) is a congenital overgrowth disorder characterized by a spectrum of clinical features and an increased predisposition to tumor development.
Clinical Features:
BWS presents with a wide range of clinical manifestations, which can vary significantly among individuals. Some of the hallmark features include:
- Macrosomia: Increased birth weight and length, often above the 97th percentile.
- Macroglossia: Enlarged tongue, which may interfere with breathing, swallowing, and speaking.
- Abdominal Wall Defects: Conditions such as omphalocele (protrusion of abdominal organs through the umbilical cord) or umbilical hernia.
- Hemihyperplasia: Asymmetric overgrowth of one side of the body or specific body parts.
- Visceromegaly: Enlargement of internal organs, including the liver, spleen, kidneys, adrenal glands, and pancreas.
- Neonatal Hypoglycemia: Low blood glucose levels in infancy, which can be persistent and may require medical intervention.
- Ear Anomalies: Creases or pits in the skin near the ears.
N.B. BWS IS A SPECTRUM: individuals may exhibit many of these features or only one or two.
Genetic and Epigenetic Basis:
BWS is associated with abnormalities in the imprinted gene regions on chromosome 11p15.5. These abnormalities can include:
- Loss of Methylation at IC2: Accounts for approximately 50% of BWS cases.
- Paternal Uniparental Disomy (UPD): Presence of two paternal copies of chromosome 11p15.5, leading to overexpression of paternally expressed genes.
- Gain of Methylation at IC1: Found in about 5% of individuals with BWS.
- Mutations in the CDKN1C Gene: Occur in a subset of cases and can be inherited in an autosomal dominant manner with variable expressivity.
These genetic and epigenetic alterations disrupt the normal regulation of growth-controlling genes, leading to the overgrowth and tumor predisposition seen in BWS.
Tumor Risk and Surveillance:
Children with BWS have an increased risk of developing embryonal tumors, particularly Wilms tumor (a type of kidney cancer) and hepatoblastoma (a liver cancer). Tumors develop in about 10% of individuals with BWS, usually appearing in childhood.
Regular surveillance, including abdominal ultrasound every three months until at least eight years of age and measurement of serum alpha-fetoprotein (AFP) every six weeks until at least four years of age, is recommended to facilitate early tumor detection and treatment
Which Wilm’s tumour suppressor gene has been show to be an essential regulator of ureteric development?
The Wilms’ tumor suppressor gene WT1 has been shown to be one of these essential regulators of kidney/ ureteric development and mutations in this gene result in the formation of tumors and developmental abnormalities such as the Denys-Drash and Frasier syndromes.
what do we mean by stage and grade in cancer
Stage = describes the extent or spread of cancer in the body at the time of diagnosis. It helps determine how advanced the disease is.
Grade= refers to the behavior of cancer cells/ aggressiveness of tumour
what is leukocoria and what is it indicative of?
leukocoria is an abnormal white reflection from the retina when you shine a torch; it is indicative of retinoblastoma (tumour of retina)
the tumour grows in the vitreous humor of the eye
Genetic predisposition syndromes for childhood cancer. Name the syndrome and the mutation it causes
WAGR= 11p13 deletion= Wilms tumour
Beckwith-Wiedeman= 11p15 abnormal imprinting= Hepatoblastoma, Wilms tumour
Familial Retinoblastoma= RB1 (tumour suppressor gene inactivated)= Retinoblastoma, sarcoma, melanoma, glioma, carcinoma
Familial Neuroblastoma= ALK (anaplastic lymphoma kinase) = neuroblastoma
Basal-cell nevus= PTCH1= medulloblastoma, basal-cell carcinoma, ovarian fibromas
Li-Fraumeni= TP53= brain tumour, bone or soft tissue sarcoma
define hypertelorism
Hypertelorism is a term used to describe an abnormally large distance between the eyes.
what are the 8 hallmarks of cancer?
- self-sufficiency in growth signals (autocrine signalling)
- insensitivity to anti-growth signals
- evading apoptosis
- limitless reproductive potential
- sustained angiogenesis
- tissue invasion + metastasis
- deregulating cellular energetics
- avoiding immune detection
which growth factor is closely associated with angiogenesis of cancer cells
Vascular Endothelial Growth Factor (VEGF) causes angiogenesis (blood vessel formation) to be sustained and increased around tumours
If a HER2 receptor (member of a tyrosine kinase receptor) is mutated and activated, what happens?
Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. When its mutated it is a oncogene (previously a proto-oncogene)
The activation as a result of mutation of HER2 will activate initiation of growth pathway: autophosphorylation of tyrosine= the receptor changes shape= activated= enhanced kinase (PI3K, MAPK) activity= uncontrolled signalling= tumour
N.B. HER2 IS HIGHLY ONCOGENIC AS IT DOES NOT NEED A GROWTH FACTOR TO BE ACTIVATED hence why we screen for HER2 mutations in families!
Which 2 pathways activate gene expression
PI3K (Phosphatidylinositol 3-kinase) pathway + MAPK (Mitogen-activated protein kinase) pathway activate gene expression
What is immunohistochemistry (IHC)?
This technique employs antibodies that specifically bind to antigens (proteins) of interest, when diagnosing cancer.
The antibody is conjugated to a detectable label, such as:
Enzymes (e.g., horseradish peroxidase or alkaline phosphatase): These enzymes catalyze colorimetric reactions, producing a visible signal (e.g., a brown or red stain).
Fluorescent dyes: These allow visualization under a fluorescence microscope.
Fecal occult blood tests (FOBTs) and Immunochemical Fecal Occult Blood Test (iFOBT or FIT) both take a stool sample to detect either colorectal cancer or GI bleeding. Which test is preferred due to its higher sensitivity + specificity?
- Guaiac-Based Fecal Occult Blood Test (gFOBT)= Detects both human and animal hemoglobin (non-specific). Therefore
requires dietary restrictions (e.g., avoiding red meat, certain vegetables, and vitamin C before the test). - Immunochemical Fecal Occult Blood Test (iFOBT or FIT); Detects heme, a component of hemoglobin, by reacting with a chemical substrate to produce a colour change.
FIT/iFOBT is preferred due to its higher sensitivity and specificity
N.B. bleeding in stool can be due to ulcers, polyps or malignancies
what is the antibody to HER2 used to detect the tumour? (immunohistochemistry technique)
antibody used to detect HER2 is HERCEPTIN (antibody that binds to HER2 and is used to detect it with a dye)
CDK4/6 and cyclin D together form active complexes, which phosphorylates Rb protein. Phosphorylated Rb1 releases transcription factor E2F. Explain how E2F effects cell cycle
CDK4/6 and cyclin D together form active complexes, which phosphorylates Rb protein. Phosphorylated Rb1 releases transcription factor E2F…. Release from Rb1 allows for E2F-driven transcription of genes triggering the cell cycle progression
How does p53 transcription factor (aka TP53) tumour suppressor gene work?
n.b. in human cancers, TP53 is the most commonly mutated gene
p53 transcription factor increases expression of p21 (cyclin dependent kinase inhibitors)
-inhibits cyclin B/CDK1 complex causing G2/M arrest
-inhibits cyclin E/CDK2 complex stopping G1/S phase progression so DNA repair can occur
if however p53 gains a ‘loss in function’ then these processes will go unchecked = cancer/tumour
Breast cancer susceptibility gene BRCA1 + BRCA2 are tumour suppressor genes responsible for DNA repair (‘caretakers’) at the G2M checkpoint.
BRCA2 specifically appears to involve regulating the function of RAD51 (ATPase) in the repair by homologous recombination. Promoting efficient and precise repair of double strand breaks.
What happens when BRCA1/2 are mutated?
Mutated BRCA1 + BRCA2= repair of double strand DNA breaks by a homologous recombination is severely impaired
- increase use of error prone pathways e.g. non homologous end joining (NHEJ) or single stranded annealing (SSA) result in insertions, deletions or chromosomal rearrangements.
- genomic instability mutations lead to accumulation of unrepaired or misrepaired DNA damage
- elevated cancer risk mutations and BRCA1/2 strongly associated with hereditary breast, ovarian, prostate and pancreatic cancer
Anti-apoptotic proteins are _____.
Pro-apoptotic proteins are ______.
Anti-apoptotic proteins (e.g. BCL-2) are ONCOGENES.
Pro-apoptotic proteins are TUMOUR SUPPRESSOR GENES.
n.b. think anti-death vs pro-death
