Cancer Flashcards
What is cancer? (3)
Disease of malignant cell growth
Usually due to DNA damage in specific genes leading to aberrant signal transduction
Results in abnormal + uncontrolled cell proliferation
Why is cancer predominantly a disease of the elderly? (3)
Result from accumulation of mutations in certain gens
~4-8 required for cancer to develop
These accumulate over time
What are some causes of cancer? (5)
Genetic predisposition Immunosuppression Chemical exposure + smoking Radiation exposure Viruses e.g. EBV, HTLV-1
Which 3 types of genes are affected in order to cause cancer? (6)
Proto-oncogenes -> oncogens (e.g. BCL-ABL in CML)
Tumour suppressor genes (e.g. Tp53 which codes for p53)
- mutated supressor genes lose their ability to properly regulate cell division
Metastasis-promoting + -suppressing genes
Explain the role of Rb cell cycle reg? (4)
Rb is bound to E2F
@ G1/S checkpoint, Rb is phosphorylated
pRb detaches from E2F
E2F acts as a TF + upregulates cyclins + CDKs required for the next cell cycle checkpoint
Also upregulates enzymes needed for S phase
Explain the role of p53 in cell cycle reg? (6)
Activated upon DNA damage
Normally bound to Mdm2 but dissociates when there is DNA damage, hypoxia or cell cycle abnormalities
Causes cell cycle arrest allowing DNA to be repaired
If repaired cell cycle is resumed
If not, cell is programmed for apoptosis
Explain the process of metastasis (4)
Cell from primary tumour spread to 1st organ/tissue connected by lymph or blood (e.g. GI cancers spread to liver via hepatic circ)
Organ pref model - some tumours require certain environment e.g. certain GFs + so metastasise to certain organs (e.g. prostate to bone)
What therapies are available for cancer? (7)
Chemo (cytotoxic drug mix) Radiotherapy Stimulate tumour suppressors (Mdm2, p53) Block oncogens e.g. Gleevec for BCR-ABL gene Stimulate immune system Hormone therapy Anti-angiogenic drugs
Common carcinogens (4)
Chemical = cigarette smoke, coal tar Radiation = UV light, asbestos (structure) Viral = EBV Genetic = inherited predispositions (BRCA 1+2 mutations)
How do carcinogens promote cancer development? (3)
Carcinogens gents directly involved in causing cancer either by DNA damage or disruption of met. processes
Co-carcinogens promote activity of other carcinogens
Sources of radiation + how they promote cancer development? (7)
Background radiation is most common e.g. radon
Occupation exposure
Medical irradiation
Remnants of atomic weapons
High energy of ionising radiations disrupt chem bonds causing production of highly reactive radicals
React with nearby molecules + can cause DNA damage
Most ss breaks can be repaired normally, ds breaks are harder to repair
How does ataxia telangiectasia predispose an individual to cancer? (3)
Ataxia telangiectasia = defect in ATM gene
Responsible for cell response to dsDNA breaks
Ataxia, increased cancer risk, slowed rate of growth
How does xeroderma pigmentosum predispose individual to cancer? (4)
Defect in nucleotide excision repair (NER)
Defective DNA repair
DNA damage greatly increases after UV exposure
Severe sunburn, limited growth of hair, many freckles
How does Fanconi’s anaemia predispose an individual to cancer? (3)
Defect in proteins responsible for DNA repair
Most patients develope AML + BM failure by 40yrs
Congenital defect common, short stature
What viruses are associated with human cancer? (5)
DNA viruses - EBV (Burkitt's lymphoma) - HPV (cervical cancer) - HBV (hepatoma) RNA retroviruses - HTLV-1 (adult T-cell leukaemia lymphoma) - HIV (many cancers)
What properties are required of tumourigenic viruses? (3)
Stable association with cells (chromosomal integration)
Not kill cells
Evade immune surveillance
What is Knudson’s hypothesis for heriditary cancer? (4)
Only requires single ‘hit’ (mutation event) as first hit is inherited
Could be due to point mutations, gene conversion, deletions, BRCA1
First hit = loss of heterozygosity
Second hit = leads to loss of function
What is the function of proto-oncogenes? (3)
Stimulate growth
May be mutated -> oncogenes
Mutations causing cancer have a dominant phenotype (but rarely inherited as som. mutations)
Describe the life cycle of a retrovirus (6)
Enveloped viruses that replicate via reverse transcription
Bind to receptor on cell surface + fuse with membrane
Stimulates uncoating which releases +ve sense ssRNA into cysoplasm
Can produce DNA using its own reverse transcriptase enzyme
DNA integrated into host genome
Allows for transcription + translation of viral proteins
(assemble in cytoplasm + exit cell via exocytosis)
What chromosomal translocations are involved in Burkitt’s lymphoma and CML? (4)
Burkitt’s lymphoma = chr8 (MYC) + chr14 (Ig heavy chain) -> unreg expression of MYC
CML is due to Philadelphia chr (95% case) = translocation b/w chr9 (ABL) + chr22 (BCR) to create BCR-ABL oncogene
- enhances tyrosine kinase activity
Which therapies target oncogenes? (2)
Monoclonal Abs target surface receptor proteins on tumour cells:
- trastuzumab, cetuximab
Small molecule inhibitors (usually kinase inhibitors):
- Imatinib (BCR-ABL)
What is the function of tumour suppressor genes? (3)
Regulate cell cycle checkpoints, differentiation or DNA repair
What is β-Catenin? (4)
Protein that regualtes coordination of cell-cell adhesion + gene transcription
Can bind to APC + form degredation complex or to TPC promoting gene transcription
β-Catenin-APC complex is inhibited by Wnt
Which genes are involved in heritable breast cancer? (2)
BRCA1 + TP53 tumour supressor gene mutations
What are oncogenic retroviruses? (3)
Viruses that cause cancer
Viral genome may be inserted into promoter region of proto-oncogene causing it to become an overactive oncogene
What is the molecular basis of tumour progression? (4)
Acquisition of specific mutations
Clonal expansion due to tumour promoters
Genomic instability
Epigenetic changes
What are the key steps in tumour progression? (5)
ANGIOGENESIS - growth of cells, hypoxia, factors that stimulate directional growth of endothelial cells (e.g. VEGF) -> angiogenesis
ACQUISITION of ability to undergo epithelial to mesenchymal transition
- loss of epithelial cell shape
- acquisition of fibroblast-like shape, invasiveness + mesenchymal gene expression
COLONISATION
REL. of metastatic cells
RESISTANCE to drug interventions
Describe the mechanism of tumour cell invasion (3)
Cellular proliferation increase mechanical pressure
Mesenchymal cell traits increase motility
Increase in degradative enzymes - tumour cells activate plasminogen activator (increased plasmin production -> increased matrix metalloproteases -> increases invasion)
What determines the pattern of tumour spread? (4)
Mechanical hypothesis = metastases travel in blood + lymph (anatomical considerations)
‘Seed + soil’ hypothesis = specific adhesion b/w tumour + endothelial cells in target organ = favourable environment in which the tumour can thrive
What is hypertrophy? (3)
Increase in cell size (mainly effects muscle)
Physiological = exercise, myometrial hypertrophy in preg.
Pathological = LV hypertrophy in hypertension
What is hypotrophy? (1)
Decrease in cell size
What is atrophy? (3)
Decrease in cell size + number
Physiological = thymus atrophy @ puberty
Pathological = muscle wasting due to disuse
What is hyperplasia? (3)
Increase in cell number (mainly effects glandular tissue)
Physiological = breast hyperplasia @ puberty + preg
Pathological = Grave’s/Cushing’s or tumour driven
What is hypoplasia? ()
Decrease in cell number
Physiological = endometrial hypoplasia after menopause
Pathological = loss of stim, pressure on organ from adjacent structures, hypoxia, destruction of cells
What is aplasia? (2)
Failure to form tissue/defective development
E.g. spina bifida
What is the difference between hamartoma and ectopia/heterotopia? (3)
Hamartoma = haphazard, tumour-like mass of tissue appropriate to the site Ectopia/heterotopia = well developed tissue at the wrong site (heterotopia also get retention of original tissue type in its correct anatomical site)
Define metaplasia + give examples (3)
Protective mechanism characterised by reversible change in tissue type due to environmental stimulus Barret's oesophagus = squamous epithelium -> column mucosal (like those in stomach) Osseous metaplasia (cartilage to bone)
What is dysplasia? How is this linked to malignancy? (3)
Disorder maturation of cells within a tissue
Pre-malignant state
Dysplastic cells display cytological features of malignancy
But cannot invade/metastasise
What is the role of SCs in malignancy? (3)
Tumours are believed to contain mutated versions of normal SCs
What percent of cancers are due to inheritance of a single cancer susceptibility gene? (1)
5%
Compare and contrast sporadic + hereditary cancers (8)
Sporadic
- due to som mutations (mutations that occur after division of fertilised egg + are not present in every cell of the body
- not inherited from parents, only occasionally passed to offspring
- no increased risk of other cancers
- screening not offered
Hereditary
- inherited from parents
- present in every cell of body
- high rate of reccurrence
- high cancer risk in relatives
- screening + preventative management offered
How can hereditary cancers be distinguished from sporadic cancers? (2)
Hereditary cancers are familial so FHx can be taken to see if any underlying genetic susceptibility
Genetic testing or screening may be indicated
Explain the role of BRCA1 + 2 in breast cancer (3)
BRCA1+2 are usually expressed in breast tissue
Involved in repair of dsDNA breaks
Only 0.11% of pop. carry BRCA1+2 mutations but they are responsible for 16% familial breast cancers
Which genes in HNPCC have germline mutations? (3)
Hereditary non-polyposis colorectal cancer syndrome (Lynch)
Mutated genes = MLH1, MSH2, MSH6 + PMS2
Primary tumour is usually rectal
What are the screening options for HNPCC? (1)
Colonoscopy every 18-24 months for 25+ yrs
Screening + treatment options for breast Ca? (4)
30-50yrs = annual mamograms + annual MRI screening
50+yrs = annual mamograms
Surgery = risk-reducing mastectomy (breast reconstruction available)
Treat with PARP inhibitors
Define neoplasm (2)
New growth
Usually synonymous with cancer
Benign tumour typical features (9)
Bland cut surface Little haemorrhage or necrosis May be encapsulated No obvious spread to adjacent tissue or nodes Tumour ressembles original tissue Low tumour cellularity (relative no. of tumour to normal cells) Nuclei normal No dysplasia in adjacent tissue
Malignant tumour typical features (9)
Irregular edge
Focal necrosis + haemorrhage
Ill-defined margin of capsule penetration
Infilitration of adjacent tissue or nodes
Little resembelance of original tissue
High tumour cellularity
Nuclei abnormal
Dysplasia often present in adjacent tissue
What types of epithelial tumours are there? (6)
BENIGN = squamous papilloma, adenoma, transitional papilloma MALIGNANT = squamous cell carcinoma, adenocarcinoma, transitional cell carcinoma
What types of non-epithelial tumours are there? (7)
BENIGN = osteoma (bone), chondroma (cartilage), leimyoma (smooth muscle), rhabdomyoma (striated muscle), lipoma (adipose tissue), fibroma (fibrous), neurofibroma (nerve) MALIGANT = osteosarcoma, chondrosarcoma etc.
Define grade and stage in terms of cancer progression (2)
Grading is degree of differentiation (i.e. similarity to tissue of origin)
Stage is extent of tumour spread
How can cancers spread? (4)
Blood
Lymph
Along nerves
Across coelomic cavities + into adjacent tissue
What are the main factors in predicting tumour prognosis? (4)
Classification (histological subtype)
Grade (differentiation)
Stage (spread)
Molecular features (e.g. expression of specific receptor)
What is cachexia? (3)
20% of cancer deaths associated with cachexia
Abnormally low body weight, weakness + general decline
Involves depletion of fat + muscle (unlike starvation which only depletes fat stores)
Driven by cytokines in cancer e.g. TNF + ILs
Worst in upper GI cancer
Explain the TNM staging system (3)
Tumour size = T1-T4 (with T1 being smallest)
Nodes (N1 = regional lymph node involvement, N2 = distant nodes)
Metastases (M0 = none, M1 = present, MX = unknown)
Explain the Duke’s staging system (4)
For colorectal Ca A = confined to bowel wall B = through bowel wall. not into nodes C = involves lymph nodes (~20% patients with colorectal cancer present late with distant metastases + are inoperable)
Explain the Ann Arbor staging system (4)
For Hodgkin’s disease
Stage I = 1 node group
Stage II = more than 1 node group, same side of diaphragm
Stage III = more than 1 node group, either side of diaphragm
Stage IV = non-lymphoreticular organs involved
