Ch 7 - Neoplasia Flashcards
Normal cellular genes whose products promote cell proliferation
Proto-oncogenes
Mutated or overexpressed versions of proto-oncogenes that function autonomously, having lost dependence on normal growth promoting signals
Oncogenes
A protein encoded by an oncogene that drives increased cancer cell proliferation, which may result from a variety of aberrations
Oncoprotein
Activation of this tyrosine kinase by point mutations is often involved in myeloproliferative neoplasms
JAK2
This tyrosine kinase receptor of the EGF-receptor family is often affected by gene amplification in breast cancer.
HER2
Gene is ERBB2
Point mutations of this family of genes constitute the most common abnormality involving proto-oncogenes in human tumours
RAS
Transcription factor that is most commonly affected in cancer
MYC
Gain of function mutations in these cyclin/CDK genes promotes unregulated G1S progression
D cyclin genes and CDK4
Action of RB on E2F transcription factors when hypophosphorylated?
Inhibition of E2 transcription factors
How is RB inactivated by growth factors?
Hyperphosphorylation
Syndrome where individuals have inherited mutations in TP53
Li-Fraumeni syndrome
Inhibits p53 in normal healthy cells
MDM2
Protein of HPV that can inactivate RB and p53
E6
Germline mutations affecting this tumour suppressor gene are associated with familial adenomatous polyposis
APC
The target of APC which translocates to the nucleus and binds to TCF as part of the WNT signaling pathway
Beta-catenin
This gene encodes two protein products:
- p16/INK4a cyclin-dependent kinase inhibitor
- p14/ARF which activates the p53 pathway
Germline mutations of this are associated with familial forms of melanoma and sporadic mutations have been implicated in other cancers
CDKN2A
Encodes a component of a ubiquitin ligase complex that is responsible for degradation of hypoxia-induced factors (HIFs), transcription factors that alter gene expression in response to hypoxia
Mutations associated with renal cell carcinoma
VHL (von Hippel-Lindau)
Encodes a lipid phosphatase that is an important negative regulator of Pi3K/AKT signaling.
Germline mutations cause Cowden syndrome, an autosomal dominant disorder associated with a high risk of breast and endometrial carcinoma.
Biallelic loss of function common in diverse cancers.
PTEN
Term for the distinctive form of cellular metabolism displayed by cancer cells characterised by high levels of glucose uptake and increased conversion of glucose to lactose via the glycolytic pathway
Warburg effect
Oncometabolite resulting from IDH mutations
2-hydroxyglutarate
phenomenon whereby metastatic cells take root and survive within different tissues but fail to grow
tumour dormancy
Loss of this protein function is the preeminent source of genomic instability in cancers
p53
Syndrome due to inherited loss of function in genes involves in nucleotide excision repair. Associated with high risk of skin cancers
xeroderma pigmentosum
Patients with this syndrome have defects in the mismatch repair system. Genome shows microsatellite instability, characterised by changes in the length of short repeats throughout the genome
HNPCC (Lynch syndrome)
Inflammatory mediators thought to play a role in cancer cachexia
TNF, IL-1, IL-6
signs and symptoms that cannot readily be explained by the anatomic distribution of the tumour or by the elaboration of hormones indigenous to the tissue from which the tumour arose
Paraneoplastic syndromes
Tumours that are most often associated with paraneoplastic hypercalcaemia
Carcinomas of the breast, lung, kidney, ovary
programmed cell death occurring upon cell detachment from the correct extracellular matrix, thus disrupting integrin ligation
Anoikis
What is the most common chromosomal rearrangement that activates proto-oncogenes?
Translocation
The most common translocation seen in Burkitt lymphoma?
MYC containing segment of chromosome 8 moves to chromosome 14q32 placing it close to the immunoglobuin heavy chain gene
Chromosomal change seen in acute promyelocytic leukaemia (APML)
Reciprocal translocation between chromosomes 15 and 17 producing a PML-RARA fusion gene
all-trans retinoic acid binding to PML-RARa in cases of APML is the first example of what kind of treatment
differentiation therapy (immortal tumour cells are induced to differentiate into their mature progeny which have limited lifespans)
Deletions involving chromosome 13q14 are associated with what type of cancer
Retinoblastoma
Chromosome ‘shattering’ that occurs in about 1-2% of cancers; more common in osteosarcomas and gliomas.
Chromothrypsis
chromosome is “shattered” and then reassembled in a haphazard way
This gene is a commonly mutated tumour suppressor gene in SCC and also the most commonly mutated oncogene in T-cell acute lymphoblastic leukaemia
NOTCH1
What are the 2 categories of chemicals that can cause initiation of carcinogenesis and what is the difference between them?
- Direct acting: do not require metabolic conversion to become carcinogenic
- Indirect acting: require metabolic conversion to become active carcinogens; the carcinogenic products are called ultimate carcinogens
How are most indirect carcinogens metabolised?
By cytochrome p450 dependent monooxygenases
Gene involved in metabolising polycyclic aromatic hydrocarbons such as benzo[a]pyrene
Susceptible form significantly increases risk of lung cancer from smoking
CYP1A1
There is a strong correlation between the dietary level of this food contaminant and the incidence of hepatocellular carcinoma in Africa and the Far East
Aspergillus (grows on improperly stored grains and nuts. Produces aflatoxin B1)
Explain the difference between initiators and promoters in the initiation-promoter sequence of carcinogenesis
- initiation results from exposure of cells to a sufficient dose of a carcinogenic agent that causes permanent DNA damage
- promoters: can induce tumours to arise from initiated cells, but they are not tumourigenic themselves.
Which form of UV radiation is the most significant in the formation of cancer and what is its wavelength?
UVB (280-320nm)
Mechanism by which UV radiation damages DNA
Causes pyrimidine dimers to form in DNA
Oncogenic RNA virus firmly implicated in the pathogenesis of cancer in humans
Human T-cell Leukaemia Virus Type 1 (HTLV-1)
Genes responsible for the oncogenic properties of HPV and their function
E6 - degradation of p53 and increases expression of TERT
E7 - binds to Rb and displaces E2F transcription factors promoting progression through cell cycle
inactivates p21 and p27
What proportion of hepatocellular carcinomas worldwide are associated with Hep B or Hep C infection?
70-85%
Cancers associated with H.pylori infection
- gastric adenocarcinoma
- B cell lymphoma (MALToma)
Several different point mutations of this gene encoding EGFR are found in a subset of lung adenocarcinomas
ERBB1
Which gene is overexpressed in over 85% of follicular B cell lymphomas?
BCL2 (an anti-apoptotic gene)
Lesions that incapacitate which pathways of cell death are the most common in cancers?
Intrinsic (mitochondrial) pathway
Relative lack of oxygen stabilises this transcription factor that activates pro-angiogenic factors
HIF1-alpha
Growth factors transcribed by HIF1-alpha
VEGF
bFGF (basic fibroblast growth factor)
Anti-angiogenic molecule stimulates by p53
Thrombospondin-1
Are nuclei likely to be larger or smaller in malignant cells?
Characteristically, cancer cells have nuclei that are disproportionately large
(nuclear to cytoplasm ratio may approach 1:1 instead of the normal 1:4 -1:6)
What is a carcinoma in situ?
When dysplasia is severe and involves the full thickness of the epithelium but the lesion does not penetrate the basement membrane
How to carcinomas tend to spread?
Via the lymphatics
How do sarcomas tend to spread?
Haematogenous
What are the three mechanisms by which HIV is transmitted to the newborn child?
- In utero by transplacental spread
- During delivery through an infected birth canal
- After birth by ingestion of breast milk
What 2 genes are thought to be involved in the pathogenesis of ATLL from HTLV-1
tax and HBZ
What proportion of people infected with HTLV-1 develop leukaemia?
3-5%
Which human retrovirus is firmly implicated in the pathogenesis of cancer in humans?
HTLV-1
Which cells do HTLV-1 have tropism for?
CD4+ T cells
Oncogene of EBV
Latent membrane protein 1 (LMP-1)
EBV gene that activates NF-kB and JAK/STAT signaling pathways and promotes B cell survival and proliferation
Prevents apoptosis by activating BCL-2
LMP-1
EBV protein that encodes a nuclear protein that mimics a constitutively active Notch receptor
EBNA2
Role of EBV in Burkitt lymphoma
- not directly oncogenic
- acts as a polyclonal B cell mitogen which sets the stage of the acquisition of the (8;14) translocation and other mutations that ultimately produce cancer
Gene of H. pylori that may contribute to carcinogenesis by stimulating growth factor pathways
CagA
