Carcinogenesis Flashcards
Name the cancers associated with these environmental risk factors:
EBV
HBV
Schistoma
Aflatoxins
HPV
EBV - burkitts lymphoma
HBV - hepatocellular carcinoma
Schistosomiasis - bladder cancer
Aflatoxins - hepatocellular carcinoma
HPV - cervical carcinoma
What are the four types of thyroid epithelial cell cancer?
Anaplastic - not related to the cell type it is derived from, spreads by any means, worse prognosis
Papillary - finger-like projections, lymphatic spread, affects younger patients
Follicular - formed from follicular cell, invades capsule to the basement mambrane
Medullary - C-cells lying in the basal layer
Oncogenes
promote autonomous cell growth
i.e. In absence of normal growth signals
Products are oncoproteins
Proto-oncogene is a normal non-mutated gene. Biological regulators of cell proliferation
Name 3 oncogenes commonly mutated
Ras - constitutive activation of signalling cascades,
c-myc - transcriptional activator, synthesis upregulated due to translocation
her2 - cell membrane receptor (growth factor), amplification of copy number on chromosome
Tumor supressor genes
Halt cell cycle progression
Describe the mechanism of pRB
The Rb tumor suppressor protein (pRb) binds to the E2F transcription factor and inhibits it.
E2F mediates the activation of target genes that facilitate the transition from G1-Sphase. E2F target genes encode proteins involved in DNA replication
Phosphrylation by CDKs inactivates pRb and causes it to dissociate from E2F, which allows progression through the cell cycle.
Retinoblastoma
Malignant tumour of the photoreceptor progenitor cells.
Unilateral and bilateral forms. Unilateral form presents earlier and has a better prognosis. Bilateral cases develop later, and have a worse prognosis. Increased risk of other tumours later in life.
Autosomal dominant.
What is loss of heterozygosity?
The majority of somatic cells have two copies of the genome, one from each parent. However, one parental copy of a region can sometimes be lost e.g. via mututation.
If this is a tumor supressor gene, this does not always have an adverse effect on the cell becaue the other copy of the gene compensates. However when both genes are lost then cancers result.
Describe the 2-hit hypothesis
Used to explain the inheritance of retinoblastoma
Affected parents pass mutated gene to offspring, who are heterozygous for the defective gene, but will not produce tumours.
However if another sporadic mutation occurs which results in loss of the normal gene, cells homozygous for the mutations will produce tumours
Name two tumour supressor genes
pRb
p53
Describe the role of pRb and p53 in preventing cancer
pRb controls the R point, which is the transition between G1/S. pRb beinds to E2F and prevents expression of late G1 genes until it is phosphorylated by CDKs. If cells overexpress cyclin D or pRb is mutated then there is no regulation of the R point and the cell moves through the cycle.
In a normal cell p53 is activated in response to DNA damage, and arrests the cell cycle to allow DNA repair. In cells where DNA repair is not possible, p53 induces apoptosis.
Loss of p53 activity allows the cells to proliferate with DNA damage.
Carcinogenesis
Process that results in the transformation of normal cells to neoplastic cells by causing permanent (non-lethal) genetic alterations
Carcinogen
Environmental agent participating in the causation of tumours – all act on DNA
Three genetic mechanisms that promote neoplasia
Point mutations that cause production of an abnormal oncogene or loss of a tumour suppressor gene
Gene amplification causing excessive production of oncoproteins/growth factors
Chromosomal rearrangements that cause inappropriate activation of genes
Name three common chemical carcinogens and associated cancers
Polycyclin aromatic hydrocarbons: found in tars and cigarette smoke. Cause skin carcinoma and lung cancer
Aromatic amines: encountered via industrial exposure, converted to toxic agents in teh liver and become concentrated by exretion in the urine. Cause uroepithelial carcinoma
Nitrosamines: conversion of dietary nitrates and nitrites to nitrosamines causes GI cancer
Alkylating agents: used in chemotherapy, bind directly to DNA and cause mutagenesis.
Name 3 microorganisms associated with cancer
Bacteria: H.pylori, gastric carcinoma and lymphomas
Fungi: aflotoxins (aspergillus), hepatocellular carcinoma
Parasites: schistosoma, high affinity for transitional epithelium, squamous cell carcinoma of the bladder.
Host factors which influence cancer development
Ethnicity/environmental factors
Diet
Age
Inherited risks
Premalignant conditions
Name four medical conditions associated with increased risk of malignancy
Chrons disease
Ulcerative colitis
Hasimotos thyroiditis
Chronic atrophic gastritis
Barrats oesophagus
Chronic increased proliferation of cells resuls in dysplasia
What are the stages of carcinogenesis?
Initiation: induction of a permanent DNA mutation in cells by a carcinogen
Promotion: Induction of cell proliferation.
Progression: persistent cell proliferation results in initiated cells acquiring secondary mutations which lead to dysregulation and autonomous cell growth.
How does radiation cause neoplasia?
Radiation causes DNA damage through the formation of DNA breaks and DNA adducts, causing instability of the DNA.
Ionising radiation is abdorbed into teh tissues where it produces free radicals that cause DNA breaks and abnormal cross-linking. Cell types with a high turnover are more sensitive. Increases risk of leukemias, squamous cell carcinomas, breast and bone tumours.
UV radiation damages epidermal cells. Increases risk of melanoma and basal cell carcinomas.
Xeroderma pigmentosum
Mutation in an endonuclease responsible for DNA repair.
Autosomal recessive disease
Children develop severe abnormalities in the spidermis and develop multiple squamous cell carcinomas/melanomas.
Viruses associated with neoplasia
HPV: causes increased proliferation of squamous epithelial cells. Inactivates products of p53 (normally half cell division) and pRb
HBV - causes cirrhosis, which increases risk of cancer.
EBV - establishes latent infection in B-cells. Causes c-myc translocation (8,14). Stimulates gene amplification and cell proliferation
Role of hormones in tumour growth
Breast cancer: oestrogens stimulate proliferation of breast and endometrial tissue, and can predispose to development on cancer. Breast cancers can be treated with anti-oestrogen drugs
Testicular cancer: prostate cancer can be treated by removal of testosterone.
Describe the role ras, c-myc and c-ERB2
Ras: activated by growth factor receptors and initiates MAPK cascade which promotes cell proliferation
c-myc : transcription factor activated by growth factors that regulates gene expression
c-ERB2: growth factor receptor.
Four cancers with an inherited predisposition
FAPP: caused by a mutation in the APC gene. Autosomal dominant inheritance. Results in multiple adenomatous polps throughout the colon.
Retinoblastoma: loss of function mutation in rb gene causes uncontrolled cell proliferation.
Breast cancer: BRAC1, BRAC2. increases risk of breast and ovarian cancer. Risk increased if first degree relative has breast cancer
Neurofibromatosis: mutation in NF1 neurofibronin which normally switches off ras. Mutation causes loss of function resulting in increased growth.
Why do Down’s syndrome patients have increased risk of cancer?
Extra copy of chromosome 21. Increased gene products.
Risk of cancer in patients with ataxia telangiectasia
Louis-Bar syndrome
Rare neurodegenerative disease that causes severe disability. Caused by a failure of DNa repair.
Patients have poor coordination, dilated blood vessels, low Ig production and so are more susceptible to infection, failure of DNA repair increases risk of cancer.
People with A-T have an increased sensitivity to ionizing radiation, which increases risk of cancer.
Risk of cancer in Down’s syndrome
Increased risk of leukemias, however incidence of solid tumours is lower due to the presence of tumour suppressor genes on chromosome 21
