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Flashcards in Carcinogenesis Deck (28):
1

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

2

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

3

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

4

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

5

Tumor supressor genes

Halt  cell cycle progression

6

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.

7

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.

8

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. 

 

 

9

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

10

Name two tumour supressor genes


pRb

p53

11

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.

12

Carcinogenesis

Process that results in the transformation of normal cells to neoplastic cells by causing permanent (non-lethal) genetic alterations

13

Carcinogen

Environmental agent participating in the causation of tumours – all act on DNA

14

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

15


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.

16

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.

17

Host factors which influence cancer development


Ethnicity/environmental factors

Diet

Age

Inherited risks

Premalignant conditions

18

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

19

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.

20

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.

21

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.

22

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

23

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.

24

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. 

25

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. 

26

Why do Down's syndrome patients have increased risk of cancer?

Extra copy of chromosome 21. Increased gene products. 

27

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.

28

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

 

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