Carcinogenesis

Question 1

Name the cancers associated with these environmental risk factors:

EBV

HBV

Schistoma

Aflatoxins

HPV

Answer 1

EBV - burkitts lymphoma

HBV - hepatocellular carcinoma

Schistosomiasis - bladder cancer

Aflatoxins - hepatocellular carcinoma

HPV - cervical carcinoma

Question 2

What are the four types of thyroid epithelial cell cancer?

Answer 2

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

Question 3

Oncogenes

Answer 3

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

Question 4

Name 3 oncogenes commonly mutated

Answer 4

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

Question 5

Tumor supressor genes

Answer 5

Halt cell cycle progression

Question 6

Describe the mechanism of pRB

Answer 6

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.

Question 7

Retinoblastoma

Answer 7

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.

Question 8

What is loss of heterozygosity?

Answer 8

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.

Question 9

Describe the 2-hit hypothesis

Answer 9

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

Question 10

Name two tumour supressor genes

Answer 10

pRb

p53

Question 11

Describe the role of pRb and p53 in preventing cancer

Answer 11

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.

Question 12

Carcinogenesis

Answer 12

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

Question 13

Carcinogen

Answer 13

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

Question 14

Three genetic mechanisms that promote neoplasia

Answer 14

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

Question 15

Name three common chemical carcinogens and associated cancers

Answer 15

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.

Question 16

Name 3 microorganisms associated with cancer

Answer 16

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.

Question 17

Host factors which influence cancer development

Answer 17

Ethnicity/environmental factors

Diet

Age

Inherited risks

Premalignant conditions

Question 18

Name four medical conditions associated with increased risk of malignancy

Answer 18

Chrons disease

Ulcerative colitis

Hasimotos thyroiditis

Chronic atrophic gastritis

Barrats oesophagus

Chronic increased proliferation of cells resuls in dysplasia

Question 19

What are the stages of carcinogenesis?

Answer 19

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.

Question 20

How does radiation cause neoplasia?

Answer 20

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.

Question 21

Xeroderma pigmentosum

Answer 21

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.

Question 22

Viruses associated with neoplasia

Answer 22

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

Question 23

Role of hormones in tumour growth

Answer 23

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.

Question 24

Describe the role ras, c-myc and c-ERB2

Answer 24

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.

Question 25

Four cancers with an inherited predisposition

Answer 25

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.

Question 26

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

Answer 26

Extra copy of chromosome 21. Increased gene products.

Question 27

Risk of cancer in patients with ataxia telangiectasia

Answer 27

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.

Question 28

Risk of cancer in Down’s syndrome

Answer 28

Increased risk of leukemias, however incidence of solid tumours is lower due to the presence of tumour suppressor genes on chromosome 21