MoD Session 10 Flashcards
What are the extrinsic factors that increase cancer risk?
Environment
Lifestyle
What are the 5 leading behavioural and dietary risks in developing cancer?
High BMI Low fruit and veg intake Lack of physical activity Tobacco use Alcohol use
Which leading behavioural and dietary factors act synergistically to increase cancer risk?
Tobacco and alcohol use
When adjusted for age, what does the incidence of cancer compared to that in the 1900s show?
It hasn’t changed much, individual risk has increased due to extrinsic factors
Why does increasing dietary intake of fruit and veg reduce the risk of cancer?
Decreases GI transit time
Fibre absorbs carcinogens and removes them
Rich in antioxidants
What are the three main categories of extrinsic factors that increase cancer risk?
Infections
Radiation
Chemicals
What did 2-napthylamine, an industrial carcinogen, show about neoplasia?
Long delay
Depends on dosage
Organ specificity
What does the organ specificity of a carcinogen depend on?
Where it comes into contact with
Give three examples of industrial carcinogens.
Vinyl chloride
Coal tars
Asbestos
What type of cancer is vinyl chloride associated with?
Liver
What explains the lag time between carcinogen exposure and development of neoplasia?
Need for high level of promoter exposure over a long period of time in combination with an initiator to form a monoclonal population
Describe the Ames test when it shows a mutagen is an initiator.
Rat liver, salmonella which requires histamine and possible mutagen–> media w/minimal histidine –> incubate –> high number of revertants
What is an initiator?
A mutagen
What do promoters do on neoplasia?
Cause prolonged proliferation
What are pro-carcinogens?
Chemicals converted by P450 to become carcinogens
What is a complete carcinogen?
A chemical which is both an initiator and a promoter
How does cigarette smoke act as a complete carcinogen?
Initiator = 2-napthylamine Promoter = hot water
What classes can initiators be sorted into?
Polycyclic aromatic hydrocarbons Aromatic amines N-nitroso compounds Alkylating agent Diverse natural products
How do alkylating agents cause DNA damage?
Disrupts covalent bonds on DNA
Give two examples of natural carcinogens.
Aflatoxin
Asbestos
How can N-nitroso compounds be formed?
In industry
Smoked food
Produced in stomach
How far does UV radiation penetrate?
No deeper than the skin
How does ionising radiation such as X-Ray and nuclear radiation cause DNA damage?
Strips electrons from atoms
What are the three types of direct damage caused by ionising radiation?
Alter bases
Single/double strand breaks
What is the main exposure for most people to ionising radiation?
Radon released from rocks
How does radiation cause indirect DNA damage?
Free radical production
How can carcinogenic infections cause cancer?
Directly affect genes that control cell growth
Indirectly carcinogenic
Reduced immunity
How does HPV cause cervical cancer?
Expresses E6 which inhibits p53
Expresses E7 which inhibits pRB
No apoptosis and no cell-cycle breaks
How does EBV behave as an indirect carcinogen?
Chronic liver inflammation –> free radicals
How do Hep B and C act as indirect carcinogens?
Cause regeneration
How does Helicobacter pylori cause cancer?
Indirectly carcinogenic causing gastric inflammation
How do parasitic flukes cause cancer?
Lay eggs in bile ducts and bladder mucosa –> metaplasia and inflammation
What viral infection leads to Kaposi’s sarcoma?
Human herpes virus 8
How does reducing immunity cause cancer?
Allows other potentially carcinogenic infections to occur
How many hits are needed for germline mutations to occur?
2
How does the pathogenesis of inherited familial cancers differ to that of sporadic cancers?
Familial - 1st hit in germline, only need one somatic hit
Sporadic - 2 somatic hits needed
How do the graphs of unilateral (sporadic) and bilateral (inherited) cancer v.s. time differ?
Bilateral - straight line
Unilateral - curve
What are oncogenes?
Abnormally activated proto-oncogenes
How many alleles must be activated for an oncogene to be turned on?
1
How does a RAS mutation cause cell cycle entry?
G-protein activated –> cyclin D –> CDK
How does mutant RAS cause a constant cell cycle?
It is always active so allows cells past the cell cycle restriction point
What proto-oncogene mutation is common in colorectal cancer and melanoma?
RAS
What is the function of tumour suppressor genes?
Inhibit neoplasticism growth
How many alleles must be inactivated in tumour suppressor gene mutation?
2
What allows unrestrained passage of cells through the restriction point?
Inactivation of both RB alleles
Give examples of some proto-oncogenes.
BRAF BCL2 RAS HER2 Cyclin D1 PDGF MYC
What is BLC2?
An apoptosis regulator
What is BRAF?
Intracellular kinase
What is MYC?
Transcription factor
What are the three methods of DNA repair which are mutated in carcinoma?
Nucleotide excision
Mismatch repair
Double strand DNA breaks
What causes Xeroderma Pigmentosum?
Autosomal recessive mutation of 1 of 7 genes affecting nucleotide excision repair
What does Xeroderma Pigmentosum cause?
Early onset skin cancer from UV exposure
What inheritance pattern does hereditary non-polyposis colon cancer show?
Autosomal dominant
What does mismatch repair mutation cause?
Microsatellite instability
What are the intrinsic factors that increase cancer risk?
Age
Sex
Heredity
How do BRAC1 and BRAC2 cause familial breast carcinoma?
Causes double strand DNA break which causes chromosomal instability
What does nucleotide excision mutation cause?
Nucleotide instability
What is genetic instability?
Alterations accounting for accelerated mutation rate
What is genetic instability counteracted by?
‘Caretaker’ tumour suppressor genes
Do mutations to DNA repair have to be inherited?
No, seen in sporadic cases
What normal cellular replication process can be abnormal in malignant cells?
Chromosome segregation
How does the adenoma-carcinoma sequence progress?
Normal epithelium –> early adenomal dysplastic crypt –> intermediate adenoma –> late adenoma –> carcinoma –> metastasis
What is progression in malignant neoplasm?
Alterations of multiple TS genes and proto-oncogenes which involves genetic instability
How many mutations are needed for malignant neoplasm to establish?
What are the 6 hallmark cellular behaviours from cancer mutations?
Self-sufficiency in growth signals Resistance to growth stop signals Cell immortalisation Sustained angiogenesis ability Resistance to apoptosis Ability to invade and metastasise
What is the one enabling feature seen with the 6 hallmarks of cellular behaviours in cancer mutations?
Genetic instability
Which cellular behavioural hallmark is only seen in malignant neoplasm?
Ability to invade and metastasise
What does HER2 gene amplification in breast cancer cause?
Self-sufficiency in growth signals
What does CDKN2A gene deletion in melanoma cause?
Resistance to growth stop signals
What do most cancers do to overcome cell senescence?
Activate telomerase genes
What does VEGF activation, which occurs in many cancers, allow?
Sustained angiogenesis ability
What does BLC2 gene transcription in lymphoma do?
Cause resistance to apoptosis
In gastric cancer, what allows for invasion and metastasis?
E-Catherine mutation
How does a neoplasm become more genetically heterogenous?
More mutations are acquired as proto-oncogenes and TSG interact to affect hallmarks of cancer
Give a brief overview of the progression of cancer.
Somatic cells exposed to environmental carcinogens –> monoclonal population forms –> progression over many years/decades –> hallmarks of cancer
What increase in risk does having a sibling with a given cancer cause?
2-3 fold
What are cancer family syndromes?
Patients are afflicted by several types of cancer and often develop more than one type
How can secondary cancers be caused by therapy for primary cancer?
X-Rays and antineoplastic drugs are powerful carcinogens
What can be considered as a phenotype that predisposes to melanoma?
Fair complexion
What phenotype predisposes dye-stuff workers to bladder cancer?
Poor acetylator
What inborn differences can be considered as a cancer phenotype?
Enzymes that inactivate or detoxify carcinogens
What is usually the first sign of cancer in retinoblastoma?
Abnormal reflection in pupil (child does not complain of poor eyesight) - leukokoria = cat’s eye reflex
How does retinoblastoma usually progress?
Develops from outer layer of retina –> grows backwards into eye
When do hereditary and sporadic retinoblastoma usually appear?
Hereditary - children, often bilateral
Sporadic - adults, usually unilateral
How do two successive mutations cause retinoblastoma?
1st mutation affects one locus on one chromosome
2nd affects same locus on the other allele
What happens to the RB1 genes in a normal, healthy individual?
Occasional cell inactivates one of its two good RB1 genes but won’t cause a tumour
Why does the occasional cell inactivation of an RB1 copy in people with hereditary retinoblastoma cause a tumour to develop?
They only have one good copy
When is the first mutation in hereditary retinoblastoma present?
In the sperm or ovum before fertilisation
When is a likely time for the only functioning RB1 gene in a patient with hereditary retinoblastoma to be lost?
Development of the retina when mitoses are occurring
Why does retinoblastoma become dominant by pedigree analysis?
It occurs commonly in mutant retinoblastoma carriers
What are children with hereditary retinoblastoma at a greater risk of?
Other tumours e.g. Osteosarcoma, risk increased by irradiation which may be used therapeutically
How does pRB stop the normal cell cycle?
Encodes a phosphoprotein that binds to DNA which is phosphorylated through the cycle and loses its suppressor function
What is the most common genetic change in human cancer?
Mutation in TSG p53
What is the pathogenesis of familial polyposis of the colon?
Carriers inherit predisposition to develop polyps of colon in adolescence –> turn into carcinoma at 40 in 80% of patients
What is the treatment of familial polyposis?
Early preventative colectomy
How are breast and colon cancers thought to occur in adults?
Dominantly inherited syndromes which predispose to these cancers
What enzyme is lacking in Xeroderma Pigmentosum?
Endonuclease that repairs UV light DNA damage
How can an error during meiosis to form ovum or sperm increase the risk of neoplasia?
Meiotic instability forms root of later mitotic instability
How does Down’s syndrome affect the risk of developing leukaemia?
Increases by 20 fold
What do men with Klinefelter’s syndrome have a 2-3 fold increased risk of?
Breast cancer
Congenital defects in which system predispose to cancer?
Immune
How can karyotyping be used to examine tumour progression?
Increasingly severe karyotypic aberrations are seen with tumour progression
What chromosome change is seen in 90% of chronic myelogenous leukaemia cases?
Balanced translocation of Philadelphia chromosome (chromosome 22)
What is the usual chromosomal change seen in balanced translocation of the Philadelphia chromosome?
Part of gene on 22 fuses with abI oncogene on chromosome 9
What is the result of a balanced Philadelphia translocation?
More powerful than normal tyrosine phosphorylase
Where is the Philadelphia chromosome found in chronic myelogenous leukaemia patients?
All myeloid cells - incl. erythrocyte, granulocyte and megakaryocyte
What indicates that a clone deriving from a pleuripotent stem cell has overcome the entire bone marrow in CML?
Presence of Philadelphia chromosome in all myeloid cells
What is seen with the N-myc gene in neuroblastoma and the neu (Her2) gene in breast cancer?
Gene amplification in association with tumour progression
What chromosomal abnormality occurs in many tissues where it may have survival value?
Polyploidy
What chromosomal abnormalities become a visible aspect of progression in tumours?
Aneupoidy and polyploidy
What precipitates a cascade of increasing chromosomal instability in tumour development?
Destabilising mutation early in tumour development
What are chromosomal fragility syndromes?
Rare inborn abnormality of DNA repair
Give three examples of chromosomal fragility syndromes.
Fanconi’s anaemia
Ataxia telangiectasia
Xeroderma Pigmentosum
What are chromosomal fragility syndromes associated with?
An increased risk of tumour development
What do many, if not most, cancers develop from?
Precursor lesions
Give examples of some known precancerous lesions.
Forms of metaplasia, dysplasia, carcinoma in situ, some benign lesions and sundry lesions
How do epithelial and connective tissue metaplasias vary?
Epithelial virtually all precancerous
CT generally safe
What does metaplasia imply?
Expression of a different but normal set of genes
Give two examples of precancerous metaplasia.
Gastric epithelium in oesophagus - Barrett’s epithelium
Abnormal hyperplastic epithelium (leukoplakia) on tongue or exocervix
What does dysplasia refer to?
Cellular changes that are too irregular for hyperplasia and not irregular enough for neoplasia
What does dysplasia in surface epithelia blend into which is definitely neoplastic?
Carcinoma in situ
Describe what is meant by ‘carcinoma in situ’.
Covering epithelium replaced by layer of cancer cells
All boundaries respected
Thickness about the same as normal epithelium
Basement membrane intact
What changes the diagnosis of in situ carcinoma to invasive?
Epithelial boundary breakdown
In carcinoma in situ of the cervix, what does Pap smear show?
Epithelial cells sloughed off failed to mature
Not normal flat, eosinophilia cell with shrivelled pyknotic nucleus
Cells retain structure and basophilia of basal cells
What is Bowen’s disease?
Carcinoma in situ of epidermis which appears reddened, scaly and crusty
Why is carcinoma in situ of the exocervix better visualised after swabbing with iodine?
Normal squamous cells have glycogen and stain brown
Carcinoma cells don’t produce glycogen so remain unstained
How does the peak age for cervix carcinoma in situ and carcinoma compare?
In situ - 30 y.o.
Carcinoma - 45 y.o.
How does the time taken for progression in cervix carcinoma compare to that in bladder, stomach and lung.
Cervix - 15 years
Bladder - 5 years
Stomach and lung -
What can happen to both dysplasia and carcinoma in situ of the cervix?
Unpredictably persist, regress or progress to invasive cancer
Is it possible to tell what the course of either dysplasia or carcinoma in situ of the cervix will be?
Nope
Why can a sarcoma in situ not exist?
Lack the boundary of a basement membrane to serve as a definition of invasiveness
Give examples of benign growths which given enough time can progress to carcinoma.
GI polyps Paipllomas of the larynx Large congenital naevi Pigmented moles V. occasionally: leiomyomas of the uterus and fibroadenomas of breast
Why can ongoing chronic inflammation be a precursor to cancer?
Likely to be secondary due to sustained cell proliferation from constant epithelial damage and regeneration
How long does chronic inflammation have to persist in liver cirrhosis to cause carcinoma?
Decades
Why does decades of chronic inflammation in cirrhosis lead to hepatocellular carcinoma?
Has a strong inflammatory response
Which two types of chronic gastritis can prelude gastric carcinoma?
Autoimmune or bacterial
Which chronic inflammatory disease carries a heavy risk of colon cancer?
Ulcerative colitis
How does asbestos lead to carcinoma?
Causes chronic inflammation
Absorbs carcinogens onto fibre surface
Which type of asbestos is more dangerous?
Blue - sharp spikes get stuck in peripheral lungs where they cannot be wafted out by mucociliary escalator
What is asbestos?
Naturally occurring silicate fibre of which there is a whispy white type and sharper blue type
What is the most common condition associated with asbestos exposure which is benign and doesn’t usually cause a problem?
Pleural plaques
