S9) Causes & Mechanisms of Neoplasia Flashcards

1
Q

Explain how the cause of neoplasia is multi-factorial

A
  • A combination of intrinsic host factorse.g. heredity, age and gender andextrinsicfactors e.g. environment and behaviour account for cancer risk
  • Much of the increased cancer incidence over the last century is due to prolonged life- span
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2
Q

About 30% of cancer deaths are due to the five leading behavioural and dietary risks.

What are they?

A
  • High body mass index
  • Low fruit and vegetable intake
  • Lack of physical activity
  • Tobacco use (¼ of all cancer deaths)
  • Alcohol use
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3
Q

Extrinsic factors account for approximately 85% of a population’s cancer risk.

Identify the three categories of extrinsic carcinogens

A
  • Chemicals
  • Radiation
  • Infections
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4
Q

Which important lessons about carcinogenesis do we learn from malignant neoplasms caused by 2-napthylamine?

A
  • There is a long delay between carcinogen exposure and malignant neoplasm onset
  • The risk of cancer depends on total carcinogen dosage
  • There is sometimes organ specificity for particular carcinogens e.g. 2-napthylamine causes bladder carcinoma
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5
Q

With reference to the Ames test, explain how chemical carcinogenesis involves initiation and promotion

A
  • The Ames test shows that initiators are mutagens, while promoters cause prolonged proliferation in target tissues
  • This culminates in a monoclonal expansion of mutant cells
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6
Q

How can chemical carcinogens be classified according to their nature?

A
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7
Q

Define the following terms:

  • Pro-carcinogen
  • Complete carcinogen
A
  • Pro-carcinogens are chemicals which are only converted to carcinogens by the cytochrome P450 enzymes in the liver
  • Complete carcinogens are chemicals which act as both initiators and promoters
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8
Q

What is radiation?

A

Radiation is any type of energy travelling through space

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9
Q

Describe the properties of the following types of radiation:

  • UV radiation
  • Ionising radiation
  • Nuclear radiation
A
  • Ultraviolet radiation does not penetrate deeper than skin
  • Ionising radiation strips electrons from atoms and includes X-rays and nuclear radiation arising from radioactive elements
  • Nuclear radiation comprises alpha particles, beta particles and gamma rays
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10
Q

Describe the effect of radiation on DNA

A

Radiation can damage DNA directly and also indirectly by generating free radicals

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11
Q

Explain how ionising and UV radiation are mutagenic

A
  • UV radiation is important as we are exposed to it daily from sunlight leading to increased skin cancer risk
  • Background ionising radiation from radon damages DNA bases and causes single and double strand DNA breaks
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12
Q

Explain how some infections are carcinogenic and can act directly or indirectly

A
  • Some infections act directly to affect genes that control cell growth
  • Other infections act indirectly by causing chronic tissue injury where the resulting regeneration acts either as a promoter for pre-existing mutations / initiator for new mutations
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13
Q

Briefly, explain how the following pathogens act as carcinogens either directly/indirectly:

  • Human Papilloma Virus
  • Hepatitis B & C Viruses
  • Helicobacter pylori
  • Parasitic flukes
  • Human Immunodeficiency Virus
A
  • HPV expresses E6 and E7 proteins which directly inhibit p53 and pRB protein function in cell proliferation (cervical carcinoma)
  • Hepatitis B,C act indirectly and cause chronic liver cell injury and regeneration
  • Helicobacter pylori causes chronic gastric inflammation (gastric carcinoma)
  • Parasitic flukes act indirectly to cause inflammation in bile ducts and bladder mucosa (cholangio- and bladder carcinomas)
  • HIV acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur
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14
Q

Explain why initiation and promotion lead to neoplasms when they affect proto-oncogenes and tumour suppressor genes

A
  • Tumour suppressor genes are genes which inhibit neoplastic growth – both alleles must be inactivated to allow neoplastic growth (two hits)
  • Oncogenes are genes which enhance neoplastic growth and are the abnormally activated versions of normal proto-oncogenes – only one allele of each proto-oncogene needs to be activated to favour neoplastic growth
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15
Q

In four steps, illustrate how the restriction point, in the cell signalling pathway for growth control, can be deregulated by the combination of an activated oncogene and an inactivated TS gene

A

⇒ The RAS proto-oncogene encodes a small G protein that relays signals into the cell & pushes the cell past the cell cycle restriction point

⇒ The mutant RAS oncogene encodes a protein that is always active, producing a constant signal to pass through the cell cycle’s restriction point

⇒ The RB gene restrains cell proliferation by inhibiting passage through the restriction point

Inactivation of both RB alleles therefore allows unrestrained passage through the restriction point

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16
Q

Describe the role of proto-oncogenes and tumour suppressor genes respectively

A
  • Proto-oncogenes can encode growth factors e.g. PDGF, growth factor receptors e.g. HER2, plasma membrane signal transducers e.g. RAS, cell cycle regulators e.g. CYCLIN D1 or apoptosis regulators e.g. BCL2
  • TS genes encode proteins in the same pathways but with anti-growth effects e.g. TP53
17
Q

For the following conditions, describe the type of repair system which is mutated and its overal effect on the genome:

  • Xeroderma pigmentosum
  • Hereditary non-polyposis colon cancer syndrome
  • Familial breast carcinoma
A
  • Xeroderma pigmentosum: nucleotide excision repair → nucleotide instability
  • HNPCC syndrome: mismatch repair → microsatellite instability
  • Familial breast carcinoma: double strand break (BRCA1&2) → chromosomal instability
18
Q

What is genetic instability?

A

Genetic instability are a series of alterations in chromosome segregation during mitosis which account for the accelerated mutation rate found in malignant neoplasms

19
Q

Which genes maintain genetic stability?

A

Genes that maintain genetic stability belong to a class of tumour suppressor genes called caretaker genes

20
Q

This steady accumulation of multiple mutations is called cancer progression.

In terms of a colon carcinoma, illustrate how multiple mutations are required to make a neoplasm

A
21
Q

It is now believed that a fully evolved malignant neoplasm exhibits six hallmark signs of cancer plus one enabling feature.

What are these hallmark signs?

A
  • Self-sufficiency in growth signals
  • Resistance to growth stop signals
  • No limit on the number of times a cell can divide (cell immortalisation)
  • Sustained ability to induce new blood vessels (angiogenesis)
  • Resistance to apoptosis
  • The ability to invade and produce metastases
22
Q

It is now believed that a fully evolved malignant neoplasm exhibits six hallmark signs of cancer plus one enabling feature.

Identify an enabling characteristic of malignant neoplasms

A

Genetic instability is regarded as an enabling characteristic

23
Q

Approximately 12% of breast cancers are known to be hereditary/familial and most of these are attributed to mutations in the BRCA1 or BRCA2 genes.

What type of genes are the aforementioned and what do they do?

A
  • BRCA1 or BRCA2 genes are tumour suppressor genes
  • Their proteins repair damaged DNA and maintain genomic integrity
24
Q

Illustrate Knudson’s two hit hypothesis for oncogenesis in familial and sporadic cancers

A
25
Q

What other cancers are people with germline BRCA1 and BRCA2 likely to suffer from?

A
  • BRCA1 – ovary (20-40%), prostate, pancreas, fallopian tube
  • BRCA2 – ovary (10-20%), male breast cancer, prostate, pancreas
26
Q

Breast cancers associated with BRCA1 are commonly poorly differentiated and triple negative.

In this context, what does triple negative mean and what implications does this have for the treatment of the patient?

A

Triple negative cancers do not express oestrogen receptor, progesterone receptor or Her2 receptors:

  • Thus, they don’t respond to endocrine treatment or treatment with Herceptin (trastuzumab)
  • However, they often show a better response to chemotherapy than some other breast cancers

27
Q

Which other germline gene mutations confer an increased risk for breast cancer?

A
  • p53 (Li-Fraumeni syndrome)
  • CHEK2
28
Q

What effect does smoking have on the bronchial epithelium?

A

It acts as an irritant and causes squamous metaplasia which can progress to squamous dysplasia which can result in carcinoma-in-situ and then invasive carcinoma

29
Q

What types of lung cancer are associated with smoking?

A
  • Squamous cell carcinoma
  • Small cell carcinoma
  • Adenocarcinoma (lesser extent)

30
Q

What other types of tumours are associated with cigarette smoking?

A

Carcinomas of mouth, pharynx, larynx, oesophagus and pancreas

31
Q

Colon cancer can occur in families.

What are they two recognised inherited forms of colon carcinomas?

A
  • Familial adenomatous polyposis (FAP)
  • Hereditary non-polyposis colon cancer (HNPCC)
32
Q

What is Hereditary non-polyposis colon cancer?

A
  • HNPCC is an autosomal dominant familial syndrome due to mutations in the DNA mismatch repair genes (caretaker genes)
  • Cancers tend to occur in patients < 50 years old and malignancies are often in the caecum and proximal colon
33
Q

What is familial adenomatous polyposis?

A
  • FAP is an autosomal dominant inherited condition in which numerous adenomatous polyps form mainly in the epithelium of the large intestine
  • While these polyps start out benign, malignant transformation into colon cancer occurs when they are left untreated
34
Q

What are the clinical and pathological features of familial adenomatous polyposis?

A
  • Colonic adenomas that carpet the mucosal surface (2500-5000)
  • Polyps (tubular adenomas) elsewhere in the GI tract e.g. ampulla of Vater, stomach
35
Q

Describe the treatment and incidence of FAP

A
  • Progression to colon cancer occurs in approximately 100% of patients by the age of 50 years
  • The disease needs early detection and prophylactic colectomy – also in siblings and first degree relatives
36
Q

Which gene is involved in the progression of FAP and HNPCC to colon cancer?

A

An autosomal dominant mutation of the tumour suppressor gene – adenomatous polyposis colon (APC) gene

37
Q

Under normal circumstances, what does the APC gene do?

A

The APC gene encodes a protein that binds to microtubule bundles and promotes cell migration and adhesion and plays a role in normal intestinal epithelial development

38
Q

Illustrate the adeno-carcinoma sequence

A
39
Q

How do alterations in DNA mismatch repair genes make an individual susceptible to cancer?

A
  • These genes are involved in genetic ‘proofreading’ during DNA replication
  • With homozygous loss of mismatch repair genes, mutation rates are up to 1,000 times higher than normal