Lecture 12 - Cancer

Question 1

Cancer

Answer 1

Neoplasia, either malignant (invading adjacent tissue - 2nd tumour generation) or benign (restricted to anatomical site)

Question 2

Tumours

Answer 2

Monoclonal in origin

Takes years to develop as it progressively increases

Normal epithelium -> hyperplastic epithelium -> dysplastic epithelium -> benign neoplasm > malignant neoplasm -> metastasis

Question 3

Dysplasia

Answer 3

Abnormal cell growth in tissue to a precancerous degree - may not always become cancerous but has the potential to be

Question 4

Hyperplasia

Answer 4

Abnormal cell growth in tissue - often used with regard to cancer

Question 5

Epithelial cancer

Answer 5

Carcinoma - 80% of cancers

Glandular/mucular cancer - adenocarcinoma

Question 6

Connective tissue/muscle/fat/bone cancers

Answer 6

Sarcoma:

Myosarcoma/liposarcoma/osteosarcoma

Question 7

Brain/nervous system cancer

Answer 7

Blastoma

Neuroblastoma, glioblastoma, Schwannoma

Question 8

Blood/bone marrow/lymphoid cancer

Answer 8

Leukaemia, lymphoma

Question 9

Neural crest/neuroendocrine

Answer 9

Diverse - melanoma is one

Question 10

Carcinogens and aetiological factors

Answer 10

Agents strongly associated with cancer

Factors that have an extremely strong association with cancer:

watch leccy

Question 11

Cancer risk factors: what do they do and what are some examples?

Answer 11

Risk factors increase our exposure to aetiological agents and/or otherwise exacerbate disease progression

• Occupation - e.g. asbestos mining and mesothelioma
• Reproductive history - e.g. age of first pregnancy, number of pregnancies and breast cancer
• Diet - e.g. high-fat, red meat, processed food
• Lifestyle - e.g. smoking, drinking, sexual promiscuity, sunbathing
• Family history - cancer susceptibility can show Mendelian inheritance or polygenic inheritance

Question 12

Ames test

Answer 12

Used to test carcinogenic properties

Used in testing products to determine their mutagenic properties for safety

Mutagenicity and carcinogens are directly correlated

Question 13

Tumour promoters

Answer 13

Not all agents that induce tumours are mutagens/genotoxic (e.g. asbestos), these substances are called tumour promoters

They stimulate the growth of mutated cells

Promoters can be endogenous or exogenous growth factors, but also toxic compounds that induce compensatory proliferation

Potentially, it is ‘environmental’ exposure to promoters rather than carcinogens (which are often only present at low doses in the environment) which constitutes the commonest avoidable cancer risk

Question 14

Oncogenes

Answer 14

Act dominantly - one allele enough

Protooncogene

• Amplification
• Translocation
• Missense mutation (gain of function)
• Incorporation into acutely transforming retroviruses
• Insertion of retrovirus/transposon
• ?

Transcriptional activation

SRC, RAS, MYC

Question 15

Tumour suppressor genes

Answer 15

Act recessively - need both copies mutated for an effect

• Deletion
• Nonsense mutation
• Missense mutation - loss of function (LOF)
• Inactivated by proteins encoded by DNA tumour viruses (?)
• Insertion of retrovirus or transposon

Transcriptional repression, promoter silencing by methylation

p53, RB, APC, PTEN

Question 16

Abl in leukaemia: what two genes are formed by translocation, what chromosomes are involved in the translocation, what is the end result, what does the protein normally do, what does the carcinogenic form do, and what cancers are produced?

Answer 16

The translocation in CML results in the rearrangement of two genes: Breakpoint Cluster Region (BCR) and the Abelson Leukaemia Virus proto-oncogene (ABL)

Expression of a fusion protein

ABL encodes a non-receptor tyrosine kinase involved in growth and survival signalling

Somehow the fused product is deregulated (signals constitutively) stimulating the proliferation of leukaemia cells

ALL, acute lymphoblastic leukaemia; CML, chronic myeloid leukaemia; CNL, chronic neutrophilic leukaemia

Question 17

Retinoblastoma: what is it, what are the forms, how is the second hit formed, how is the first hit formed, and what is encompassed in both forms?

Answer 17

Hereditary - passed down from the parents

Sporadic retinoblastoma - random form involving one eye, passed down spontaneously

Familial retinoblastoma - familial form involving both eyes, passed down from parents

Second hits occur through independent mutational events and non-disjunction events - mitotic recombination is perhaps the commonest mechanism for generating a second hit

The former had one hit in a tumour suppressor gene in the germline that was passed down

The latter required that the first and second mutations occur in a somatic cell

It is accompanied by a loss of heterozygosity (LOH) in the affected area - so can be used to visualise LOH and pinpoint TSG location as LOH is frequently detected the closer the physical distance between the marker and affected gene

Question 18

Driving tumour progression: normal -> hyperplastic epithelia -> early adenomas -> intermediate adenomas -> late adenomas -> carcinoma -> invasion and metastasis

Answer 18

Loss of adenomatous polyposis coli (APC) - tumour suppressor gene

DNA hypomethylation - decrease in the content of 5-methylcytosine in the genome (decrease in tissue-specific transcription control)

Activation of k-Ras - Ras is involved in the regulation of cell growth, division, and differentiation transducing signals from the extracellular environment to the cell nucleus

Loss of 18q TGS - loss of a TSG

Loss of p53 - p53 gene makes a tumour suppressor protein (TP53)

Question 19

How many mutations from carcinogens are needed to cause cancer?

Answer 19

6-7 mutagenic events roughly

Question 20

How is genome instability caused?

Answer 20

DNA damage, defective chromosome maintenance and segregation

Question 21

DNA damage: what causes it, what specific molecules cause it, and what does it cause?

Answer 21

Carcinogens/mutagens

Reactive oxygen species O₂*⁻, H₂O₂, NO, OCl⁻ (oxidative phosphorylation, intracellular metabolism, ionizing radiation, phagocytes)

• Errors during DNA replication
• Defective repair mechanisms

Question 22

Defective chromosome maintenance and segregation

Answer 22

Defective mitosis
Erosion of telomeres

Question 23

DNA damage repair pathways

Answer 23

Direct reversal pathway
Mismatch repair pathway
Nucleotide excision repair pathway
Base excision repair pathway
Homologous pathway
Non-homologous end-joining pathway

Question 24

Direct reversal pathway: what is it, name one big strength, and what mechanisms are there behind it?

Answer 24

Direct repair of the DNA

No DNA synthesis is required to correct the error - error-free

Photolyases, alkyltransferases, and dioxygenase-mediated mechanisms used along with the main two mechanisms - O6-methylguanine-DNA methyltransferase (MGMT) and the alkylated DNA repair protein B (AlkB) homologs

Question 25

Mismatch repair pathway: the four main steps

Answer 25

Recognition of a mismatch by the MutS homologs (MSHs)

Recruitment of the MutL homologs (MLHs) by ATP-bound MSHs that then connect the mismatch recognition signal to the distant DNA strand scission where excision begins

Excision of the DNA strand containing the wrong nucleotide

Resynthesis of the excision gap by the replicative DNA polymerase using the remaining DNA strand as a template

Question 26

Nucleotide excision repair pathway

Answer 26

Removal of a damaged nucleotide by dual incisions bracketing the lesion, accomplished by a multisubunit enzyme – excision nuclease or exonuclease

Question 27

Base excision repair pathway

Answer 27

Corrects small DNA lesions (e.g., those caused by oxidation) - a DNA glycosylase removes the damaged base; short-patch or long-patch repair then fills the gap

Small base lesions are corrected in a way that does not significantly distort the DNA helix structure

Question 28

Homologous pathway: what is it and when does it occur?

Answer 28

Mechanism in cells to repair double-strand DNA lesions

Occur in DNA before the cell enters mitosis during the S and G2 phases of the cell cycle

Question 29

Non-homologous end-joining pathway

Answer 29

Highly versatile pathway that utilizes an array of processing enzymes to modify damaged DNA ends and enable their ligation

Question 30

Aneuploidy

Answer 30

The condition of having an abnormal number of chromosomes in a haploid set

Question 31

Darwinian evolution theory in cancer progression

Answer 31

Each mutation could potentially help a cancer cell adapt to its environment better to survive, more and more mutations occur until the cancerous cell is dominant in the neoplasm