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Cellular and Molecular pathology > 9. Cancer genetics 1: inherited mutations in oncogenes > Flashcards

9. Cancer genetics 1: inherited mutations in oncogenes Flashcards

1. The genetic role of cancer predisposition 2. Inherited proto-oncogenes 3. Clinical applications of molecular genetics in human cancer

1
Q

what is cancer?

A

A genetic disease

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2
Q

What kind of things can be carcinogens?

A
  1. Fungi/Viruses/bacteria
  2. Environmental agents like UV, smoke and asbestos
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3
Q

How many cancer genes are there?

A

more then 700 or 2/3% of the human genome

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4
Q

what is the distribution of mutation type in cancer genes?

A

80% are affected by only somatic mutations
10% are affected by only germline mutations
10% are affected by both somatic and germline mutations

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5
Q

What percentage of cancers are caused by somatic mutations?

A

95%

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6
Q

What is the disease process for sporadic cancers?

A
  1. a somatic mutation where 1 cell is affected.
  2. usually needs more then 1 mutation
  3. needs time to develop mutations and grow into a tumour.
  4. late onset
  5. 1 main tumour
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7
Q

What percentage of cancers are caused by germline mutations?

A

~5%

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8
Q

what is the disease process for germline cancers?

A
  1. Inherited mutation that affects all cells
  2. Doesn’t always need multiple mutations
  3. much earlier onset with a family history of the disease
  4. multiple cancer and other abnormalities
  5. shares characteristics with other genetic disorders
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9
Q

Examples of germline cancers being more problematic than sporadic

A
  1. Germline breast cancers are much more likely to affect both breasts or invade the lymph nodes
  2. Much more likely to develop other primary cancers once the initial one if cured
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10
Q

What is Lynch syndrome?

A
  1. a hereditary nonpolyposis colon cancer
  2. effects siblings and across multiple generations
  3. often early onset in 40s
  4. use NGS to assess the risk to other family members
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11
Q

Why do we focus on inherited cancers when they are only 5% of cancers?

A
  1. Find targets and improve genetic testing
  2. help identify the driving mutations needed for all cancers
  3. less heterogeneity so they are easier to study
  4. find treatments that will work on all cancers
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12
Q

What are proto oncogenes?

A
  1. a gene where a mutation in 1 allele can give a phenotypic change
  2. gain of function mutation or enhancing the function
  3. dominant mutation
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13
Q

What is a tumour suppressor gene?

A
  1. a gene where a mutation in both alleles is needed to cause a phenotypic change
  2. loss of function mutation so deletions or inactivations
  3. usually DNA repair genes
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14
Q

What tends to be the normal role of proto-oncogenes?

A

Fundamental cell processes like:
1. Regulation of cell proliferation
2. Regulation of differentiation
3. Regulation of apoptosis
4. Regulation of senescence

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15
Q

When do proto-oncogenes contribute to cancer?

A
  1. If the gene product is altered
  2. if the gene is inappropriately expressed. Either wrong cell or wrong time
  3. if the gene is overexpressed and produces too much protein
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16
Q

How can oncogenes be activated?

A
  1. A point mutation in the DNA sequence that only leads to an altered protein
  2. Gene amplification which leads to overexpression of a normal protein
  3. Chromosomal translocations or rearrangements
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17
Q

how can chromosomal translocations or rearrangements lead to activation of proto-oncogenes?

A
  1. give rise to a new gene product
  2. move the proton-oncogene to a transcriptionally active region so a normal protein is not expressed or controlled in the usual way
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18
Q

Are proto-oncogenes important in inherited cancers?

A
  1. yes
  2. It was once thought that the proto-oncogenes were fundamental to life and that a mutation in one would result in death. This is not the case
  3. Many proteins come from a family of genes that can compensate for the loss of another protein
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19
Q

What is RET?

A
  1. An oncogene that causes multiple endocrine neoplasia
  2. Activated by a germline missense mutation
  3. causes 2 conditions called MEN2A and MEN2B
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20
Q

What is MEN2A?

A
  1. Multiple endocrine neoplasia 2A
  2. 100% of people with this condition will develop thyroid cancer
  3. 50% will develop pheochromocytoma. (a benign adrenal tumour)
  4. 10-20% will develop parathyroid hyperplasia (dysregulates the amount of calcium in the blood
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21
Q

What is MEN2B?

A
  1. multiple endocrine neoplasia
  2. 100% will get thyroid cancer
  3. 50% will get pheochromocytoma
  4. 98% will get GI and mucosal neuromas which attack the mucosal surface
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21
Q

What happens when RET is mutated?

A
  1. mutations in the extracellular domain that causes ligand-independent dimerisation and activation
  2. mutations in the intracellular domain which so the signalling is always active (more aggressive cancers)
21
Q

What cancers can RET mutations be found in?

A

sporadic and inherited thyroid cancers

22
Q

What does the location of the mutation determine?

A
  1. what type of cancer will develop
  2. how quickly the cancer will develop
22
Q

What is the structure and function of RET?

A
  1. it encodes a tyrosine kinase
  2. uses the ligand GDNF and the coreceptor GDNFRa
  3. normally dimerises when the ligand is bound and causes a kinase signalling cascade
23
Q

What does inactivation of RET lead to?

A
  1. Hirschsprung disease
  2. not any cancer
  3. causes a lack of innervation of the gut meaning the intestines don’t work properly
24
Q

What is MET?

A
  1. another tyrosine kinase that promotes matric invasion
  2. Ligand = hepatocyte growth factor (HGF)
  3. gene on chromosome 7q
25
Q

What do germline MET mutations cause?

A
  1. Hereditary papillary renal carcinoma
  2. Missense mutations
  3. Mutation is homologous to RET
    (somatic MET mutations also found in kidney cancer)
26
Q

What is KIT and what cancers does it effect?

A
  1. Another tyrosine kinase receptor
  2. Ligand = stem cell factor
  3. it is important in development and haematopoiesis
  4. somatic and germline mutations are found in gastrointestinal cancers
  5. melanocyte can have this mutation
  6. loss of function mutations can cause piebaldism
27
Q

What is haematopoiesis?

A

the development of blood from stem cells

28
Q

What is ALK and what cancers is it found in?

A
  1. a tyrosine kinase with an unknown ligand which makes it hard to study
  2. somatic and germline mutations in neuroblastomas
29
Q

What is the function of CDK4?

A
  1. Phosphorylates Rb1 to allow the cell to enter the S phase
  2. It is important for cell cycle control
30
Q

What is p16?

A
  1. It is a CDK4 inhibitor
  2. It keeps the function of CDK4 in the correct place in the cell cycle
  3. Prevents the cell cycle progressing if the cell fails the G1 check point
31
Q

What does a mutation in p16 or CDK4 cause?

A
  1. Unregulated Cell cycle
  2. Familial malignant melanoma
32
Q

What is the most common oncogenic mutation in CDK4?

A

A dominant missense mutation that prevents p16 binding CDK4 leaving its activity unregulated

33
Q

What are the 3 Ras genes?

A
  1. K-Ras
  2. H-Ras
  3. N-Ras
34
Q

What can germline mutations in Ras signalling cause?

A
  1. cancers
  2. developmental syndromes
35
Q

What are indicators to send someone for genetic screening?

A
  1. Family history
  2. Early onset tumour
  3. Multiple tumours
  4. Other abnormalities about their cancer
36
Q

What kind of molecular genetic tests are done?

A
  1. Karyotyping if a chromosomal abnormality is suspected
  2. Next gen sequencing to search for known mutations
37
Q

What are the benefits of genetic screening in cancers?

A
  1. Early screening = early diagnosis and treatment = better survival
  2. Genetical counselling for prospective parents
  3. prenatal diagnosis
38
Q

what non-inherited factor do we genetically screen for?

A

Papillomavirus that causes cervical cancer which we screen using PCR

39
Q

How do we normally provide cancer diagnosis and when is this not suitable?

A
  1. Using staining and microscopy by a pathologist
  2. In very undifferentiated tumours it is hard to see the differences so we use molecular genetics
40
Q

Molecular genetic screening: gene expression

A
  1. Expression profiling using microarrays or RNA sequencing
  2. Microarrays show the unregulated and down regulated genes and the combination of these can give a diagnosis and inform treatment
41
Q

Molecular genetic screening: chromosome translations

A
  1. Use karyotyping with a probe for specific chromosomes to see bits in the wrong place
  2. RT-PCR where you design primers that flank the region of the fusion protein as a band will appear
42
Q

What is Ewing sarcoma?

A
  1. A bone cancer
  2. Caused by a Chr11 to Chr22 translocation
  3. causes a fusion protein
43
Q

Molecular genetic screening: Immunoglobulin and T cell receptor rearrangements

A
  1. Use to detect the different rearrangements in the cells
  2. There should be the same amount of all the clones
  3. Mutated T cells or Ig could have a growth advantage and then create an imbalance in the number of cells
  4. This can cause cancer
44
Q

Molecular genetic screening: Whole genome sequencing

A
  1. See specific mutations
  2. see the copy number of each gene
  3. look at the combination of mutations to inform treatment
  4. most cancers have a molecular signature
45
Q

Molecular genetics in prognosis: Gene amplification

A
  1. Myc-N amplification is more likely to indicate a poor prognosis in neuroblastoma
  2. a higher fold increase indicates a worse prognosis
  3. detect this and provide more aggressive initial treatment
46
Q

Molecular genetics in prognosis: Minimal residual disease in leukaemia

A
  1. A small number of cancer cells are left in the body after treatment despite no symptoms and it looking like remission
  2. We used to detect these by eye looking at blood samples
  3. months or years later a relapse would occur as the cancer wasn’t eliminated
  4. now done by PCR as it is much more sensitive
47
Q

Molecular genetics in prognosis: expression profiling

A
  1. using microarrays
  2. see the amplified genes to inform treatment
48
Q

Molecular genetics in therapy: Improved diagnosis

A
  1. Optimises conventional treatment
  2. detect and treat cancers earlier
  3. target novel therapies to the right patients
49
Q

Molecular genetics in therapy: New treatments

A
  1. potential gene therapy to replace TSG, shut off oncogenes or interfere
  2. A decade of research hasn’t found a good gene therapy
  3. Anti-p53 virus to selectively kill mutant p53 in cells but this only works well in vitro
  4. Rational drug design like inhibitors
50
Q

What is gefitinib?

A
  1. A EGFR inhibitor for lung cancer
  2. worked really well in animal models
  3. targets mutation in only 15% of cancers so not a universal treatment but one for personalised medicine

Cellular and Molecular pathology (25 decks)

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