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Genetics > Cancer in families and individuals > Flashcards

Cancer in families and individuals Flashcards

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1
Q

Cancer is a genetic disease

A

Caused by accumulation of genetic changes in malignant cells that lead to altered levels of transcription/ aberrant gene transcripts

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2
Q

Aneuploidy

A

Full chromosomal number changes:

monosomy, trisomy

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3
Q

Translocation

A

Bits of chromosomes translocated to other chromosome

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4
Q

Macro-deletions and macro-insertions

A

whole arm/ most arm deleted/ duplicated

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5
Q

Large insertions or deletions

A

Large insertions/ deletions
200 kb inserted/ deleted
Not so significant in cancer

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6
Q

Full chromosome mutations

A

Aneuploidy
Translocation
Macro-deletions and Macro-insertions

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7
Q

3 types of point mutation

A

Silent
Missense
Nonsense

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8
Q

Silent mutation

A

change in base results in triplet coding for same protein so no change in primary structure of protein

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9
Q

Missense mutation

A

change in codon means that it codes for a different protein

Hence alters structure of the protein= abnormal

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10
Q

Nonsense mutation

A

change means mutated codon becomes a stop codon

=truncated protein

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11
Q

Which point mutation is most relevant in cancer genetics?

A

Nonsense mutation

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12
Q

What are the main types of cancer genetic mutations?

A

Aneuploidys

Point mutations

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13
Q

What are the 6 hallmarks that characterise all cancers?

A 
Dysregulated growth
	Autologous pro-growth signalling
	Insensitive to anti-growth signalling
Evasion of apoptosis
Limitless replication
Sustained angiogenesis
Invasion/metastasis
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14
Q

What are the 4 additional hallmarks of cancer?

A

Dysregulation of energy metabolism
Promotion of inflammation
Genome instability and mutation
Evasion of immune system

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15
Q

Polyclonal disease

A

many clones exist in 1 tumour
Different clones in tumour going for different selective advantages
Confer a selective advantage to cell
BUT fatal to organism

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16
Q

Driver mutation

A

1st key mutation in cell, turning normal cell into malignant cell

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17
Q

Why is it important to understand driver mutations?

A

Understand how disease develops
Diagnose more accurately
Devise targeted therapy
Monitor response to therapy

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18
Q

Tumour suppressor genes

A

STOP signals in cell cycle

Mediators of DNA replication

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19
Q

Where do tumour suppressor genes act as “checkpoint proteins”?

A

G1-S checkpoint

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20
Q

Where do tumour suppressor genes lead damaged cells?

A

To cell repair or apoptosis

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21
Q

What do mutations in tumour suppressor genes result in?

A

Uncontrolled cell division

= Malignancy

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22
Q

Two-hit hypothesis

A

Both TSG alleles must have mutated for cancerous cell to arise

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23
Q

What is usually the 1st hit in the two-hit hypothesis?

A

Point mutation

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24
Q

What is usually the 2nd hit in the two-hit hypothesis?

A

A more gross change:
which removes the other allele of gene
hit 2 is often a larger deletion

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25
Q

What effect does hit 1 have?

A

Reduces transcript/protein level

But is insufficient to cause a phenotypic effect.

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26
Q

What gives the cell malignant potential?

A

Inactivation of 2nd allele of TSG

Causing total loss of transcription

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27
Q

What does Retinoblastoma (pRB) checkpoint protein usually do?

A

Binds to a transcription factor E2F

Prevents E2F from functioning

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28
Q

What happens if there is a mutation in retinoblastoma (pRB)?

A

E2F doesn’t bind effectively

E2F gives uncontrolled growth signals to cells

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29
Q

Familial retinoblastoma

A

Child born with 1 RB mutation (Hit 1)
Acquires 2nd later in life
Often bilateral

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30
Q

Sporadic retinoblastoma

A

Acquire 1st somatic mutation (Hit 1)

Acquire 2nd somatic mutation in same cell (Hit 2)

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31
Q

Loss of Heterozygosity (LOH)

A

1st hit a point mutation on gene in 1 of the alleles
2nd hit a large deletion, which removes TSG in other chromosome along with a relatively large amount of other genetic material.
As 2nd hit removes a large chunk of DNA, there will be some alleles which were originally heterozygous which will be removed.
So, only 1 allele of a previously heterozygous gene would remain and hence appear to be homozygous.

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32
Q

Names a primitive way of finding cancer genes

A

Searching for regions of loss of heterozygosity

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33
Q

Single-nucleotide polymorphism (SNP)

A

DNA sequence variation occurring when a single nucleotide A,T,G or C in the genome (or other shared sequence) differs between members of a species or paired chromosomes in an individual.

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34
Q

Prevalence of SNPs in the DNA sequence

A

SNPs occur frequently

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35
Q

On an SNP array what are there many of?

A

Heterozygous SNPs

36
Q

What happens if you sequence a deleted area of chromosome (e.g. Hit 2)?

A

Through millions of bases there would be no SNPs
As there’s only 1 chromosome
This indicates regions containing oncogenes

37
Q

Proto-oncogenes

A

Normal genes that promote growth and proliferation

38
Q

Give 3 examples of Proto-oncogenes

A

Growth factors
Transcription factors
Tyrosine Kinases

39
Q

Activated oncogenes

A

Porto-Oncogenes that have gained a function change

“Over-ride” apoptosis, allowing damaged cells to survive and proliferate

40
Q

Origins of cancer

A

99% Sporadic (non-inherited): random events of ageing cells

1% Germline (Inherited): born with change that predisposes them to cancer

41
Q

Inherited predisposition to breast cancer

A

2-4% breast cancer cases caused by germline mutation of BRCA1 (More common) or BRCA2

42
Q

What does germline mutation of BRCA1 or BRCA2 increase risk of?

A

Ovarian cancer

43
Q

What do BRCA2 mutations predispose men to?

A

Breast cancer

44
Q

What is the lifetime risk of breast cancer for those with BRCA mutations?

A

60%

45
Q

Describe the role of functioning BRCA genes.

A

BRCA genes are DNA repair genes

Repair double strand breaks in DNA by homologous recombination

46
Q

Describe the patho-genetic mechanism of mutated BRCA genes.

A

DNA repair proteins are impaired leading to dysfunctional DNA repair proteins
Can’t repair double strand breaks in DNA
Large insertions/deletions develop

47
Q

BRCA is a large gene

A

No 1 mutation

Many different mutations (deletions, insertions, non-sense)

48
Q

BRCA screening

A

Involves sequencing entire BRCA gene

49
Q

What are 2 syndromes that predispose to colorectal cancer and what are the relative lifetime risks?

A

Familial Adenomatous Polyposis: ~100%

Hereditary Non-Polyposis Colorectal Cancer (HNPCC): 80%

50
Q

Familial adenomatous polyposis (FAP)

A

Innumerable number of polyps in colon, each has a small chance of becoming malignant

51
Q

What is the genetic cause of FAP?

A

Mainly by mutation of APC gene on chromosome 5, autosomal dominant condition.
Very small % caused by defects in MUTYH gene, autosomal recessive.

52
Q

What is Hereditary Non-Polyposis Colorectal Cancer (HNPCC) also called?

A

Lynch syndrome

53
Q

What is the most common inherited syndrome increasing risk of colorectal cancer?

A

Lynch syndrome

54
Q

What are those with Lynch syndrome at risk of?

A

Other malignancies

Endometrial, Ovarian, Upper GI, Brain, Skin

55
Q

What is the genetic cause of Lynch syndrome?

A

Mutations of MSH2 and MLH1 genes
Both autosomal dominant
Strong family history of cancer, usually at an early age

56
Q

When are inherited cancer syndromes suspected?

A

Strong family history of cancer
Manchester criteria: suspect women with BRCA mutations
Amsterdam criteria: suspect people with colorectal cancer

57
Q

What action is taken if cancer is suspected?

A

Genetic screening

Genetic counselling

58
Q

What action is taken if someone is mutation positive?

A

Surveillance: e.g. More frequent mammogram tests
Prophylactic surgery: e.g. Colon removed
Chemoprevention: e.g. long term suppressant
Family work-up: ensure those at risk tested

59
Q

Genome wide association studies (GWAS)

A

“SNP fishing” for SNPs more common in cancer

Identifies possible candidate genes/genomic regions

60
Q

Transcriptome Chips/mRNA array

A

Compares expression profile of malignant vs. normal tissues: compare which genes are over/ under expressed in the tumour.
Identifies possible candidate genes
Tries to identify which proteins might be implicated in pathogenesis of disease.

61
Q

Cytogenetic changes

A

Visible changes in chromosome structure or number

62
Q

Examples of cytogenetic changes

A

Aneuploidy
Translocation
Macrodeletions
Macroduplications

63
Q

What are important in all cancers?

A

Cytogenetic changes

64
Q

When do cytogenetic changes arise?

A

Causal “driver”
or
Accumulate during disease progression

65
Q

What causes cytogenetic changes to arise?

A

Non-disjunction during cell division

66
Q

Translocations in cancer

A

2 regions of chromosomes abnormally joined to form hybrids

Can lead to fusion genes, with potentially oncogenic properties

67
Q

Chronic myeloid leukaemia (CML)

A

Clonal myeloproliferative disorder

= overproduction of mature granulocytes

68
Q

What accounts for 15% of adult leukaemia?

A

Chronic myeloid leukaemia

69
Q

What are the 3 stages of chronic myeloid leukaemia?

A

Chronic (benign)
Accelerated (ominous)
Blast crisis (acute leukaemic, invariably fatal) (1/3 patients)

70
Q

What is chronic myeloid leukaemia characterised by?

A

Philadelphia chromosome
Formed by translocation where part of Chr9 fuses with Chr22
Forms BCR-ABL1 fusion protein

71
Q

What does the BCR-ABL1 fusion protein become?

A

New Tyrosine Kinase that shouldn’t exist

Perfect target- is a protein only the cancer produces and is cause of cancerous behaviour of CML cells

72
Q

Describe, using an example, a targeted therapy for CML.

A

Imatinib
Blocks ATP binding site of BCR-ABL1
=Targeted gene therapy

73
Q

How is early detection of disease relapse in CML achieved?

A

Quantitative Reverse Transcriptase PCR (q-RT-PCR)

74
Q

Prevalence of Acute myeloid leukaemia (AML) relative to CML

A

AML is much rarer than CML

75
Q

What characterises AML histologically?

A

Auer rods in the cell

76
Q

Name a variant of AML?

A

Acute promyelocytic leukaemia (APML/ AML-M3)

77
Q

What is Acute promyelocytic leukaemia (APML/ AML-M3)?

A

Abnormal accumulation of immature granulocytes called promyelocytes

78
Q

What causes Acute promyelocytic leukaemia (APML/ AML-M3)?

A

Translocation between Chr 17 and 15

79
Q

Which 2 genes are involved in the APML/AML-M3 translocation?

A

Chromosome 15 = PML (Promyelocytic Leukaemia)

Chromosome 17 = RARA (Retinoic Acid Receptor Alpha)

80
Q

What is RARA?

A

Regulator of DNA transcription

81
Q

How is PML-RARA protein harmful?

A

Binds too strongly to DNA
Blocks normal transcription and differentiation of granulocytes
All blasts produced (immature cells) are malignant

82
Q

What is present in all APML?

A

PML-RARA

83
Q

What does all trans retinoid acid (ATRA) therapy do?

A

Dissociates PML-RARα from DNA allowing normal transcription and normal differentiation
ATRA does not kill cells

84
Q

How is APML monitored

A

Cytogenetics
and/or FISH
and/or RQ-PCR

85
Q

What is the point of Pharmacogenomics?

A

Examines effect of genetic variation on drug choice
Identify which patients are most likely to respond to certain cancer drugs
Assay presence/absence of particular somatic mutations

86
Q

What cells are involved in Lymphoid leukaemias?

A

B Cells

T Cells

87
Q

What cells are involved in Myeloid leukaemias?

A

Monocytes

Neutrophils

Genetics (7 decks)

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