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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
What effect does hit 1 have?
Reduces transcript/protein level | But is insufficient to cause a phenotypic effect.
26
What gives the cell malignant potential?
Inactivation of 2nd allele of TSG | Causing total loss of transcription
27
What does Retinoblastoma (pRB) checkpoint protein usually do?
Binds to a transcription factor E2F | Prevents E2F from functioning
28
What happens if there is a mutation in retinoblastoma (pRB)?
E2F doesn't bind effectively | E2F gives uncontrolled growth signals to cells
29
Familial retinoblastoma
Child born with 1 RB mutation (Hit 1) Acquires 2nd later in life Often bilateral
30
Sporadic retinoblastoma
Acquire 1st somatic mutation (Hit 1) | Acquire 2nd somatic mutation in same cell (Hit 2)
31
Loss of Heterozygosity (LOH)
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.
32
Names a primitive way of finding cancer genes
Searching for regions of loss of heterozygosity
33
Single-nucleotide polymorphism (SNP)
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.
34
Prevalence of SNPs in the DNA sequence
SNPs occur frequently
35
On an SNP array what are there many of?
Heterozygous SNPs
36
What happens if you sequence a deleted area of chromosome (e.g. Hit 2)?
Through millions of bases there would be no SNPs As there's only 1 chromosome This indicates regions containing oncogenes
37
Proto-oncogenes
Normal genes that promote growth and proliferation
38
Give 3 examples of Proto-oncogenes
Growth factors Transcription factors Tyrosine Kinases
39
Activated oncogenes
Porto-Oncogenes that have gained a function change | "Over-ride" apoptosis, allowing damaged cells to survive and proliferate
40
Origins of cancer
99% Sporadic (non-inherited): random events of ageing cells | 1% Germline (Inherited): born with change that predisposes them to cancer
41
Inherited predisposition to breast cancer
2-4% breast cancer cases caused by germline mutation of BRCA1 (More common) or BRCA2
42
What does germline mutation of BRCA1 or BRCA2 increase risk of?
Ovarian cancer
43
What do BRCA2 mutations predispose men to?
Breast cancer
44
What is the lifetime risk of breast cancer for those with BRCA mutations?
60%
45
Describe the role of functioning BRCA genes.
BRCA genes are DNA repair genes | Repair double strand breaks in DNA by homologous recombination
46
Describe the patho-genetic mechanism of mutated BRCA genes.
DNA repair proteins are impaired leading to dysfunctional DNA repair proteins Can't repair double strand breaks in DNA Large insertions/deletions develop
47
BRCA is a large gene
No 1 mutation | Many different mutations (deletions, insertions, non-sense)
48
BRCA screening
Involves sequencing entire BRCA gene
49
What are 2 syndromes that predispose to colorectal cancer and what are the relative lifetime risks?
Familial Adenomatous Polyposis: ~100% | Hereditary Non-Polyposis Colorectal Cancer (HNPCC): 80%
50
Familial adenomatous polyposis (FAP)
Innumerable number of polyps in colon, each has a small chance of becoming malignant
51
What is the genetic cause of FAP?
Mainly by mutation of APC gene on chromosome 5, autosomal dominant condition. Very small % caused by defects in MUTYH gene, autosomal recessive.
52
What is Hereditary Non-Polyposis Colorectal Cancer (HNPCC) also called?
Lynch syndrome
53
What is the most common inherited syndrome increasing risk of colorectal cancer?
Lynch syndrome
54
What are those with Lynch syndrome at risk of?
Other malignancies | Endometrial, Ovarian, Upper GI, Brain, Skin
55
What is the genetic cause of Lynch syndrome?
Mutations of MSH2 and MLH1 genes Both autosomal dominant Strong family history of cancer, usually at an early age
56
When are inherited cancer syndromes suspected?
Strong family history of cancer Manchester criteria: suspect women with BRCA mutations Amsterdam criteria: suspect people with colorectal cancer
57
What action is taken if cancer is suspected?
Genetic screening | Genetic counselling
58
What action is taken if someone is mutation positive?
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
Genome wide association studies (GWAS)
“SNP fishing” for SNPs more common in cancer | Identifies possible candidate genes/genomic regions
60
Transcriptome Chips/mRNA array
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
Cytogenetic changes
Visible changes in chromosome structure or number
62
Examples of cytogenetic changes
Aneuploidy Translocation Macrodeletions Macroduplications
63
What are important in all cancers?
Cytogenetic changes
64
When do cytogenetic changes arise?
Causal "driver" or Accumulate during disease progression
65
What causes cytogenetic changes to arise?
Non-disjunction during cell division
66
Translocations in cancer
2 regions of chromosomes abnormally joined to form hybrids | Can lead to fusion genes, with potentially oncogenic properties
67
Chronic myeloid leukaemia (CML)
Clonal myeloproliferative disorder | = overproduction of mature granulocytes
68
What accounts for 15% of adult leukaemia?
Chronic myeloid leukaemia
69
What are the 3 stages of chronic myeloid leukaemia?
Chronic (benign) Accelerated (ominous) Blast crisis (acute leukaemic, invariably fatal) (1/3 patients)
70
What is chronic myeloid leukaemia characterised by?
Philadelphia chromosome Formed by translocation where part of Chr9 fuses with Chr22 Forms BCR-ABL1 fusion protein
71
What does the BCR-ABL1 fusion protein become?
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
Describe, using an example, a targeted therapy for CML.
Imatinib Blocks ATP binding site of BCR-ABL1 =Targeted gene therapy
73
How is early detection of disease relapse in CML achieved?
Quantitative Reverse Transcriptase PCR (q-RT-PCR)
74
Prevalence of Acute myeloid leukaemia (AML) relative to CML
AML is much rarer than CML
75
What characterises AML histologically?
Auer rods in the cell
76
Name a variant of AML?
Acute promyelocytic leukaemia (APML/ AML-M3)
77
What is Acute promyelocytic leukaemia (APML/ AML-M3)?
Abnormal accumulation of immature granulocytes called promyelocytes
78
What causes Acute promyelocytic leukaemia (APML/ AML-M3)?
Translocation between Chr 17 and 15
79
Which 2 genes are involved in the APML/AML-M3 translocation?
Chromosome 15 = PML (Promyelocytic Leukaemia) | Chromosome 17 = RARA (Retinoic Acid Receptor Alpha)
80
What is RARA?
Regulator of DNA transcription
81
How is PML-RARA protein harmful?
Binds too strongly to DNA Blocks normal transcription and differentiation of granulocytes All blasts produced (immature cells) are malignant
82
What is present in all APML?
PML-RARA
83
What does all trans retinoid acid (ATRA) therapy do?
Dissociates PML-RARα from DNA allowing normal transcription and normal differentiation ATRA does not kill cells
84
How is APML monitored
Cytogenetics and/or FISH and/or RQ-PCR
85
What is the point of Pharmacogenomics?
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
What cells are involved in Lymphoid leukaemias?
B Cells | T Cells
87
What cells are involved in Myeloid leukaemias?
Monocytes | Neutrophils

Genetics (7 decks)

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