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Clinical Applications of Genomics in Rare Disease and Cancer > Cancer Genetics 2 > Flashcards

Cancer Genetics 2 Flashcards

1
Q

What are the mutational processes in cancer genomics

A

Intrinsic mutational processes - each division inevitably results in some mistakes

Environmental and lifestyle exposures

Mutator phenotype - the more it divides due to driver mutations, the more mutations it picks up

Chemotherapy - selective for resistance

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2
Q

What are the mutational types in cancer genomics

A

Passenger mutations - mutations acquired that do not impact the function of the cell

Driver mutations - mutations that drives growth and division, escaping cell cycle mechanisms
Genetic instability which influences the gathering of more passenger and driver mutations

Chemotherapy resistance mutation

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3
Q

What is the genomic equivalent of predisposed and acquired mutations

A

Constitutional (germline) mutations

Somatic mutations - tumour specific

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4
Q

What is a tumour specific mutation

A

Tumour specific mutation = genetic variation which is present in the whole genome sequencing of the tumour but NOT the germline is considered somatically acquired

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5
Q

How can you identify tumour specific mutations

A

Need to WGS two whole genomes - to find what mutations were acquired after birth

Germline genome
Tumour genome

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6
Q

Where do you get germline DNA to test for tumour specific mutations

A

For solid tumours germline (lung, breast, ovarian) = lymphocytic DNA (blood sample)

For haematological malignancies the tumour sample is from blood and germline will be another tissue
For example fibrocytic DNA from a skin biopsy

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7
Q

What is a circos plot

A

This forms a ring of circles, each ring giving different pieces of information as seen below

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8
Q

What does a circos plot identify

A

Mutations to be sorted into passenger and driver mutations according to the gene they’re in

Tumour mutational burden

The number of somatically acquired mutations present in cancer DNA

Mutational signature
A pattern of mutation types which can give clues to the underlying mutagenic processes at work in the cancer cells

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9
Q

What is a mutational signature

A

A pattern of mutation types which can give clues to the underlying mutagenic processes at work in the cancer cells

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10
Q

What is a tumour mutational burden

A

The number of somatically acquired mutations present in cancer DNA

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11
Q

What are the classes of cancer genes

A

Oncogenes (accelerator on)

Tumour suppressor genes (cutting the brake cables)
Need to lose both copies for oncogenesis

DNA repair genes (not mending the car) – most of these are also classed as tumour suppressor gene

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12
Q

What are the potential tests for somatic mutations

A

Single driver mutations
Gene panels

Whole genome sequencing - pricy as you need to sequence two genomes (germline and somatic)
Childhood cancer
Haematological malignancies
Certain metastatic cancers

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13
Q

What are some examples of driver genes

A

Single driver mutation
BRAF V600E – Oncogene

Gene panel
Rb1 – Tumour suppressor gene
BRCA1 or BRCA2 – Tumour suppressor gene/DNA repair gene
MLH1 – Tumour suppressor gene/DNA repair gene

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14
Q

What is the pathogenic pathway of the BRAF V600E mutation

A

BRAF V600E – Oncogene

Over activation of RAS-MAPK pathway

BRAF inhibitor therapies can be given

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15
Q

What is the pathogenic pathway of RB1 mutations

A

Rb1 – Tumour suppressor gene
Control of cell cycle, prevents activation of replication

Thus failure = replication

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16
Q

What is the pathogenic pathway of BRCA1/2 mutations

A

BRCA1 or BRCA2 – Tumour suppressor gene/DNA repair gene

Failure of homologous recombination - can’t do HDR

Damaged chromosomes/ds-breaks/replication forks not repaired

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17
Q

What is the pathogenic pathway of MLH1 mutations

A

MLH1 – Tumour suppressor gene/DNA repair gene

Can have epigenetic suppression: (hyper)methylation of promotor region

Failure of mismatch repair

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18
Q

What are passenger mutations

A

Don’t in theory contribute to oncogenesis

However, high mutational burden may lead to a more unstable mutagenic phenotype

Sometimes it may be hard to tell if a variant in a cancer gene is a driver mutation or is actually a benign variant not impacting on the function of the gene

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19
Q

Why should you undertake germline testing after identifying a driver mutation

A

If we only undertake driver mutation testing or large panel sequencing without paired germline we do not know if a variant is somatic only or may also be present in the germline

If it was in germline it can affect relatives, so it may be needed to offer germline testing

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20
Q

When do you offer a germline test

A

If the somatic mutation is a Class 4/5 (likely pathogenic) variant in a known cancer susceptibility gene

VAF >30% (variant allele frequency - how many reads has the variant been seen in)
Each cancer biopsy may have different driver mutations, but if it is in 50% then it suggests that most cells have it as it was the original germline genome

Need to consider difference between on-tumour and off-tumour findings
Mutations not usually found in that type of cancer e.g. BRCA mutation in LUNG cancer

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21
Q

What happens if you cannot find a driver mutation

A

We don’t always find a driver mutation

We don’t know the driver mutations for every cancer type

Cancer genomes can have huge numbers of mutations
We can look at other information from the cancer genome to help guide management

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22
Q

What is tumour mutational burden

A

Tumour mutational burden - number of specific types of mutations that have been somatically acquired and found in tumour DNA

Refers to the number of SNP or the overall mutational burden

High mutational burden = genome is very different to germline, and looks different to normal cells

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23
Q

What treatments are effective against tumours with high mutational burden

A

Immunotherapy agents have been shown to have clinical efficacy in tumours with high mutational burden

Help immune system see that these cells are so different

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24
Q

What may be a cause of high mutational burden

A

A high mutational burden can be caused by failure of DNA repair pathways and often occurs with mismatch repair deficiency or proof-reading polymerase deficiency

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25
Q

What are immunotherapies

A

Normally, activated lymphocytes/T-cells would recognise these cells with high mutational burden

However, PDL-1 hides these abnormal tumour cells from the immune system

Immunotherapies act against the PDL-1 pathway allowing T-cells to recognise the cancer cells
This can be a therapeutic strategy across cancers with high mutational burden

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26
Q

What is mutational profiling

A

Identification of mutational signatures to infer the underlying cause of a cancer

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27
Q

What are some examples of DNA mutagens

A

Different causes of DNA mutagens cause different types of mutations

Internal - reactive oxygen species, ineffective DNA repair mechanisms

External - UV light, ionising radiation, cigarette smoke, chemical consumptions

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28
Q

What are mutagenic processes

A

Each of our cells is subject to multiple mutagenic processes

The exposure to a mutagenic process can be of differing lengths

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29
Q

What do the mutational signatures show in relation to mutagenic processes

A

Each cell will contain a “pattern” of mutations which reflect the

Type of mutagenic process

Length of the exposure to the mutagenic process

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30
Q

How do you measure the type of mutation

A

SNP - measuring number of SNP and the context

What is the base preceding and subsequent to the SNP - does an SNP associate with a specific triplet

There are only 6 different types of base substitutions
C>A and G>T, C>G and G>C, T>A and A>T, T>G and A>C

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31
Q

You find that in a group of patients that HER2+ve breast cancer was due to a C>T change, this was found on a heatmap this more likely occurs when a G follows what may this mean

A

Occurs in CpG pairs

The process of mutation may be involved in methylation

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32
Q

What is non-negative matrix factorisation

A

Mathematic calculation measuring the proportion of occurrence of each feature

E.g. most people have eyes taking up 10% of their face
OR… cancers have X% of Y mutation = signature

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33
Q

What is mutational signature 7

A

The major mutation type is C>T
Commonly occurs when C or T is preceding the SNP
Showing predominance of TC>TT and CC>CT mutation

Associated with cancers in which UV light exposure is a known risk factor

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34
Q

What tumour types present with signature 7

A

Melanoma
Skin cancer
Cancers of the lip
Oral squamous cancers

All associated with UV light exposure risk

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35
Q

Why does UV light cause TC>TT / CC>CT mutations in signature 7

A

UV light mutates DNA in a specific way causing dinucleotide mutations at dipyrimidines (C and T’s)

Additionally, Signature 7 exhibits a strong transcriptional strand-bias indicating that mutations occur at pyrimidines by formation of pyrimidine-pyrimidine photodimers

These mutations are being repaired by transcription-coupled nucleotide excision repair

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36
Q

If a circos plot has many internal lines indicating structural rearrangements is this likely to be a germline or somatic mutation

A

Germline

This indicates many ds-breaks which leads to more rearrangement due to loss of homologous recombination - showing signature 3

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37
Q

In what cancers is homologous recombination deficiency - signature 3 - found

A

Elevated numbers of large (longer than 3bp) insertions and deletions

Found in breast, ovarian and pancreatic cancers

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38
Q

What are potential treatments for breast cancer caused by germline mutations

A

Treated with various drugs and platinum chemotherapy - carboplatin, as well as paclitaxel, bevacizumab

Surgery was performed

Platinum-sensitive on each occasion
Generates interstrand cross-links stopping replication
Requires intact HR pathways to repair, but this is lost thus the tumour cells die
BRCA1 + BRCA2-deficient cells therefore highly sensitive to platinum chemotherapy

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39
Q

Why are BRCA1/2 mutations sensitive to platinum therapy

A

Generates interstrand cross-links stopping replication

Requires intact HR pathways to repair, but this is lost thus the tumour cells die

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40
Q

If BRCA1/2 loss = loss of HDR pathways, how do these cells survive

A

Poly-ADP-ribose polymerase (PARP) - enzyme critical to DNA single strand break repair via BER pathway
Activated by DNA damage + recruits proteins to site of damage to create a repair complex

PARP inhibitors stop this thus used to treat BRCA1/2 cancers to stop all cell repair

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41
Q

What do PARP inhivitors do

A

PARP Inhibitors - prevents repair, and stops tumour cells from dividing (synthetic lethality)

Offer individualised treatment for ovarian cancer in women with germline BRCA mutations/tumours with somatic loss of BRCA

42
Q

What are DNA repair deficiencies

A

Accumulation of DNA damage and activation of cellular signalling

Mismatch repair - short insertions and deletion

POLE/POLD1 - point mutations
C>A in context of TCT

Homologous recombination - larger indels

Aneuploidy - CNV’s - gene dosage effects

43
Q

What are the immunosuppressive effects of DNA repair deficiencies

A

Increased neoantigens = MHC I presentation = T cell activation

Cytosolic DNA = STING pathway = Type I IFN response

STING agonists may be used to treat this

Upregulation of PDL-1
Anti-PD1/PD-L1 agents can be used

44
Q

Which cancers are related to mismatch repair deficiency

A

Colorectal cancers

45
Q

What genes are involved in mismatch repair

A

MLH1, MSH2, MSH6, PMS2 and EPCAM

46
Q

How can you test for mismatch repair deficiency

A

MSI (microsatellite instability)/MMR (mismatch repair) IHC – loss of MSH2 and MSH6

WGS

47
Q

What may be seen in a circos plot showing mismatch repair deficiency

A

Signature 6 - sign of mismatch repair deficiency (MMR)

Circos plots have thick bars = many SNP’s = high mutational burden

48
Q

What drug can be used to target DNA repair/mismatch repair deficiencies

A

Anti-PD1/PD-L1 agents can be used, pembroluzimab

49
Q

What are endocrine tumour syndromes

A

Genetic predisposition to developing tumours effecting the endocrine glands

Includes both endocrine and non-endocrine tumours too

‘Benign’ and/or malignant
Benign tumours can be a cause of morbidity via the symptoms they cause

Hormone secreting/non-secretory

50
Q

What are the symptoms of endocrine tumour syndromes

A

Overproduction of hormones

Mass effect of tumour - pressing on adjacent structures

51
Q

What are multiple endocrine neoplasia syndromes

A

Presence of tumours involving two or more endocrine glands in one individual

Autosomal dominant

Challenging to diagnose, and classification can be confusing
MEN1
MEN2 - MEN2A, MEN2B (aka MEN3), FMTC
MEN4

52
Q

What does the MEN1 gene do

A

MEN1 is a tumour suppressor gene due to inactivating mutations in MEN1 gene
Protein product of MEN1 is Menin which is involved in the regulation of transcription

It mediates between transcription factors and histone modifiers to facilitate transcription

Loss can disrupt downstream signalling pathways involved in regulation of cell growth and proliferation

53
Q

What does loss of MEN1 gene lead to

A

Loss can disrupt downstream signalling pathways involved in regulation of cell growth and proliferation

54
Q

How penetrant is MEN1

A

Highly penetrant - 50% by age 20 years, 95% by age 40 years

Variable expressivity even within families

55
Q

What systems are affected by MEN1 mutations

A

Parathyroid - hyperplasia thus hyperparathyroidism

Pituitary - pituitary adenomas

Pancreas - duodeno-pancreatic neuroendocrine tumours (DP-NETS)

56
Q

What are the parathyroid glands

A

Four parathyroid glands sitting posterior of the thyroid gland, important in regulating blood calcium

Parathyroid hormone signals bones to release calcium, signals kidneys to prevent release of calcium and increase vitamin D and signals intestines to absorb more calcium

Multiglandular involvement

Turned off via negative feedback - increased calcium

57
Q

How is the parathyroid hormones deactivated

A

Turned off via negative feedback (increased calcium)

58
Q

How are parathyroid adenomas tested

A

Uptake of radioisotope

59
Q

What is hyperparathyroidism

A

Constant hormone secretion > Hypercalcaemia

60
Q

What symptoms occur as a result of hyperparathyroidism

A

Hyperparathyroidism = constant hormone secretion

Hypercalcaemia
Bones (fracture), stones (kidney), groans (constipation) and psychic moans (confusion/depression)’

Occurs in 95% individuals with MEN1
Only 1-2% of all hyperparathyroidism is due to MEN1, consider if onset <45 years

61
Q

Does hypo or hyperparathyroidism affect individuals with MEN1

A

Occurs in 95% individuals with MEN1

Only 1-2% of all hyperparathyroidism is due to MEN1, consider if onset <45 years

62
Q

How is hyperparathyroidism treated

A

Parathyroidectomy

63
Q

What are the three types of anterior pituitary adenomas

A

Prolactinomas (60%)

Somatotrophinomas (20%)

Corticotrophinomas and non-functioning tumours (<15%)

64
Q

What are the symptoms of pituitary adenomas

A

Disrupt hormone secretion

Prolactinoma
Secretes prolactin = galactorrhoea + amenorrhoea

Somatotrophinoma
Secretes growth hormone = gigantism (all bones, children)/acromegaly (limb and face bones, adults)

Corticotrophinoma
Secretes ACTH > cortisol = Cushing’s disease

Mass effect
Headaches
Compression of the optic chiasm (‘2’ on diagram)
Bitemporal hemianopia (‘tunnel vision’)

65
Q

What is a mass effect and what is it caused by

A

Pituitary adenoma

Headaches
Compression of the optic chiasm (‘2’ on diagram)
Bitemporal hemianopia (‘tunnel vision’)

66
Q

What are pancreatic tumours

A

Tumours of gastro-entero-pancreatic tract (stomach, duodenum, pancreas, and intestinal tract)

67
Q

What are the types of pancreatic tumours

A

Gastrinoma - duodenal, metastatic potential, peptic ulcer disease

Insulinomas - hypoglycaemia

Glucagonoma - hyperglycaemia, anorexia, glossitis, anaemia, diarrhoea, venous thrombosis, rash

VIPoma - diarrhoea

Non-secreting tumours

68
Q

What are the suveillance options for individuals with MEN1

A

Predictive genetic testing from age 10

Surveillance (identify disease at asymptomatic/early stage)

From age 10 - predictive testing, annual pituitary hormones, gastric hormones, Ca, PTH

From age 16 - abdominal imaging (3-yearly), MRI brain (3-yearly)

69
Q

What is MEN2

A

Autosomal dominant, all caused by inactivating mutations in the RET proto-oncogene

Highly penetrant
Prevalence 1/30,000

70
Q

What genes cause MEN2

A

MEN2A (60-90%)

Familial Medullary Thyroid cancer (FMTC) (5-35%)
FMTC likely same as MEN2A but with reduced penetrance of hyperparathyroidism and phaeo

MEN2B (5%)

71
Q

What symptoms occur as a result of MEN2A

A

Medullary thyroid cancer (90-95%)
Early adulthood onset

Parathyroid hyperplasia (20-30%)

Phaeochromocytoma (20-30%) - tumours of the adrenal medulla, can be benign
Often bilateral

72
Q

What are the symptoms of familial medullary thyroid cancer

A

Medullary thyroid cancer - middle age

No other features

73
Q

How can you tell MEN2A and familial medullary thyroid cancer apart

A

FMTC = only medullary thyroid cancer, middle age not early and no other symptoms

74
Q

What are the symptoms of MEN2B

A

Medullary thyroid cancer - up to 100%
Early childhood onset

Phaeochromocytomas (50%)

Mucosal neuromas of the lips and tongue - bumps and lumps

Marfanoid habitus - similar characteristics of Marfan syndrome
Tall, skinny, long arm span

Medullated corneal nerve fibres

Intestinal ganglioneuromatosis

75
Q

If you had a patient who was tall, skinny and had long arm span, what could this mean

A

Marfan

MEN2B

76
Q

Which is more severe MEN2A or MEN2B

A

MEN2B

77
Q

What is medullary thyroid cancer

A

Associated with C cell hyperplasia
These are calcitonin producing cells
May see ↑ calcitonin

Often multifocal or bilateral

Symptoms:
Neck mass or pain
Diarrhoea

Metastasizes early

78
Q

What are the surveillance options for MEN2A/B FMTC and medullary thyroid cancer

A

Offer predictive testing in childhood

Risk-reducing thyroidectomy

Timing of surgery according to ATA Risk classification of pathogenic variant

Level D – highest risk (1st year of life)
Level A – lowest risk (can delay beyond 5 years)

Yearly surveillance
Clinical assessment
Calcitonin and calcium levels
Metadrenalines (plasma/urine) - measuring of hormones
Ultrasound of neck (unless post-thyroidectomy)

79
Q

What are the yearly surveillance options for MEN2A/B FMTC and medullary thyroid cancer

A

Clinical assessment
Calcitonin and calcium levels
Metadrenalines (plasma/urine) - measuring of hormones
Ultrasound of neck (unless post-thyroidectomy)

80
Q

What is a phaeochromocytoma

A

Tumour of adrenal gland

These are organs which sit above the kidneys

81
Q

What is a tumour of adrenal gland called

A

Phaeochromocytoma

82
Q

What is a paraganglioma

A

Tumour of nerve cells

May be called ‘extra-adrenal phaeos’

83
Q

What is a tumour of the nerve cells called

A

Paragangliomas

May be called ‘extra-adrenal phaeos’

84
Q

Where are the adrenal medulla and ganglia of sympathetic nervous system derived from

A

Adrenal medulla and ganglia of sympathetic nervous system are both neural crest derivatives

85
Q

What do the adrenal medulla and ganglia of sympathetic nervous system do

A

Synthesise and secrete catecholamines (adrenaline, noradrenaline)

86
Q

What does a pheochromocytoma secrete

A

Catecholamine

87
Q

What are the symptoms of pheochromocytoma

A

Episodic symptoms – headaches, sweating, palpitations, tremor, hypertension & arrhythmias
Can be life-threatening

88
Q

What are paragangliomas derived from and where are they found

A

Rare tumours derived from neural tissues
From within autonomic nervous system

Sympathetic NS often retroperitoneal
Parasympathetic NS often adjacent to aortic arch, neck, skull base

May be hormone secreting (catecholamines) or cause mass effect

89
Q

What are genetic causes of phaeochromocytoma

A

RET gene -MEN2A/MEN2B

SDHB/D/A/C
SDHAF2
MAX
TMEM127
Familial paraganglioma

VHL

NF1

90
Q

What is familial phaeochromocytoma and paraganglioma syndrome (PPGL) caused by

A

SDHB, SDHD, SDHA, SDHAF2, MAX, TMEM127

SDHB risk of malignancy +/- renal cancer

Autosomal dominant

91
Q

What is the unique genetic feature of PPGL

A

Parent of origin effect in SDHD, SDHAF2 and MAX

Disease only seen after PATERNAL transmission

92
Q

What are the screening options for PPGL

A

Age to commence screening varies per gene

Clinical evaluation

Biochemistry (urine/plasma metadrenalines)

Imaging of neck, thorax, abdomen 2-5 yearly

93
Q

What is another name for familial isolated pituitary adenomas

A

Pituitary adenoma predisposition

94
Q

What are the causes of familial isolated pituitary adenomas

A

Mutations in aryl hydrocarbon receptor interacting protein (AIP) gene

Autosomal dominant

95
Q

What tumours are found as a result of familial isolated pituitary adenomas

A

Variability in tumour type within different family members

Often macroadenomas (>10mm)

Type of pituitary adenoma impacts the hormone involved thus the symptoms

There may also be a mass effect and cause deficiencies of other pituitary hormones

96
Q

What are the different types of pituitary adenoma

A

Prolactinoma
Secretes prolactin = galactorrhoea + amenorrhoea

Somatotrophinoma
Secretes growth hormone = gigantism (all bones, children)/acromegaly (limb and face bones, adults)

Corticotrophinoma
Secretes ACTH > cortisol = Cushing’s disease

Somatomammotropinoma - growth homrone and proclactin

Nonfunctioning - none

Thyrotropinoma - TSH > hyperthyroidism

97
Q

What are the management and surveillance options with endocrine tumour syndromes

A

Medical therapy e.g., somatostatin analogues, growth hormone receptor antagonists, dopamine agonists

Surgery, +/- radiotherapy

Surveillance
Annual clinical assessment
Annual pituitary function tests
Pituitary imaging

98
Q

What is Von Hippel Lindau Syndrome caused by

A 
Autosomal dominant
 Highly penetrant (age-dependent, 98% penetrance by age 60) , with mean diagnosis at 25 years
Variability in phenotype within families

Caused by inactivating mutations in VHL tumour suppressor gene

99
Q

What is the inheritance pattern of Von Hippel Lindau Syndrome

A 
Autosomal dominant
 Highly penetrant (age-dependent, 98% penetrance by age 60) , with mean diagnosis at 25 years
Variability in phenotype within families
100
Q

What are the tumours associated with Von Hippel Lindau Syndrome (VHL)

A

Wide range of tumours, most commonly retinal angiomas and cerebellar haemangioblastomas

Cysts in kidneys, pancreas and epididymis

Suspect if >1 VHL associated tumour or family history

101
Q

What is the normal and abnormal function of VHL

A

VHL protein complex ubiquitylates α-subunits of HIF transcription factors = target for proteolysis

Absence of VHL protein complex causes stabilisation of HIF α- subunits

As they don’t undergo proteolysis HIF transcription factors activate downstream growth factors including VEGF

102
Q

What are the surveillance options for VHL

A

From age 5 - annual ophthalmology

From age 8 - annual metanephrines (plasma/24h urinary)

From age 16

Annual clinical neurological examination and MRI/US abdomen

MRI brain every 1-3 years, MRI spine if neurological symptoms or signs

Annual audiological questionnaire

Clinical Applications of Genomics in Rare Disease and Cancer (10 decks)

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