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

Cancer Genetics 2 Flashcards

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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
What are immunotherapies
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
26
What is mutational profiling
Identification of mutational signatures to infer the underlying cause of a cancer
27
What are some examples of DNA mutagens
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
28
What are mutagenic processes
Each of our cells is subject to multiple mutagenic processes The exposure to a mutagenic process can be of differing lengths
29
What do the mutational signatures show in relation to mutagenic processes
Each cell will contain a “pattern” of mutations which reflect the Type of mutagenic process Length of the exposure to the mutagenic process
30
How do you measure the type of mutation
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
31
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
Occurs in CpG pairs The process of mutation may be involved in methylation
32
What is non-negative matrix factorisation
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
33
What is mutational signature 7
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
34
What tumour types present with signature 7
Melanoma Skin cancer Cancers of the lip Oral squamous cancers All associated with UV light exposure risk
35
Why does UV light cause TC>TT / CC>CT mutations in signature 7
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
36
If a circos plot has many internal lines indicating structural rearrangements is this likely to be a germline or somatic mutation
Germline This indicates many ds-breaks which leads to more rearrangement due to loss of homologous recombination - showing signature 3
37
In what cancers is homologous recombination deficiency - signature 3 - found
Elevated numbers of large (longer than 3bp) insertions and deletions Found in breast, ovarian and pancreatic cancers
38
What are potential treatments for breast cancer caused by germline mutations
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
39
Why are BRCA1/2 mutations sensitive to platinum therapy
Generates interstrand cross-links stopping replication Requires intact HR pathways to repair, but this is lost thus the tumour cells die
40
If BRCA1/2 loss = loss of HDR pathways, how do these cells survive
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
41
What do PARP inhivitors do
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
What are DNA repair deficiencies
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
What are the immunosuppressive effects of DNA repair deficiencies
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
Which cancers are related to mismatch repair deficiency
Colorectal cancers
45
What genes are involved in mismatch repair
MLH1, MSH2, MSH6, PMS2 and EPCAM
46
How can you test for mismatch repair deficiency
MSI (microsatellite instability)/MMR (mismatch repair) IHC – loss of MSH2 and MSH6 WGS
47
What may be seen in a circos plot showing mismatch repair deficiency
Signature 6 - sign of mismatch repair deficiency (MMR) | Circos plots have thick bars = many SNP's = high mutational burden
48
What drug can be used to target DNA repair/mismatch repair deficiencies
Anti-PD1/PD-L1 agents can be used, pembroluzimab
49
What are endocrine tumour syndromes
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
What are the symptoms of endocrine tumour syndromes
Overproduction of hormones Mass effect of tumour - pressing on adjacent structures
51
What are multiple endocrine neoplasia syndromes
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
What does the MEN1 gene do
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
What does loss of MEN1 gene lead to
Loss can disrupt downstream signalling pathways involved in regulation of cell growth and proliferation
54
How penetrant is MEN1
Highly penetrant - 50% by age 20 years, 95% by age 40 years Variable expressivity even within families
55
What systems are affected by MEN1 mutations
Parathyroid - hyperplasia thus hyperparathyroidism Pituitary - pituitary adenomas Pancreas - duodeno-pancreatic neuroendocrine tumours (DP-NETS)
56
What are the parathyroid glands
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
How is the parathyroid hormones deactivated
Turned off via negative feedback (increased calcium)
58
How are parathyroid adenomas tested
Uptake of radioisotope
59
What is hyperparathyroidism
Constant hormone secretion > Hypercalcaemia
60
What symptoms occur as a result of hyperparathyroidism
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
Does hypo or hyperparathyroidism affect individuals with MEN1
Occurs in 95% individuals with MEN1 Only 1-2% of all hyperparathyroidism is due to MEN1, consider if onset <45 years
62
How is hyperparathyroidism treated
Parathyroidectomy
63
What are the three types of anterior pituitary adenomas
Prolactinomas (60%) Somatotrophinomas (20%) Corticotrophinomas and non-functioning tumours (<15%)
64
What are the symptoms of pituitary adenomas
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
What is a mass effect and what is it caused by
Pituitary adenoma Headaches Compression of the optic chiasm (‘2’ on diagram) Bitemporal hemianopia (‘tunnel vision’)
66
What are pancreatic tumours
Tumours of gastro-entero-pancreatic tract (stomach, duodenum, pancreas, and intestinal tract)
67
What are the types of pancreatic tumours
Gastrinoma - duodenal, metastatic potential, peptic ulcer disease Insulinomas - hypoglycaemia Glucagonoma - hyperglycaemia, anorexia, glossitis, anaemia, diarrhoea, venous thrombosis, rash VIPoma - diarrhoea Non-secreting tumours
68
What are the suveillance options for individuals with MEN1
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
What is MEN2
Autosomal dominant, all caused by inactivating mutations in the RET proto-oncogene Highly penetrant Prevalence 1/30,000
70
What genes cause MEN2
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
What symptoms occur as a result of MEN2A
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
What are the symptoms of familial medullary thyroid cancer
Medullary thyroid cancer - middle age | No other features
73
How can you tell MEN2A and familial medullary thyroid cancer apart
FMTC = only medullary thyroid cancer, middle age not early and no other symptoms
74
What are the symptoms of MEN2B
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
If you had a patient who was tall, skinny and had long arm span, what could this mean
Marfan MEN2B
76
Which is more severe MEN2A or MEN2B
MEN2B
77
What is medullary thyroid cancer
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
What are the surveillance options for MEN2A/B FMTC and medullary thyroid cancer
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
What are the yearly surveillance options for MEN2A/B FMTC and medullary thyroid cancer
Clinical assessment Calcitonin and calcium levels Metadrenalines (plasma/urine) - measuring of hormones Ultrasound of neck (unless post-thyroidectomy)
80
What is a phaeochromocytoma
Tumour of adrenal gland These are organs which sit above the kidneys
81
What is a tumour of adrenal gland called
Phaeochromocytoma
82
What is a paraganglioma
Tumour of nerve cells May be called ‘extra-adrenal phaeos’
83
What is a tumour of the nerve cells called
Paragangliomas May be called ‘extra-adrenal phaeos’
84
Where are the adrenal medulla and ganglia of sympathetic nervous system derived from
Adrenal medulla and ganglia of sympathetic nervous system are both neural crest derivatives
85
What do the adrenal medulla and ganglia of sympathetic nervous system do
Synthesise and secrete catecholamines (adrenaline, noradrenaline)
86
What does a pheochromocytoma secrete
Catecholamine
87
What are the symptoms of pheochromocytoma
Episodic symptoms – headaches, sweating, palpitations, tremor, hypertension & arrhythmias Can be life-threatening
88
What are paragangliomas derived from and where are they found
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
What are genetic causes of phaeochromocytoma
RET gene -MEN2A/MEN2B ``` SDHB/D/A/C SDHAF2 MAX TMEM127 Familial paraganglioma ``` VHL NF1
90
What is familial phaeochromocytoma and paraganglioma syndrome (PPGL) caused by
SDHB, SDHD, SDHA, SDHAF2, MAX, TMEM127 SDHB risk of malignancy +/- renal cancer Autosomal dominant
91
What is the unique genetic feature of PPGL
Parent of origin effect in SDHD, SDHAF2 and MAX Disease only seen after PATERNAL transmission
92
What are the screening options for PPGL
Age to commence screening varies per gene Clinical evaluation Biochemistry (urine/plasma metadrenalines) Imaging of neck, thorax, abdomen 2-5 yearly
93
What is another name for familial isolated pituitary adenomas
Pituitary adenoma predisposition
94
What are the causes of familial isolated pituitary adenomas
Mutations in aryl hydrocarbon receptor interacting protein (AIP) gene Autosomal dominant
95
What tumours are found as a result of familial isolated pituitary adenomas
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
What are the different types of pituitary adenoma
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
What are the management and surveillance options with endocrine tumour syndromes
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
What is Von Hippel Lindau Syndrome caused by
``` 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
What is the inheritance pattern of Von Hippel Lindau Syndrome
``` Autosomal dominant Highly penetrant (age-dependent, 98% penetrance by age 60) , with mean diagnosis at 25 years Variability in phenotype within families ```
100
What are the tumours associated with Von Hippel Lindau Syndrome (VHL)
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
What is the normal and abnormal function of VHL
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
What are the surveillance options for VHL
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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