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Clinical Applications of Genomics in Rare Disease and Cancer > Cancer Genetics 1 > Flashcards

Cancer Genetics 1 Flashcards

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1
Q

What are the two major mutational types

A

Constitutional (germline) mutations

Somatic mutations

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2
Q

What proportion of cancers are sporadic, familial, high risk cancer gene

A

Sporadic - 65%

Familial - 25%, multifactorial polygenic risk

High risk cancer genes - 10%, single genetic factor

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3
Q

True or False - BRCA1/2 breast risk increases dramatically with age Vs polygenic/general risk

A

True

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4
Q

Why should we identify patients with increased risk

A

Informs medical management and surgical options

Providers reasons for why they developed cancer

Informs patient about future cancer risk

Informs relatives about cancer risk - access to screening/risk reducing surgery

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5
Q

What features are used to identify patients with increased genetic predisposition to cancer

A

Family history -history of cancer?, multiple cancers?, young onset?

Syndromic features - features in tumour itself, linking it to a high risk CPG

Pathology of cancer

Tumour testing - looking for mutations in the tumour, to then check if it is in germline

High risk CPG

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6
Q

Are polygenic risk scores performed by the NHS currently

A

No

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7
Q

How are polygenic risk scores made

A

Risk SNP’s from GWAS used and added up

Tested in SNP chip

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8
Q

What are examples of syndromic features seen in some cancers

A

Trichilemmoma - white lumps on forehead, associated with mutation in Cowden’s syndrome (PTEN)

Mucocutaneous pigmentation - dots on lip, mutations in STK11

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9
Q

What syndromic features are seen with PTEN mutations

A

Trichilemmoma - white lumps on forehead, associated with mutation in Cowden’s syndrome (PTEN)

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10
Q

What syndromic features are seen with STK11 mutations

A

Mucocutaneous pigmentation - dots on lip, mutations in STK11

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11
Q

Why test tumours

A

Cancer patients now being offered large cancer gene panel sequencing of their tumour

If we find a disease causing change in a cancer predisposition gene on testing the tumour, it is possible it might also be in the germline

We can then offer a blood test to check this

Screening, Prevention and Early Detection (SPED) e.g. mammograms, colonoscopies, chemoprevention

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12
Q

Why use WGS rather than gene panels

A

Increased mutation detection

Increased understanding of mutagenesis

Greater understanding of phenotypic spectrum/ cancer risk if ascertained outside typical syndrome

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13
Q

What is predictive testing

A

A test in a WELL person to predict future risk

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14
Q

What is stratified prevention

A

Detecting those with a higher multifactorial risk can allow the categorisation of the population into risk groups, and offer a different intervention - using algorithm to assess risk from mainly family history

Those with increased risk can be given an increased screening programme - cost effective

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15
Q

Are most inherited cancer predispositions AD or AR

A

Most are AD

They may be linked to an accompanying autosomal recessive disorder e.g. BRCA2 = fanconi anaemia, ATM = ataxia telangiectasia

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16
Q

Is the MUTYH gene AR or AD and what does it do

A

AR

Predisposition to colon polyps and cancer

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17
Q

What are the outcomes of diagnostic genetic testing

A

No disease causing variant identified
Manage on basis of family history and personal diagnosis - multifactorial risk

Variant of uncertain significance identified
Analyse variant with scientist
Manage on basis of personal and family history
Try to get information to help classify variant if possible

Disease causing (Pathology) variant identified
Manage as per gene specific protocol
Can offer cascade screening to relatives

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18
Q

What is an example of chemoprevention

A

Tamoxifen

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19
Q

What is the inheritance pattern of BRCA1/2

A

Autosomal dominant inheritance: heterozygous pathogenic variants

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20
Q

Are BRCA1/2 oncogenes or tumour supressor genes

A

Tumour suppressor genes

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21
Q

What 3 phases do cancers undergo to avoid immune destruction

A

Phase I - unchecked proliferation and random mutation
Due to genome instability

Phase II - recognition, elimination and selection of immunoresistant cells

Phase III - immunoresistance due to acquired escape mechanisms

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22
Q

What are some high risk non-BRCA breast cancer risk genes

A

PALB2 - 20-60% breast, 5% ovarian, 2-3% pancreatic

TP53 - Li-Fraumeni syndrome
Cancers include breast cancer, osteosarcoma, soft tissue sarcomas, brain tumours, adrenocortical carcinomas, childhood cancers including leukaemia

STK11 - Peutz-Jeghers syndrome

PTEN - PTEN-hamartoma-tumour-syndrome

CDH1 - Hereditary diffuse gastric cancer

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23
Q

Which breast cancer genes may also be associated with colorectal/GI cancers

A

STK11 - Peutz-Jeghers syndrome

PTEN - PTEN-hamartoma-tumour-syndrome

CDH1 - Hereditary diffuse gastric cancer

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24
Q

What can TP53 mutations cause

A

TP53 - Li-Fraumeni syndrome
Cancers include breast cancer, osteosarcoma, soft tissue sarcomas, brain tumours, adrenocortical carcinomas, childhood cancers including leukaemia

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25
What are some moderate risk lifetime breast cancer genes
CHEK2 - 17-30% ATM - heterozygous carriers for ataxia telangiectasia, 17-30% NF1: neurofibromatosis type 1
26
What genes are looked for in a testing panel
PALB2 and CHEK2 are often found in the testing panel alongside BRCA2, the others are very syndromic and identified via their syndromes
27
What are some non-BRCA ovarian cancer risk genes
RAD51C - 1-2% up till 50 years, 10% to 80 years RAD51D - 3% up till 50 years, 10% to 80 years BRIP1 5-10% to 80 years Lynch syndrome genes MLH1 - 11% MSH2 - 17% MSH6 - 11%
28
What are two examples of stratified scoring systems
BOADICEA - breast and ovarian analysis of disease incidence and carrier estimation algorithm Manchester scoring system - calculation done by hand
29
How can you potentially stratify people for genetic testing
Age e.g. <30y female breast cancer Sex e.g. male breast cancer Ethnicity e.g. Ashkenazi Jewish ancestry female breast cancer Known founder mutations with high prevalence Individual cancer history Multiple primary cancers in one individual Types of cancer (including specific histology e.g. triple negative) Family cancer history i.e. are multiple family members affected
30
How is breast cancer managed
Breast-awareness = patients usually discover lumps themselves Surveillance (annual) MRI 30-39y, MRI +mammogram 40-49y, mammogram >50y Surgery: prophylactic mastectomy (+/- reconstruction), >25y Chemoprevention
31
Why are mammograms not given to those younger than 40
MRI for younger patients as mammogram in young may be less effective at discriminating between malignant and benign changes
32
How is ovarian cancer managed
Surveillance: ineffective Surgical: prophylactic bilateral salpingo-oophorectomy (fallopian tubes and ovary removal) Surgically induce menopause and need HRT Reproductive choices should be considered >40 years for BRCA 1 and >45 for BRCA 2
33
Why is BRCA testing not usually offered for children
Not usually offered for children as there are no treatment at young ages (until 25) so it is better to wait for their choice to exercise their autonomy
34
What is the most common childhood cancer
Leukaemia
35
What are embryonal tumours
Characterised by proliferation of tissue that is normally only seen in the developing embryo
36
What are the 6 principle types of embryonal tumours
Neuroblastoma in the sympathetic nervous system Retinoblastoma in the eye Wilms tumour (nephroblastoma) in the kidney Hepatoblastoma in the liver Medulloblastoma in the brain Rhabdomyosarcoma in the soft tissue
37
Why identify cancer predisposition syndromes
Helps to understand the cause, future risks, informs relatives about their risk and provides access to screening and risk reducing surgery and involved medical management and surgical options
38
What is the criteria for investigation
Multiple primary tumours diagnose <18 years Family history (FDR with cancer <45 years, 2 SDR with cancer <45 years of age on the same side of the family or the child's parents are consanguineous) A cancer usually diagnosed in adulthood e.g. colorectal cancer, ovarian cancer, basal cell carcinoma, melanoma, epithelial renal cancers A child with cancer and congenital abnormalities A child with excessive treatment toxicity
39
What are single cancers that may occur due to a predisposition
Retinoblastoma Wilms tumour Neuroblastoma
40
What is retinoblastoma
Nearly always presents by age of 5 Unilateral (63%), Multifocal, Bilateral Can be sporadic or inherited Commonly presents with, leukocoria (abnormal white reflection from retina), squint, acute glaucoma
41
What are the symptoms of retinoblastoma
Commonly presents with, leukocoria (abnormal white reflection from retina), squint, acute glaucoma
42
What is the inheritance pattern and gene involved in retinoblastoma
Autosomal dominant mutations in RB1 gene on chromosome 13q “Knudson’s two-hit hypothesis” - BOTH copies of the gene are damaged in one cell More likely to identify a mutation in bilateral cases or if family history
43
What is the screening procedure for retinoblastoma
In any child at increased risk of developing retinoblastoma Screening done as EUA (anaesthetic) Starts at 2-4 weeks of age and continues until 5yrs The examinations are offered at decreasing frequencies and usually total about 14
44
What are the extra-ocular features of retinoblastoma
6% increased risk of tumours outside of eye - osteosarcomas, soft tissue sarcomas,melanomas Significantly increased with radiotherapy
45
What is Wilms tumour
Embryonal tumour of the kidney also known as a nephroblastoma
46
By what age is Wilms tumour diagnosed
~75% diagnosed by 4 years ~5% bilateral ~2% familial ~5% associated with a genetic syndrome
47
What imprinting disorder is associated with Wilms tumour
Beckwith-Wiedemann syndrome
48
What are the treatment options for Wilms tumour
Surgery, chemotherapy and occasionally radiotherapy Treatment is according to stage and risk classification of tumour
49
What gene causes Wilms tumour
Variant in chromosome 11p13, WT1 gene Continuous deletion may also occur through WT1 and PAX6 which can result in aniridia This is known as WAGR syndrome (Wilms tumour, aniridia, genital abnormality, retardation)
50
What is a WAGR
Wilms tumour, aniridia, genital abnormality, retardation Deletion through WT1 and PAX6
51
What does loss of WT1 cause
Genito-urinary abnormalities, Wilms tumour (30-50%) and insidious renal disease
52
What is Denys-Drash syndrome
Characterised by Wilms tumour and Nephropathy (mesangial sclerosis), WT1 mutations in DNA binding zinc fingers
53
What is Frasier syndrome
Characterised by nephropathy with focal segmental glomerulosclerosis, gonadoblastoma Wilms tumour less common than Denys Drash but does occur 46XY DSD (ie sex reversal) Intron 9 mutation - loss of KTS splice isoform
54
What mutations leads to Frasier syndrome
Intron 9 mutation - loss of KTS splice isoform
55
What are Wilms tumour genes besides WT1
Non syndromic - CDKN1C, TRIM28, REST and CTR9
56
What is neuroblastoma
Tumour of the sympathetic nervous system | Can occur all over body but commonly occur in adrenals, next to spinal cord or in the chest
57
What is the genetic cause
Very rarely inherited in isolation Can be associated with AD inherited mutations in ALK or PHOX2B PHOX2B also causes congenital hypoventilation syndrome so look for other associated abnormalities of SNS
58
What is Beckwith-Wiedemann syndrome
Beckwith-Wiedemann (BWS) is an imprinted condition Genomic imprinting is an epigenetic mechanism by which gene expression is altered according to the parental origin of the allele BWS is due to a net increase in growth promoters at 11p15
59
What are the features of Beckwith-Wiedemann
Characterised by, overgrowth, macroglossia, abdominal wall defects Additional features - characteristic ear lobe pits/creases, hemihypertrophy, neonatal hypoglycaemia, urogenital abnormalities
60
What embryonal tumours may be found in BWS
7.5% increase in risk of developing tumours including Wilms tumour, hepatoblastoma, rhabdomyosarcoma, neuroblastoma
61
What can predict Wilms risk in BWS
11p15 status predicts Wilms risk Hypermethylation of H19 (also caused by UPD11) increases Wilms risk
62
What is Fanconi anaemia
AR condition with 14 gene all involved in the DNA repair pathway
63
What are the clinical features of Fanconi anaemia
Pre and postnatal growth retardation, microcephaly Radial ray abnormalities Café au lait patches Learning difficulties Aplastic anaemia
64
What are the cancer risks arising from Fanconi anaemia
Cancer risks - acute myeloid leukaemia, squamous carcinomas of head, neck and oesophagus, Wilms tumour, medulloblastoma
65
What is the firstline test for Fanconi anaemia
Chromosome breakage study
66
What is Li-Fraumeni syndrome
AD condition causing a wide spectrum of neoplasia in children and young adults
67
What is the genetic cause of Li-Fraumeni syndrome
AD Most cases are caused by germline mutations in the gene TP53 TP53 is a tumour suppressor gene and its product is involved in DNA repair Tumour development occurs after the “second hit”
68
What other diseases is Li-Fraumeni syndrome associated with
Breast cancer, soft tissue sarcomas, osteosarcoma, brain tumours and adrenocortical tumours
69
What is the classic Li-Fraumeni criteria
Proband with sarcoma <45 First degree relative with cancer <45 First or second degree with cancer <45 or sarcoma any age
70
What is FAP
Familial Adenomatous Polyposis Colon cancer predisposition syndrome Thousands of precancerous colonic polyps Polyps can begin developing from 7-36 years Without colectomy, colon cancer is inevitable
71
What are the extracolonic manifestations of FAP
Hepatoblastoma: 1.6% children <5 yrs Polyps of gastric fundus and duodenum Osteomas Dental anomalies Congenital hypertrophy of the retinal pigment epithelium (CHRPE) Soft tissue tumours Desmoid tumours
72
What is FAP caused by
Autosomal dominant condition Approx 75-80% of affected individuals have an affected parent Causative gene is APC gene - mutations in ~95% of affected families
73
What is neurofibromatosis type 1 caused by
Autosomal dominant condition Approx 75-80% of affected individuals have an affected parent Causative gene is APC gene - mutations in ~95% of affected families
74
What is the diagnostic criteria of neurofibromatosis type 1
Clinical diagnostic criteria- two or more of 6 café au lait patches, in children <10yrs >5mm or >10yrs >15mm Axillary or inguinal freckling Two or more typical neurofibromata or one plexiform neurofibroma Optic nerve glioma Two or more Lisch nodules First degree relative with NF1
75
What cancers are predisposed to someone with NF1
Optic gliomas may be symptomatic, or asymptomatic - seen by specialised ophthalmologists Other CNS tumours Rhabdomyosarcoma Peripheral nerve malignancy
76
What is constitutional mismatch repair deficiency (CMMRD)
Biallelic mutations in MLH1, MSH2, MSH6, PMS2 May have family history Very broad tumour spectrum - haematological, brain and bowel commonest Pigmentation abnormalities
77
How do you test for constitutional mismatch repair deficiency (CMMRD)
MSI and IHC may be false negative -germline MSI recommended Direct sequencing + MLPA including careful analysis of PMS2 Consider POLE/POLD mutations
78
When is medulloblastomas seen
Observed in conjunction with rare cancer predisposition syndromes - Gorlin, LFS and Fanconi
79
What are the four molecular subtypes of medulloblastoma
Four molecular subgroups provide information about likelihood of germline predisposition (WNT, SHH, Grp 3 and 4)
80
What is Wnt associated with in regards to medulloblastomas
Wnt - up to 10% chance of a hereditary genetic cause in the family FAP is usually WNT MB
81
What is SHH associated with in regards to medulloblastomas
SHH - up to 20% chance of a hereditary genetic cause in the family Correlated with Gorlin and LFS (SUFU, PTCH1 andTP53)
82
What do you do when you find a patient with SHH medulloblastoma
<3 years SUFU and PTCH1 (Gorlin) >3 years TP53 PALB2 and BRCA2 if negative

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