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

Cancer Genetics 1 Flashcards

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
Q

What are some moderate risk lifetime breast cancer genes

A

CHEK2 - 17-30%
ATM - heterozygous carriers for ataxia telangiectasia, 17-30%
NF1: neurofibromatosis type 1

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26
Q

What genes are looked for in a testing panel

A

PALB2 and CHEK2 are often found in the testing panel alongside BRCA2, the others are very syndromic and identified via their syndromes

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27
Q

What are some non-BRCA ovarian cancer risk genes

A

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%

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28
Q

What are two examples of stratified scoring systems

A

BOADICEA - breast and ovarian analysis of disease incidence and carrier estimation algorithm

Manchester scoring system - calculation done by hand

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29
Q

How can you potentially stratify people for genetic testing

A

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

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30
Q

How is breast cancer managed

A

Breast-awareness = patients usually discover lumps themselves

Surveillance (annual)
MRI 30-39y, MRI +mammogram 40-49y, mammogram >50y

Surgery: prophylactic mastectomy (+/- reconstruction), >25y

Chemoprevention

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31
Q

Why are mammograms not given to those younger than 40

A

MRI for younger patients as mammogram in young may be less effective at discriminating between malignant and benign changes

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32
Q

How is ovarian cancer managed

A

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

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33
Q

Why is BRCA testing not usually offered for children

A

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
Q

What is the most common childhood cancer

A

Leukaemia

35
Q

What are embryonal tumours

A

Characterised by proliferation of tissue that is normally only seen in the developing embryo

36
Q

What are the 6 principle types of embryonal tumours

A

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
Q

Why identify cancer predisposition syndromes

A

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
Q

What is the criteria for investigation

A

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
Q

What are single cancers that may occur due to a predisposition

A

Retinoblastoma
Wilms tumour
Neuroblastoma

40
Q

What is retinoblastoma

A

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
Q

What are the symptoms of retinoblastoma

A

Commonly presents with, leukocoria (abnormal white reflection from retina), squint, acute glaucoma

42
Q

What is the inheritance pattern and gene involved in retinoblastoma

A

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
Q

What is the screening procedure for retinoblastoma

A

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
Q

What are the extra-ocular features of retinoblastoma

A

6% increased risk of tumours outside of eye - osteosarcomas, soft tissue sarcomas,melanomas

Significantly increased with radiotherapy

45
Q

What is Wilms tumour

A

Embryonal tumour of the kidney also known as a nephroblastoma

46
Q

By what age is Wilms tumour diagnosed

A

~75% diagnosed by 4 years

~5% bilateral
~2% familial
~5% associated with a genetic syndrome

47
Q

What imprinting disorder is associated with Wilms tumour

A

Beckwith-Wiedemann syndrome

48
Q

What are the treatment options for Wilms tumour

A

Surgery, chemotherapy and occasionally radiotherapy

Treatment is according to stage and risk classification of tumour

49
Q

What gene causes Wilms tumour

A

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
Q

What is a WAGR

A

Wilms tumour, aniridia, genital abnormality, retardation

Deletion through WT1 and PAX6

51
Q

What does loss of WT1 cause

A

Genito-urinary abnormalities, Wilms tumour (30-50%) and insidious renal disease

52
Q

What is Denys-Drash syndrome

A

Characterised by Wilms tumour and Nephropathy (mesangial sclerosis),

WT1 mutations in DNA binding zinc fingers

53
Q

What is Frasier syndrome

A

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
Q

What mutations leads to Frasier syndrome

A

Intron 9 mutation - loss of KTS splice isoform

55
Q

What are Wilms tumour genes besides WT1

A

Non syndromic - CDKN1C, TRIM28, REST and CTR9

56
Q

What is neuroblastoma

A

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
Q

What is the genetic cause

A

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
Q

What is Beckwith-Wiedemann syndrome

A

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
Q

What are the features of Beckwith-Wiedemann

A

Characterised by, overgrowth, macroglossia, abdominal wall defects

Additional features - characteristic ear lobe pits/creases, hemihypertrophy, neonatal hypoglycaemia, urogenital abnormalities

60
Q

What embryonal tumours may be found in BWS

A

7.5% increase in risk of developing tumours including Wilms tumour, hepatoblastoma, rhabdomyosarcoma, neuroblastoma

61
Q

What can predict Wilms risk in BWS

A

11p15 status predicts Wilms risk

Hypermethylation of H19 (also caused by UPD11) increases Wilms risk

62
Q

What is Fanconi anaemia

A

AR condition with 14 gene all involved in the DNA repair pathway

63
Q

What are the clinical features of Fanconi anaemia

A

Pre and postnatal growth retardation, microcephaly

Radial ray abnormalities

Café au lait patches

Learning difficulties

Aplastic anaemia

64
Q

What are the cancer risks arising from Fanconi anaemia

A

Cancer risks - acute myeloid leukaemia, squamous carcinomas of head, neck and oesophagus, Wilms tumour, medulloblastoma

65
Q

What is the firstline test for Fanconi anaemia

A

Chromosome breakage study

66
Q

What is Li-Fraumeni syndrome

A

AD condition causing a wide spectrum of neoplasia in children and young adults

67
Q

What is the genetic cause of Li-Fraumeni syndrome

A

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
Q

What other diseases is Li-Fraumeni syndrome associated with

A

Breast cancer, soft tissue sarcomas, osteosarcoma, brain tumours and adrenocortical tumours

69
Q

What is the classic Li-Fraumeni criteria

A

Proband with sarcoma <45

First degree relative with cancer <45

First or second degree with cancer <45 or sarcoma any age

70
Q

What is FAP

A

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
Q

What are the extracolonic manifestations of FAP

A

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
Q

What is FAP caused by

A

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
Q

What is neurofibromatosis type 1 caused by

A

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
Q

What is the diagnostic criteria of neurofibromatosis type 1

A

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
Q

What cancers are predisposed to someone with NF1

A

Optic gliomas may be symptomatic, or asymptomatic - seen by specialised ophthalmologists

Other CNS tumours

Rhabdomyosarcoma

Peripheral nerve malignancy

76
Q

What is constitutional mismatch repair deficiency (CMMRD)

A

Biallelic mutations in MLH1, MSH2, MSH6, PMS2

May have family history

Very broad tumour spectrum - haematological, brain and bowel commonest

Pigmentation abnormalities

77
Q

How do you test for constitutional mismatch repair deficiency (CMMRD)

A

MSI and IHC may be false negative -germline MSI recommended

Direct sequencing + MLPA including careful analysis of PMS2

Consider POLE/POLD mutations

78
Q

When is medulloblastomas seen

A

Observed in conjunction with rare cancer predisposition syndromes - Gorlin, LFS and Fanconi

79
Q

What are the four molecular subtypes of medulloblastoma

A

Four molecular subgroups provide information about likelihood of germline predisposition (WNT, SHH, Grp 3 and 4)

80
Q

What is Wnt associated with in regards to medulloblastomas

A

Wnt - up to 10% chance of a hereditary genetic cause in the family
FAP is usually WNT MB

81
Q

What is SHH associated with in regards to medulloblastomas

A

SHH - up to 20% chance of a hereditary genetic cause in the family

Correlated with Gorlin and LFS (SUFU, PTCH1 andTP53)

82
Q

What do you do when you find a patient with SHH medulloblastoma

A

<3 years SUFU and PTCH1 (Gorlin)

> 3 years TP53

PALB2 and BRCA2 if negative

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

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