Cancer Genetics 1 Flashcards
What are the two major mutational types
Constitutional (germline) mutations
Somatic mutations
What proportion of cancers are sporadic, familial, high risk cancer gene
Sporadic - 65%
Familial - 25%, multifactorial polygenic risk
High risk cancer genes - 10%, single genetic factor
True or False - BRCA1/2 breast risk increases dramatically with age Vs polygenic/general risk
True
Why should we identify patients with increased risk
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
What features are used to identify patients with increased genetic predisposition to cancer
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
Are polygenic risk scores performed by the NHS currently
No
How are polygenic risk scores made
Risk SNP’s from GWAS used and added up
Tested in SNP chip
What are examples of syndromic features seen in some cancers
Trichilemmoma - white lumps on forehead, associated with mutation in Cowden’s syndrome (PTEN)
Mucocutaneous pigmentation - dots on lip, mutations in STK11
What syndromic features are seen with PTEN mutations
Trichilemmoma - white lumps on forehead, associated with mutation in Cowden’s syndrome (PTEN)
What syndromic features are seen with STK11 mutations
Mucocutaneous pigmentation - dots on lip, mutations in STK11
Why test tumours
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
Why use WGS rather than gene panels
Increased mutation detection
Increased understanding of mutagenesis
Greater understanding of phenotypic spectrum/ cancer risk if ascertained outside typical syndrome
What is predictive testing
A test in a WELL person to predict future risk
What is stratified prevention
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
Are most inherited cancer predispositions AD or AR
Most are AD
They may be linked to an accompanying autosomal recessive disorder e.g. BRCA2 = fanconi anaemia, ATM = ataxia telangiectasia
Is the MUTYH gene AR or AD and what does it do
AR
Predisposition to colon polyps and cancer
What are the outcomes of diagnostic genetic testing
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
What is an example of chemoprevention
Tamoxifen
What is the inheritance pattern of BRCA1/2
Autosomal dominant inheritance: heterozygous pathogenic variants
Are BRCA1/2 oncogenes or tumour supressor genes
Tumour suppressor genes
What 3 phases do cancers undergo to avoid immune destruction
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
What are some high risk non-BRCA breast cancer risk genes
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
Which breast cancer genes may also be associated with colorectal/GI cancers
STK11 - Peutz-Jeghers syndrome
PTEN - PTEN-hamartoma-tumour-syndrome
CDH1 - Hereditary diffuse gastric cancer
What can TP53 mutations cause
TP53 - Li-Fraumeni syndrome
Cancers include breast cancer, osteosarcoma, soft tissue sarcomas, brain tumours, adrenocortical carcinomas, childhood cancers including leukaemia
What are some moderate risk lifetime breast cancer genes
CHEK2 - 17-30%
ATM - heterozygous carriers for ataxia telangiectasia, 17-30%
NF1: neurofibromatosis type 1
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
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%
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
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
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
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
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
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
What is the most common childhood cancer
Leukaemia
What are embryonal tumours
Characterised by proliferation of tissue that is normally only seen in the developing embryo
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
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
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
What are single cancers that may occur due to a predisposition
Retinoblastoma
Wilms tumour
Neuroblastoma
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
What are the symptoms of retinoblastoma
Commonly presents with, leukocoria (abnormal white reflection from retina), squint, acute glaucoma
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
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
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
What is Wilms tumour
Embryonal tumour of the kidney also known as a nephroblastoma
By what age is Wilms tumour diagnosed
~75% diagnosed by 4 years
~5% bilateral
~2% familial
~5% associated with a genetic syndrome
What imprinting disorder is associated with Wilms tumour
Beckwith-Wiedemann syndrome
What are the treatment options for Wilms tumour
Surgery, chemotherapy and occasionally radiotherapy
Treatment is according to stage and risk classification of tumour
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)
What is a WAGR
Wilms tumour, aniridia, genital abnormality, retardation
Deletion through WT1 and PAX6
What does loss of WT1 cause
Genito-urinary abnormalities, Wilms tumour (30-50%) and insidious renal disease
What is Denys-Drash syndrome
Characterised by Wilms tumour and Nephropathy (mesangial sclerosis),
WT1 mutations in DNA binding zinc fingers
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
What mutations leads to Frasier syndrome
Intron 9 mutation - loss of KTS splice isoform
What are Wilms tumour genes besides WT1
Non syndromic - CDKN1C, TRIM28, REST and CTR9
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
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
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
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
What embryonal tumours may be found in BWS
7.5% increase in risk of developing tumours including Wilms tumour, hepatoblastoma, rhabdomyosarcoma, neuroblastoma
What can predict Wilms risk in BWS
11p15 status predicts Wilms risk
Hypermethylation of H19 (also caused by UPD11) increases Wilms risk
What is Fanconi anaemia
AR condition with 14 gene all involved in the DNA repair pathway
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
What are the cancer risks arising from Fanconi anaemia
Cancer risks - acute myeloid leukaemia, squamous carcinomas of head, neck and oesophagus, Wilms tumour, medulloblastoma
What is the firstline test for Fanconi anaemia
Chromosome breakage study
What is Li-Fraumeni syndrome
AD condition causing a wide spectrum of neoplasia in children and young adults
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”
What other diseases is Li-Fraumeni syndrome associated with
Breast cancer, soft tissue sarcomas, osteosarcoma, brain tumours and adrenocortical tumours
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
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
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
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
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
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
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
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
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
When is medulloblastomas seen
Observed in conjunction with rare cancer predisposition syndromes - Gorlin, LFS and Fanconi
What are the four molecular subtypes of medulloblastoma
Four molecular subgroups provide information about likelihood of germline predisposition (WNT, SHH, Grp 3 and 4)
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
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)
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
