clinical cancer genetics Flashcards
Where does the mutation occur?
Germline cells
Somatic cells
What are common architecture of genetic susceptibility to cancer?
- sporadic = 65%
- High risk cancer gene= 10%
- Familial cancer = 25%
What do high risk cancer predisposition genes depend on?
depend on type of cancer => breast,colon, prostate cancer =5-10% =>ovarian, melanoma, pancreatic = 10-15% =>medullary thyroid = 25% =>Retinoblastoma = 40%
Why do we want to identify patients with increased genetic predisposition to cancer?
- inform medical management and surgical options
- Provides reasons for why developed cancer
- informs patient about future cancer risk
- informs relatives about cancer risk - access to screening/risk reducing surgery and detection.
How can we identify patients with increased predisposition to cancer (high risk gene)?
- family history
- syndromic features
- tumour testing
- pathology of cancer
What is high risk genes?
-BRCA1
How is polygenic risk tested?
- no direct test
- genetic testing of multiple low risk factors
- not performed on NHS
- increased genetic susceptibility to cancer
- undertaken by looking for cancer associated SNPs found from genome wide association studies: large sample with cancer and large sample without cancer (control) and compare SNPs between control and cancer cases.
What are syndromic features?
- trichilemmoma - spots on forehead
-mucocutaneous pigmentation.
=>there are other flags in clinical investigation.
How can we use cancer predisposition gene to identify germline cancer?
- large cancer gene panel sequencing of tumour
- if a disease causing change in predisposition gene found in testing tumour, it is possible it might also be in germline
=> offer blood tests to confirm this
What is multifactorial cancer risk?
- individuals dont have one single high risk factor but many low risk which add up.
- GWAS best way to identify bit NHS doesn’t
- best solution is family history
Why do we want to identify individuals with multifactorial risk?
- For stratified prevention
- categorisation of the population into risk groups, each of whom would be offered a different intervention
- use the knowledge of familial risk to put them in the right side of the curve (high risk) so they can be monitored more, more screening offered, so in future we can remove women from left side and use their screening resources on women on RHS who need it.
- by using family history as a proxy for risk and placing individuals on the standard curve we save money and resources.
What is management guidelines for unaffected women with a family history of breast/ovarian cancer-B1 and B2 surveillence?
-2 categories
1. category B1 surveillance:
=>17-30 % chance
=> annual mammography 40- 50 years
=> three yearly mammography 50-70 years
- category B2 surveillance
=>30%+ risk , family history but no high risk gene
=> annual mammography 40-60
=>three -yearly 60-70
chemoprevention : using med to reduce risk
What are some screening, prevention and early detection (SPED) methods?
- mammograms
- colonoscopies
- chemoprevention
How do we test for high risk CPG?
- CPG = cancer predisposition gene
- where likelihood of finding a pathogenic variant is >10%
- according to eligibility criteria in national Genomic Test Directory.
- of patient meets these criteria screening is provided.
what other factors influence predisposition?
- age, type of pathogenic variant, risk penetrance, family history.
- Environmental exposure
- empowerment of patient
How is autosomal recessive inheritance for CPG?
- most CPG are caused by dominant inheritance , only one gene in an allele is enough to put you at high risk
- occasionally autosomal recessive
- in rare cases several autosomal dominant cancer predispositions are linked to recessive conditions when biallelic pathogenic variants are inherited eg: BRCA2 is a fanconi anemia gene
ATM = ataxia telangiectasia
What are different genetic testing?
- single gene testing
- NGS panel - more than one gene causes cancer so easier to look at a lot of genes at once.
- WES
- WGS
What are outcomes of diagnostic genetic testing of high risk cancer?
- no disease causing variant identified
- variant uncertain significance identified
- disease causing (pathogenic) variant identified.
What is SPED?
- manage according to gene specific protocol
- screening, prevention and early detection (SPED) :
1. non- invasive
2. invasive
3. chemoprevention
4. Risk reducing surgeries
What are predictive testing?
- a test in WELL person to predict future risk
- protected against discrimination by moratorium with association of British insurers
- if pathogenic variant not present can manage as population risk usually
- if pathogenic variant presents, manage as per gene specific protocol.
What are hereditary breast and ovarian cancer syndrome genes?
- BRCA1 and BRCA2
- monogenic cause for heriditary breast cancers
- 20% familial breast cancer
- contribute to 2% overall breast cancer
- involved in DNA repair and regulation of transcription.
how can you manage risk as carrier management for BRAC genes?
- screening
- risk -reducing surgery
- chemoprevention for BRCA2 carriers
- Male BRCA2 carriers recommended to have annual Prostate specific antigen (PSA) test.
What is Lynch syndrome?
- famalial colirectal cancer (CRC), endometrial and ovarian cancer
- accounts for 1 to 3% of all CRC
- mismatch repair
- prevalence 1 in 440
- MLH1, MSH2, MSH6 and PMS2
What do Lynch syndrome depend on?
- gene
- gender
What are carrier management used for Lynch syndrome?
1. Screening colorectal Gastric symptom awareness 2. Risk reducing surgery : hysterectomy 3.chemoprevention : low dose aspirin 4. Research 5. Family matters
What is consitutional (germline) mutation?
- inherited from family (genetic)
- provides information for other family members
- extremely rare relatively (25%)
What is somatic mutation?
- Acquired (sporadic)
-provides reassurance for family and future children
-more common (65%)
=>10% high risk cancer genes-predisposition
What is multifactorial/familial polygenic risk?
=> larger proportion of familial cancers than high risk cancer predisposition genes
- no single high risk gene identified
- risk conferred through multiple lower risk genetic factors +/- environmental factors
- no current testing available but is on horizon
- family history as a proxy of risk
- increased screening is available for some cancer types in at risk individuals (eg: breast, colorectal)
How do we measure cancer predisposition?
- allele frequency: how common a genetic variant is (X axis)
-Effect size : if you carry that genetic variation how likely is it you will develop cancer as a result of the genetic variant (y axis)
top left shows rare allele frequency and high effect size
bottom right shows common variants implicated in common disease
What does family history assessment look for red flags that will enable the patient getting screened for high risk gene?
- bilateral cancer or multiple cancers in same individual
- young age onset
- multiple cases of same type of cancer
- the diagnosed cancers are closely related to cancer predisposition gene
Summary of multifactorial/polygenic risk
- larger population of familial cancers than high risk cancer predisposition genes (CPGs)
- No routine genetic testing
- multiple lower risk genetic factors
- Family history as a proxy of risk
- Screening, prevention and early detection (SPED) , ie: Mammograms, colonoscopies, chemoprevention
