Clinical Cancer Genetics Flashcards
(28 cards)
What mutations can occur to cause cancer
- Constitutional (germline)
- Somatic
What are the characteristics of Constitutional mutations?
- Hereditary
- Informs future cancer risk
- Informs treatment decisions
- Provides information for other family members
What are the characteristics of somatic mutations?
- Acquired
- Informs treatment decisions
- Provides reassurance for family and future children
What is the common architecture of genetic susceptibility to cancer
- Sporadic 65%
- Familial Cancer 25%
- High risk cancer genes 10%
Explain the architecture of inherited cancer predispositions
- Very rare mutations have the highest cancer effect and common mutations cause the least cancer effect
- Some exceptions are highly common mutations causing high-effect cancers and vice versa.
What are the characteristics of Multifactorial/polygenic familial 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 the horizon
- Family history as a proxy of risk
- Increased screening is available for some cancer types in at risk individuals (e.g. breast, colorectal)
Why do we identify patients with increased genetic predisposition to cancer
- Informs medical management and surgical options
- Inform relatives about cancer risk - access to screening
- Provides reason for why cancer developed
- Informs patient about future risk
How can we identify patients with increased genetic predisposition to cancer
- Family History
- Pathology of cancer
- Syndromic features
- Tumour testing
What do we look for in a family history assessment
- Bilateral cancer or multiple cancers in the same individual
- Young age of onset
- Multiple cancer diagnoses of the same type in related indivaduals
What methods have been developed to track cancer family history easily
- Apps to enter cancer history and family history
- Easier to enter for the patient and results can be viewed and manipulated digitally
What are polygenic risk scores
- Genetic testing of multiple low risk factors
- Not currently performed on the NHS
- Can indicate increased genetic susceptibility to
cancer - Undertaken by looking for cancer associated
SNPs found from Genome Wide Association
Studies
How can we use GWAS to find cancer-causing gene’s
- Look for cancer-associated SNP’s
How can we assess histopathology and cancer predisposition genes
- Certain genes are associated with specific cancers
- Refer to lecture slide
What syndromic features can associate with cancer
- Trichilemmoma
- Mucocutaneous Pigmentation
How can we tumour test for germline cancers
- 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
What is stratified prevention?
- Categories population into risk groups for cancer
- Appropriate interventions for each stratum
Summarise Multifactorial/polygenic risk assessment
Larger proportion 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) e.g:
- Mammograms
- Colonoscopies
- Chemoprevention
Should we test for high risk CPGs
- Likelihood of finding a pathogenic variant is more than 10%
- Test according to NHS guidelines for who we can test
How is cancer predisposition nearly always less than 100%
- Not everyone with altered genes inherits and exhibit cancer
- Other factors at play such as environmental factors
Explain cancer predisposition gene inheritance
- Most inherited cancer predispositions inherited in autosomal dominant fashion therefore 50% chance of passing on to child (male or female)
- Occasionally, autosomal recessive predisposition to cancer can occur, with healthy carriers but when a child inherits 2 pathogenic variants (e.g. MUTYH gene, there is a predisposition to colon polyps and cancer)
- Several autosomal dominant cancer predispositions are linked to autosomal recessive conditions in rare cases when biallelic pathogenic variants are inherited, e.g. BRCA2 is a Fanconi anaemia gene, ATM = ataxia telangiectasia
What order do we do genetic testing
- single gene
- NGS panel
- WES
- WGS
What are the outcomes of diagnostic genetic testing
- No disease-causing variant identified
- Variant of uncertain significance identified
- Disease causing (pathogenic) variant identified
what happens if a clinically actionable pathogenic variant is found in CPG
Manage according to gene-specific protocol
Screening, Prevention and Early Detection (SPED) e.g:
- Non-invasive imaging –often more frequent and starting at younger age
- Invasive – often more frequent, starting at younger age
- Chemoprevention
- Risk reducing surgeries
what is Predictive testing
- A test in a 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 present, manage as per gene specific protocol
