Clinical cancer genetics Flashcards
What are the two types of mutations that occur in cancer ?
Constitutional (germline ) mutations
Somatic mutations
What are germline mutations ?
Hereditary
Informs future cancer risk
Informs treatment decisions
Provides information for other family members
What are somatic mutations ?
These are acquired
Informs treatment decisions
Provides reassurance for family and future children
What are the three types of cancer patients ?
Sporadic cancer
Familial cancer
High risk cancer
What is the 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)
How do the high risk cancer predisposition genes depend on cancer types?
Breast cancer5-10%
Colon 5-10%
Prostate5-10%
Ovarian 10-15%
Melanoma10%
Pancreatic10%
Medullary thyroid25%
Retinoblastoma40%
Why do we try to identify patients with increased genetic disposition to cancer ?
- Informs medical management and surgical options .
- Provides reason for why developed cancer
- Informs patients about future cancer risks
- Informs relatives about cancer risk-access to screening /risk reducing surgery
How can we identify patients with increased genetic predisposition to cancer ?
Family history
Syndromic features
Tumour testing
Pathology of cancer
Outline family history assessment
Three generational family history .
Bilateral cancer/ multiple cancer in same individual
Age of onset
Multiple cancer diagnosis of same type .
Closely related individual
Multiple cancer diagnosis or cancer related to specific CPG in closely related individuals (caused by same underlying genetic defect)
What are polygenetic risk scores?
Single value estimate of an individual’s genetic liability to a trait or disease.
Target to look at specific changes using SNP from GWAS
What are syndromic features?
Very rare cancer predisposition genes
Flags on clinical examination
- Trichielomma
- Mucocutaneous pigmentation
What is stratified prevention ?
All women are offered screening from age of 47-50.
This is the categorization of the population into risk groups, each of whom would be offered a different intervention
Individuals with a family high risk can be offered further screening
What is Tamoxifen?
This is an anti-oestrogen drug which has been shown to reduce the risk of woman developing breast cancer when coming from family’s with increased suceptibility to breast cancer - Chemo prevention
Give a summary of multifactorial /polygenic risk assessment
Larger proportion of familial cancers than high risk cancer predisposition genes
No routine genetic testing
Multiple lower risk genetic factors
Family history as a proxy of risk
Screening, prevention and early detection (SPED)
- Mammograms
- Colonoscopies
- Chemoprevention
When is testing offered to patients for high risk cancer predisposition genes ?
Where there is a likelihood of finding a pathogenic variant is greater than 10%
What are the caveats of cancer predisposition genes ?
Even if a disease causing change is found , the risk of cancer is not 100%
Large range which may have other influences
The age of the patient , type of pathogenic variant and risk penetrance must be taken into account.
Describe cancer predisposition inheritance
Most inherited cancer predispositions are inherited in autosomal dominant fashion therefore 50% chance of passing it on to child
Outline autosomal recessive cancer predisposition inheritance
Sometimes ,autosomal recessive predisposition to cancer can occur with healthy carriers but when a child inherits 2 pathogenic variants.
MUTYH gene -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 anemia gene
What are the different genetic tests which are offered ?
Single gene
NGS panel
(Next generation sequencing)
WES
(Whole exome sequencing )
WGS
(Whole genome sequencing )
What are the outcomes of diagnostic genetic testing ?
- No disease causing variant is identified
- manage on basis of family history and personal diagnosis - Variant of uncertain significance identified
- Analyze variant with scientists
- Manage on basis of personal and family history
- Try to get information to help classify variant . - Disease causing (pathogenic) variant identified
- manage as per gene specific protocol
- Can offer cascade screening to relatives
What would happen if a actionable pathogenic variant is identified?
Screening, Prevention and Early detection
- Non invasive imaging -more frequent from a young age
- Invasive-more frequent
- Chemoprevention
- Risk reducing surgeries
What is predictive testing ?
This is a test in a well person to predict future risk
Protected against discrimination
If pathogenic variant not present can manage as population risk
If pathogenic variant us present, manage as per gene specific protocol
What are the genes which are most frequent monogenic causes for hereditary breast cancer ?
BRCA1 / BRCA2 genes
-They account for 20% of familial breast cancer
Contribution to overall breast cancer
-Involved in DNA repair and regulation of transcription
-Disease causing variants result in an increased risk to develop certain cancers
-Founder mutations common in specific mutations e.g Polish
What is the carrier management ?
Screening
Risk reducing surgery Chemoprevention for BRCA2 carriers
More BRCA2 carriers recommended to have annual PSA test
