Inherited Cancer Flashcards
Where do mutations occur in hereditary cancer?
Hereditary cancers are from constitutional (germline) mutations
Informs future cancer risk
Informs treatment decisions
Provides info for other family members
Where do mutations occur for sporadic cancer?
Somatic mutations:
These are acquired
Informs treatment decisions
Provides reassurance for family and future children
Most cancers are sporadic and not inherited
Use this to explain the genetic architecture of inherited cancer predisposition
- There is a larger proportion of familial cancers (inheritance and sharing of multiple lower risk factors) than high risk cancer predisposition genes
- No single high risk gene identified
- Risk conferred through multiple lower risk genetic factors +/- environmental factors
- Current testing is uavailable but is on the horizon, instead family history is used.
- Increased screening available for some cancers in at risk individuals (e.g. breast, colorectal)
Which cancer types are more likely to be inherited?
- Breast, colon, prostate: 5-10%
- Ovarian: 10-15%
- Melanoma, pancreatic: 10%
- Medullary thyroid: 25%
- Retinoblastoma: 40%
Why and how do we identify patients with increased genetic predisposition to cancer?
- Informs medical management and surgical options bc we understand the molecular basis of the cancer
- Informs relatives about cancer risk –access to screening / risk reducing surgery
- Informs patient about future cancer risk
How do we identify them? Family history!!! Pathology of the cancer, tumor testing and syndromic features
Why would this patient be eligible for genetic screening?
Bilateral cancer or multiple cancers in the same individual
Young age of onset
Multiple cancer diagnoses of same type in closely related individuals
Multiple cancer diagnoses of cancers related to specific cpg in closely related individuals- see circled
Why do we look for syndromic features?
Some features are associated with diseases which have high cancer risk (see below)
Why do we do tumor testing?
- 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 when testing the tumour, the change might also be in the germline
- We can then offer a blood test to check this
Describe the risk assessment for potential multifactorial cancer patients
Family history is calculated as a proxy of risk
Patients are then stratified into Screening, Prevention and Early Detection (SPED) e.g.
- Mammograms
- Colonoscopies
- Chemoprevention- like anti oestrogen drug Tamoxifen to prevent breast cancer
Stratified means that eg having 3 close relatives with breast cancer means yearly mammograms instead of every 3 years
How are most inherited cancer genes passed on?
Most inherited cancer predispositions inherited in autosomal dominant fashion therefore 50% chance of passing on to child (male or female)
But cancer predisposition is < 100% penetrant- hay que consider age, type of variant, risk penetrance, family history, environment
Occasionally, autosomal recessive cancer predisposition can occur- when a child inherits 2 pathogenic variants from 2 healthy carriers. Eg MUTYH gene, there is a predisposition to colon polyps and cancer
What are the outcomes of genetic diagnostic testing?
1) No pathogenic variant. The cancer isn’t caused by a high risk inherited gene. Manage on basis of family history and personal diagnosis
2) Variant of uncertain significance identified. Analyse variant with scientists, manage on basis of personal and family history. Try to get info to classify variant if possible
3) Pathogenic variant identified. Manage as per gene specific protocol. Can offer screening to relatives
What are the main next steps if a pathogenic variant is found?
- Manage according to gene specific protocol
- Screening, Prevention and Early Detection (SPED) e.g.
- Non-invasive imaging, more frequent and starting at younger age
- Invasive – often more frequent, starting at younger age
- Chemoprevention
- Risk reducing surgeries
What is predictive testing?
Test a well person in a family where someone has a cancer predisposition gene, 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
Describe the screening management of patients who carry a pathogenic variant in a cancer predisposition gene
–Hereditary breast and ovarian cancer
- Chemoprevention for BRCA2 carriers
- Male BRCA2 carriers recommended to have annual PSA test
Describe the surgical management of patients who carry a pathogenic variant in a cancer predisposition gene
–Hereditary breast and ovarian cancer
