intro to clinical cancer genetics Flashcards
What can we do to reduce cancer risk in people at increased genetic risk?
Screening
Prevention
Early Detection
SNP - what is it and what does it increase the risk of?
single. nucleotide polymorphism, change from 1 base to another
SNP’s increase the risk of cancer
2 DNA strands - what are they and how are they read?
anti-parallel
One strand ‘read’ 5’ to 3’
Other strand read 3’ to 5’
Genetic variation may…
influence our chance of developing disease
Inherited cancer risk
external factors that can affect DNA?
smoking
exposure to UV
drugs
these cause a permanent change to the DNA - mutation
2/3 of cancers are “sporadic” - what does this mean?
acquired (somatic) mutations within a cell in cancer genes, driving the cell to become cancerous
a smaller proportion of cancers occur due to inherited genetic changes
- these can be multiple lower risk genetic variants – this is known as multifactorial or polygenic risk
- OR a single high risk genetic variant in a cancer predisposition gene
what is meant by inherited cancer risk?
genetic changes we are born with which increase the risk of developing cancer
- High risk changes - cancer predisposition genes
- Moderate risk changes
- Low risk changes
which genes are rare?
High risk cancer predisposition genes
- if you have one, you have a high chance of developing cancer in your lifetime (9 out of 10 chance)
- rare variants, large effect
which genes are more common?
Low risk genetic changes
- -common variants in the population, increases your cancer risk by a very small amount
- having multiple of these lower risk variants means you are more likely to develop cancer than the avg person in the population
Clustering of the same types of cancer indicates what?
a multifactorial risk
role of Genome Wide Association Studies
(GWAS) and Polygenic Risk Scores?
looking at cases and controls, seeing single base substitutions that are more common in cases than controls
Inherited cancer risk can be split into what?
having high risk genes (10%) and familial cancer (25%)
give examples of High risk cancer predisposition genes?
Breast cancer 5-10% BRCA Ovarian 10% BRCA Colon 5-10% Lynch Melanoma 10% CDKN2A Medullary thyroid 25% RET Retinoblastoma 40% RB1 Prostate 5-10% BRCA2 Pancreatic 10% BRCA2
% shows how how likely it is that the cancer was caused by a high risk gene
Working out someone’s genetic risk for cancer
3 generational family history assessment, looking for:
- a young age of onset
- multiple cancer diagnoses of same type in closely related individuals
- multiple cancer diagnoses of cancer related to specific CPG in closely related individuals
- consider ethnic origin
also consider the types of cancer in detail to see if they increase the chance of a high risk cancer predisposition gene (CPG)
Look for any rare syndromic features which could indicate a high risk cancer predisposition gene
Use the National Genomic Test Directory Eligibility Criteria to decide if genetic testing is indicated
Tumour testing may identify?
genetic changes which could indicate inherited risk – need to check with a blood test
e.g.
Immunohistochemistry of mismatch repair genes in Lynch Syndrome
BRCA gene sequencing in ovarian cancer
Decisions to make on assessment
Is there an increased inherited risk of cancer?
How high is the risk?
Does the patient need genetic testing to look for high risk cancer predisposition genes? (usually around a 1 in 10 chance of finding a mutation in a high risk cancer predisposition gene)
Does the patient and/or their relatives need extra screening or other measures to reduce cancer risk?
Management of inherited cancer risk
- Offer screening, prevention and early detection advice (SPED)
Assess the family history and give a risk percentage - anything over a 30% lifetime risk of getting cancer is deemed high risk
people will get screening regularly or annually etc. depending on whether they are green or yellow group
- Chemoprevention
- taking medication to reduce breast cancer risk (eg. tamoxifen, Selective estrogen reuptake moderator – SERM - side effects – hot flushes, sexual dysfunction)
- colorectal cancer: aspirin - High risk CPGs : Genetic testing considerations
- in terms on the individual, look at their risks of other cancers
- sharing info to relatives
- family planning options
Diagnostic versus predictive testing
Diagnostic testing
To confirm whether a CPG has caused the cancer
Predictive testing
To identify if an unaffected person carries a CPG
Outcomes of testing
- No genetic variant identified
- Reassuring for patient
- referral for screening
- management of family history - Disease causing variant in CPG identified
- Screening and management tailored to specific CPG
- Should be reviewed by NHS clinical genetics service - Variant of uncertain significance (VUS) identified
- Benign until proven guilty
- Referral for screening/further management only if indicated on above assessment
- May be anxiety provoking for patient, but they need to understand how common genetic variation is and that most VUS are benign
Sporadic cancer vs cancer due to CPG
Hereditary cancers
- High risks of recurrence/other associated cancers
- High cancer risks in relatives
- We can offer testing to at risk individuals
- We can offer screening and preventative management to gene carriers
- May alter treatment of affected individuals
Sporadic cancers
- No increased risk of other cancers
- Usually small increased risk to relatives
- No genetic testing indicated
- Normal clinical management for affected individuals
Germline vs somatic mutations
germline
- present in egg or sperm
- can be inherited -cause cancer family syndrome
- all cells affected in offspring
Somatic
- acquired
- occurs in nongermline tissues
- cannot be inherited
