Clinical Cancer Genetics Flashcards
- What can we do to reduce cancer risk in people at increased genetic risk?
Screening, Prevention, Early Detection
- Define DNA?
A molecule which contains the human genetic code
- What is the function of genes?
How many are in the human body?
o The instructions to tell the body how to grow, develop and function – translated into proteins.
o ~ 20,000 genes in the human genome with 2 copies of most genes – one on each chromosome
- How many bases in the entire human genome
Where is the entire length of DNA contained in?
•The human genome (3 billion bases)
The entire length of DNA contained in human cells.
- Approx how many genetic changes are there between two unrelated people?
•We have around 5 million different genetic changes compared to another unrelated person –> Genetic Variation
- List some cancer statistics:
- Lifetime risk
- % that is sporadic, familial and high risk genes
- Cancer is a common disease in humans: There is a 1 in 2 lifetime risk of developing cancer.
- 65% sporadic, 25% familial and 10% high risk genes.
- Most cancers are sporadic , what does this mean?
- Most cancers are “sporadic” – due to acquired (somatic) mutations within a cell giving it a growth advantage
- Acquired mutations in cancer genes “drive” the cell to become cancerous.
- Repair mechanisms, carcinogens etc.
- What is an inherited cancer risk?
•Some genetic changes we are born with may influence our lifetime cancer risk o High (cancer predisposition genes), moderate and low risk changes. o E.g. multifactorial breast cancer (common).
- What is more common :
- High risk cancer predisposition genes
- Low risk cancer predisposition genes?
- High risk cancer predisposition genes are rare.
* Low risk genetic changes are more common but only increase cancer risk by a little.
- How can we use GWAS to see a patients risk of developing cancer?
•Compare single nucleotide polymorphisms (SNPS) in cases and controls to see the likelihood of developing cancer.
- What is a polygenic disease?
A genetic disorder that is caused by the combined action of more than one gene.
- How does having a polygenic disease affect your risk of developing cancer?
•Presence of common variants shifts the normal distribution of developing cancer to the right (higher risk).
13. For the following cancers list the associated high risk cancer predisposing gene that goes with it and the % of • Breast cancer • Ovarian • Colon • Melanoma • Medullary thyroid • Retinoblastoma • Prostate • Pancreatic
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
- What different approaches are there for assessing inherited cancer risk?
-> 3 generations of family history assessment
and look out for :
• Bilateral (pair of organs) cancer or multiple cancers in the same individual.
• Young age of onset e.g. breast cancer under the age of 40.
• Multiple cancer diagnoses of same type in closely related individuals (number, type and how closely related)
• Multiple cancer diagnoses of cancers related to specific CPG in closely related individuals
- What are certain pathological subtypes of cancers most likely to be due to?
- Give some examples?
High risk CPG (cancer predisposing genes)
o High grade serous ovarian cancer: BRCA1/2
o Medullary thyroid cancer: RET
o Triple negative breast cancer: BRCA1/2
o Type 2 papillary kidney cancer: FH
- What kind of molecular tests would we do on a tumour?
sequencing shows genetic changes which could indicate inherited risk – need to check with a blood test e.g.
o Immunohistochemistry of mismatch repair genes in Lynch Syndrome.
o BRCA gene sequencing in ovarian cancer
- What are two syndromic features of cancer and what cancers can they be a sign on?
o Trichilemmoma (skin legions – increased risk of thyroid, breast and womb cancer). o Musculocutaneous pigmentation (increased risk of cancer and bowel polyps).
- What kinds of decisions need to be made on assessment of cancer?
• Is there an increased inherited risk of cancer and how high is it?
• Does the patient need genetic testing to look for high risk cancer predisposition genes?
o 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?
- Where would you find the criteria that needs to be met to decide whose offered genetic testing?
National Genomic Test Directory
- What type are most cancers
- Sporadic
- Inherited genetic changes
- Most cancers are sporadic due to acquired (somatic) mutations which occur only in the cancer cell
- A smaller proportion of cancers occur due to inherited genetic changes
- What two types of inherited genetic changes are there?
o These can be multiple lower risk genetic variants – this is known as multifactorial or polygenic risk
o Or a single high risk genetic variant in a cancer predisposition gene
- Summarise how you would asses for an inherited cancer risk?
o Take a 3 generational family history:
– Ages, types of cancer and number of affected relatives.
– Ethnic origin – higher rate of CPG in some populations.
o Consider the types of cancer in detail to see if they increase the chance of a high risk cancer predisposition gene (CPG).
o Look for any rare syndromic features which could indicate a high risk cancer predisposition gene.
o Use the National Genomic Test Directory Eligibility Criteria to decide if genetic testing is indicated.
- In multifactorial or polygenic cancers, what % chance is there of CPG or gene testing being negative?
<10% chance of CPG or gene testing is negative
- How can we manage inherited cancer risk?
•Offer screening, prevention and early detection advice (SPED) – use algorithms to work out who has moderate risk (mammograms every 3 years) and who has high risk (annual mammograms) to decide how they are screened.
- How does chemoprevention work?
- What is an disadvantage
o Taking a medication to reduce cancer risk e.g. tamoxifen/SERM for breast cancer or aspirin for colorectal cancer.
Disad = May have side effects on quality of life
- What are some considerations that need to thought about when doing a genetic test for High risk CPGs?
Implications for individual: Recurrence risks or Risks of other cancers
o Implications for relatives
– How to share information
– Concerns about children
– Family planning options (e.g. prenatal, PGD)
- What is the difference between diagnostic AND predictive testing?
- Diagnostic testing: To confirm whether a CPG has caused the cancer.
- Predictive testing: To identify if an unaffected person carries a CPG
- Does healthcare insurance cover predictive testing?
Current moratorium (ban) for predictive testing
- What is the next steps if no genetic variants are identified in tests (most likely outcome, 90% of cases)?
o Screening and management on personal and family history
o Referral for screening/further management only if indicated on above assessment
o Reassuring for patient but reiterate participation in population screening programmes
- What is the next steps if a disease causing variant in a CPG is found (rare-10% of cases)
o Screening and management tailored to specific CPG
o Should be reviewed by NHS clinical genetics service
- What should be the next steps if the outcome of genetic testing is that a variant of uncertain significance (VUS) is found?
o Benign until proven guilty
o Referral for screening/further management only if indicated on above assessment
o May be anxiety provoking for patient - Need to understand how common genetic variation is
- For both SPORADIC and HEREDITARY cancers, what is the likelihood of getting other cancers or recurrence of that cancer?
Hereditary :
-High risks of recurrence/other associated cancers
Sporadic:
-No increased risk of other cancers
- For both SPORADIC and HEREDITARY cancer what is the risk of cancers in relative?
Hereditary :
-High cancer risks in relatives
Sporadic:
-Usually small increased risk of cancer in relatives
34 . For both SPORADIC and HEREDITARY cancer, what type (if any) genetic testing takes place
Hereditary:
Offer testing to at risk individuals and screening/preventative management to gene carriers.
Sporadic:
No genetic testing indicated.
- For both SPORADIC and HEREDITARY what differences would there be in treatment / clinical management is there?
Hereditary:
•May have alter treatment of affected individuals.
Sporadic:
•Normal clinical management for affected individuals.
- Compare somatic and germline mutations?
Somatic :
- occur in nongermline tissue
- Cannot be inherited
- Mutation in tumour (eg breast )
Germline:
- Present in egg and sperm
- Can be inherited
- Cause cancer family syndrome
- Mutation in egg or sperm –> All cells affected in the offspring
- What type of cancer is breast cancer associated with?
Ovarian cancer
- When there is a mutation in the BRCA1 gene, what risks are there in UNAFFECTED carriers?
Give the chance % of getting that cancer
- Breast Cancer (lifetime risk to 80yrs) 60-90% chance
- Ovarian Cancer (lifetime risk: mainly after 40) 40-60%
- Male Breast Cancer (lifetime risk) 0.1-1.%
4.Prostate Cancer
(Lifetime risk similar to population risk) 8%
- When there is a mutation in the BRCA1 gene, what risks are there in AFFECTED carriers?
Give the chance % of getting that cancer
- Women with unilateral breast cancer (lifetime risk of contralateral breast cancer) -50%
Overall 5 year risk - 10%
- When there is a mutation in the BRCA2 gene, what risks are there in UNAFFECTED carriers?
Give the chance % of getting that cancer
- Breast Cancer (lifetime risk to 80yrs) 45-85% chance
- Ovarian Cancer (lifetime risk, mainly after 50) 10-30%
- Male Breast Cancer (lifetime risk) 5-10%
4.Prostate Cancer
(Lifetime risk ) 25%
- When there is a mutation in the BRCA2 gene, what risks are there in AFFECTED carriers?
Give the chance % of getting that cancer
- Women with unilateral breast cancer (lifetime risk of contralateral breast cancer) -50%
Overall 5 year risk - 5-10%
- What kind of surveillance is needed for
- Breast Cancer
- Ovarian Cancer
- Other Cancers
Breast:
- Advise on breast awareness
- Annual mammography from 40-70
- Annual MRI from 30-50
- No breast surveillance for male carriers
Ovary:
-Ovarian Surveillance is not recommended
Other Cancers:
- No surveillance is recommended for other cancers
- Carrier might be used for research
- Is Chemoprevention suitable for BRAC1 or BRAC2 mutation carriers?
BRAC1 carriers:
-Not suitable
BRACA2:
- Discuss benefits and side effects
- Can be offered if no contra-indications
- What risk reducing surgery can be done to reduce breast cancer?
- Bilateral risk-reducing mastectomy
- Breast cancer risk reduction 90-95%
- What risk reducing surgery can be done to reduce ovarian cancer as well as breast cancer
what are some side effects
what is a medicine alternative?
- Bilateral salpingo-oophorectomy (remove ovary and fallopian tubes) once childbearing is complete
- Reduces risk of ovarian cancer by 95%
- Reduces risk of breast cancer by 50%
- Side effect : premature menopause
- HRT should be offered to women until 50 in women who have not had ER positive breast cancer
- The management of cancer depends on the risk level :
- What kind of management would you need for moderate - high risk?
– Screening and early detection mainstay of management and chemoprevention as risk increases
- The management of cancer depends on the risk level :
- What kind of management would you need for high risk cancer predisposition genes?
– Gene specific guidelines: Screening, Chemoprevention and Surgical management
