Clinical Genetics: Clinical Cancer Genetics Flashcards
What can we do to reduce cancer risk in people at increased genetic risk?
- Screening
- Prevention programmes
- Early Detection programmes
What is DNA?
- A molecule which contains the human genetic code
What is a gene?
- A functional unit that consists of sections of DNA which the cell translates into proteins
- Contains the instructions to tell the body how to grow, develop and function
- Aroeund 20,000 genes in the human genome
- Genome contains 2 copies of most genes – one on each chromosome
What is the human genome?
- The entire length of DNA contained in human cells
- 3 billion bases
How much genetic variation is there between 2 unrelated people?
- Around 5 million different genetic changes compared to another unrelated person
What is the risk that someone will develop cancer within their lifetime?
- There is a 1 in 2 lifetime risk of developing cancer
What are the main reasons for the development of cancer within an individual?
- Most cancers are “sporadic” – due to acquired (somatic) mutations within a cell giving it a growth advantage
- Some genetic changes we are born with may also influence our lifetime cancer risk (inherited cancer risk)
What % of cancers are sporadic and what % of cancers are classed as other types?
- Sporadic - 65%
- Familial cancer (inheritance of multiple lower risk genetic variants; known as multifactorial/polygenic risk) - 25%
- High risk genes (single high risk genetic variant of cancer predisposition gene) - 10%
What are some of the things that cause sporadic cancers?
- Raective oxygen species
- UV light/ionising radition
- Ineffective DNA repair mechanisms
- Carcinogens
What are the different types of changes that contribute to a person’s inherited cancer risk?
-
High risk changes
- Cancer predisposition genes
- Moderate risk changes
- Low risk changes
What does the following graph show about inherited cancer risk?
- X axis = How common a genetic variant is within the population (allele frequency)
- Y axis = How likely genetic variant is to cause cancer (effect size)
- Shows that genetic variants in cancer predisposition genes are very rare but have a very likely chance of causing cancer if they’re inherited
- Also shows that common genetic variants will be inherited by quite a lot of people within the population but don’t have a high risk of causing cancer
- Only having 1 common genetic variant means you probably won’t develop cancer
- However, having 30 common genetic variants will increase your risk of developing cancer to quite a high level
How does a polygenic risk score allow you to calculate the risk of someone developing cancer?
- Allows you to look at the number common SNPs associated with cancer that a person has which is then used to define that person’s lifetime risk of developing a particular cancer
How can you test for the number of common genetic variants (SNPs) associated with cancer a person has?
- Genome wide association studies (GWAS)
- Polygenic risk scores
- NOTE: SNPs more common in people with cancer (cases) compared to people without (controls)
What hapens to the risk of developing a particular cancer if somone is found to have multiple common genetic variants associated with cancer?
- If you have multiple common genetic varinats associated with cancer then your risk of developing cancer is pushed up compared to normal distribution (more likely to develop cancer)
For each of the following cancers state how likely that cancer is to be caused by a high risk gene and name the most likely high risk gene that causes that cancer
Breast cancer
Ovarian
Colon
Melanoma
Medullary thyroid
Retinobalstoma
Prostate
Pancreatic
When conducting a family history assessment to see if there’s an increased inherited risk what do you look for?
- You look at 3 generations within the family and see if:
-
The same individual has/had bilateral cancers or multipe cancers
- Indicates increased inherited genetic risk
-
Young age of onset for a particular cancer - e.g. breast cancer in individual under age of 40
- Indicates increased inherited genetic risk as it’s unusual to have young age of onset in sporadic cancer
- Multiple cancer diagnoses of same type in closely related individuals
-
Multiple cancer diagnoses of cancers related to same cancer predispostion gene in closely related individuals
- E.g. Presence of genetic variant in BRCA gene would increase risk of both breast and ovarian cancer
What types of tests are conducted when testing for cancer?
-
Look at pathology/histiological subtype of cancer - certain pathological subtypes of cancers have higer risk of being caused by high risk CPGs e.g.
- High grade serous ovarian cancer: BRCA1/2
- Medullary thyroid cancer: RET
-
Molecular testing - 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 (Hereditary nonpolyposis colorectal cancer, HNPCC)
- BRCA gene sequencing in ovarian cancer
What are some syndromic features that may be signs of particular inherited risk cancers?
- Trichilemmoma (small white bumps) - strongly associated with mutations of p10 gene which causes cowden syndrome which increases risk of thyroid, breast and uterine cancer
- Mucocutaneous pigmentation - Strongly ssociated with mutations in STK11 gene which causes a condition called Peutz-Jeghers syndrome. This increases the risk of breast cancer and bowel polyps
What decisions need to made on the assessment of families with multiple cancers or families with early onset cancers?
- Is there an increased inherited risk of cancer?
- How high is the risk?
- Does the patient need genetic testing to look for mutations in 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?
How would you manage the risk of inherited cancer in a person who you suspect has an increased multifactorial/polygenic risk of cancer?
- Offer screening, prevention and early detection advice (SPED)
What is chemoprevention?
- Taking a medication to reduce risk of developing a particular cancer
- Breast cancer: Tamoxifen/SERM (selective oestrogen reuptake modulater)
- Colorectal cancer: Aspirin
What are some of the disadvantages of chemoprevention?
- Medication used have side effects of their own
- Medication taken to reduce risk of breast cancer may cause menopausal symptoms, e.g. hot flushes, or in extreme cases may cause sexual dysfunction
What things need to be considered before offering an individual genetic testing for high risk cancer predisposition genes?
-
Implications for individual
- Recurrence risks
- Risks of other cancers
-
Implications for relatives
- How to share information
- Concerns about children - high risk CPGs usually are inherited via autosomal dominant inheritance so greater chance of inheritance vai offspring
- Family planning options (e.g. prenatal, PGD)
What are the diferent types of tests used to identify high risk CPGs?
- Diagnostic testing - To confirm whether a CPG has caused the cancer
- Predictive testing - To identify if an unaffected person carries a CPG
- NOTE: Don’t have to tell results of predictive test to insurance comapanies unlike with diagnostic testing
