Cancer Flashcards
Define cancer
The uncontrolled and abnormal division of cells without control and can invade nearly tissues.
Characterise benign and malignant tumours
- Benign neoplasm proliferate and divide but do not invade the surrounding tissue, nor metastasise.
- Malignant neoplasms show evidence oof invasion into adjacent tissue/ have ability to metastasise.
Define Oncogenes
Oncogenes promote cell proliferation and stop cell death, resulting in cancer.
Three primary groups of genes
- Oncogenes
- Tumour suppressor genes
- DNA mismatch repair genes
Define tumour suppressor genes
Protective genes normally limit the development and/or growth of tumours, when gene is mutated, it may fail to prevent a cancer from growing
Define DNA mismatch repair genes
Maintain integrity of the genome and the accuracy of information transfer from one generation of cells to the next, loss of function of DNA mismatch repair genes could make a cell error-prone.
Oncogene activations can result from:
- Chromosomal translocation (normal in leukaemias ) leads to upregulation and over production of protein.
- Gene amplifications leads to normal protein being greatly overproduced.
- Subtle intragenic mutations leads to hyperactive protein made in normal amounts
Function of tumour suppressor genes
- Prevent inappropriate cell cycle progression
- Steer deviant cells into apoptosis
- Keep the genome stable.
Explain the two hit hypothesis
To cause cancer two mutations ( 2 hits ) are required , if one mutation is inherited the person only requires one other mutation which will be quicker to accumulate than 2, thus this person will have an early age of onset of cancer. The person will also have bi-lateral cancer as the mutation will be inherited and thus present in all cells thus second mutations can happen in multiple cells.
Tumour suppressor genes inactivated by some combination of;
- Intragenic mutation
- Gene deletion
- Transcriptional (Epigenetic) silencing
Purpose of DNA repair genes
Their purpose is to keep genetic alterations to a minimum to keep the genome stable and to ensure accurate replication and repair.
Define Pleiotropy
Single gene influences multiple phenotypic traits
Types of cancer origins.
- Sporadic- acquired
- Familial -Family clusters (multifactorial). Multifactorial cancers are cancers that run in a family but are not inherited but may be caused by environmental factors.
- Inherited- Mendelian inheritance pattern
Characteristics of inherited cancer syndrome
- Early age at onset- usually younger than age 50
- Cancers in both organs, e.g both kidneys, both breast or both eyes
- Cancer in two or more generations
- Multiple family members with the same or related cancers
- Several family members with uncommon or rare type of cancer
- There is more than one case of childhood cancer in siblings
Breast cancer causing mutations
- BRAC1 and BRAC2
- CHEK2
- TP53
Breast cancer risk
- Carries of the BRACA mutations have up to 80% risk of developing breast cancer and about 20-40% risk of developing ovarian cancer.
- Males with BRAC1 mutation have an increased risk of developing prostate cancer
- Males with BRA2 mutation have an increased risk of breast cancer
Characterise lynch syndrome
- Hereditary non polyposis colon cancer
- Autosomal dominant
- Lynch syndrome can cause multiple cancers therefore it is easy to mistake it for other syndrome or other causes of cancers.
- Caused by mutations in mismatch
- Founder mutation in South Africans : MLH1 gene
Characterise constitutional mismatch repair deficiency syndrome. (CMMR-D)
- Rare genetic syndrome
- autosomal recessive
- Result of bi-allelic/ homozygous mutation in mismatch repair genes.
- It’s an early age of onset cancer (0-8yrs)
- Causes Spectrum of cancers. CMMR has features of other syndromes.
Characterise LI-Fraumeni syndrome.
- TP53-mutations
- Early age of onset
- Wide range of cancers
- High penetrance
- Carriers have a 58% risk of developing cancer before the age of 40 years and an 80% chance of developing cancer before 70 years of age.
What is a diagnostic test.
- Patient has a confirmed diagnosis of cancer.
- Always best to start testing on someone with cancer to confirm or refute an inherited cancer syndrome.
What is a predictive test
- Patient is at risk of developing cancer but is currently healthy.
- A mutation should ideally have been identified in the family beforehand.
- Generally, from age 18 years, except for FAP where predictive testing is from 10 years of age.
Indications for genetic testing.
- Breast cancer diagnosis <40 years of age.
- Bilateral breast cancer
- Male breast cancer
- Breast/colon cancer patient with Aa first -or second degree relative with breast/colon cancer.
- Ovarian cancer diagnosed <60 years of age.
- Colon cancer diagnosed <50 years of age
- Multiple family members affected with the same or closely related cancers.
- Multiple affected generations
- Multiple primary tumours in an individual
Why test/screen for cancer in individuals.
- Risk of tumour recurrence
- Risk of additional tumours in other organs
- Tailor screening and management
Why test for cancer in families.
- 50% RR for first degree relatives. Siblings, children
- Prevention/ increased screening which can lead to prophylactic surgery, increased reproductive options and alleviation of anxiety for those who test negative.
Testing options for cancer variants
- Founder mutations
- Familial mutations
- Single gene tests
- Multi gene panels
Characterise founder mutation testing
Involves testing only for the specific founder mutation.(populations groups have common mutations in certain cancer-predisposing genes)
Limitations of founder mutation testing
What if a person has a different mutation
Characterise testing for a familial mutation.
- If a mutation has been detected in a blood relative, then it is only necessary to test an individual for that specific Mutation.
- Unless there is a history of cancers from the other side of the family which needs to be considered.
- Testing should be quicker and cheaper, and the results are simpler to interpret
Characterise single gene testing
- Test for a single gene at a time
- Sanger sequencing
- If you don’t find what you are looking for but still suspect inherited cancer you need to sequence the next gene, then the next gene…… (time consuming)
3 types of multigene panels
- Syndrome -specific test : e.g BRACA1 and BRCA2
- Cancer -specific - high + moderate penetrance gene panel
- Comprehensive cancer panels : genes associated with multiple hereditary cancer syndromes
Challenges with multigene panels
1.what about mutations in genes that we don’t yet understand.
2. Pathogenic versus normal genetic variantion?
3. Variants of uncertain significance
4. Reference sequences mainly from Caucasian population.
5. Risk of incidental findings
Advantages of genetic testing
- Early and appropriate cancer screening
- Lifestyle changes - adopt things that might help lower risk
- Learn about options to help reduce the risk of certain types of cancer, such as drugs or surgery.
- Early diagnosis and treatment interventions
Challenges of genetic tests
Uncertainty of genetic test results:
1. A positive test results does not always mean you will get the disease (incomplete penetrance)
2. A neg result does not mean you have no risk of getting the disease.
Limitations of genetic testing
- Genetic testing is not always appropriate for all types of cancer.
- No precise answer
- Testing can only tell you if you have a specific gene mutation.
