Clinical Cancer Genetics Flashcards
As a recap, what is DNA?
Deoxyribonucleic acid (DNA) is a molecule encoding the genetic instructions used in the development and functioning of living organisms.
As a recap, what are genes?
They are the instructions to tell the body how to grow, develop and function.
it consist of sections of DNA which the cell translates into proteins.
We have about ~20,000 genes in the human genome.
We have 2 copies of most genes – one on each chromosome.
Exapnd on genetic variation.
it is what makes us unique - “polymorphisms” .
It:
- is the basis for evolution
- is the basis for disease
- is caused by intrinsic errors in DNA replication and repair
- is also caused by external factors
In basic terms, what is cancer?
Normal cells divide, replicating their DNA before division.
DNA replication is complicated and can result in errors in a gene/s (i.e. a somatic mutation).
Normal cells die when an error cannot be repaired.
Cancer results when mutations accumulate, cell does not die and cell growth is uncontrolled.
What are some general cancer statistics?
Cancer is a common disease in humans.
There is a 1 in 2 lifetime risk of developing cancer.
Most cancers are caused by a combination of genetic, environmental and lifestyle factors – multifactorial/ sporadic.
Only ~5-10% of cancers are due to the inheritance of a single cancer susceptibility gene.
What is the difference between a germline mutation and a somatic mutation?
A germline mutation is either inherited or occurs at the point of conception. All the cells of the body will be affected.
A somatic mutation occurs after the point of fertilisation (at some point during development). Only certain cells in the body will be affected.
List some differences between sporadic and hereditary cancers.
SPORADIC CANCERS:
- no increased risk of other cancers
- usually small increased risk to relatives
- no genetic testing indicated
- normal clinical management for affected individuals
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
Exaplin Knudson’s “Two Hit Hypothesis” using the example of retinoblastoma.
For a retinoblastoma to develop, a cell needs to carry two faulty copies of the RB1 gene.
In hereditary retinoblastoma, if the sperm has a faulty RB1 gene, the fertilised egg has a 50% chance of inheriting the RB mutation.
Then, this mutation in one copy of the RB gene is inherited in all body cells. This gives it a higher chance of mutation of the second copy of the RB gene occuring in one or more retina cells.
In non-hereditary retinoblastoma, the fertilised egg inherits no RB mutation. Thus, both mutations of the RB gene need to occur spontaneously for the retinoblastoma to present, which may take longer.
What is penetrance in terms of cancer?
NOT every person with a germline mutation develops the disease; this is known as reduced penetrance.
We can give risks of developing disease for a given genotype:
- based on family/ population studies
- unknown modifying factors
Describe cancer susceptibility genes.
Different classes of genes are targeted in cancer, which function in normal cell regulation:
- Growth promoting proto-oncogenes: e.g. RET in MEN2
- Growth inhibiting tumour suppressor genes: e.g. RB1 in retinoblastoma
- Genes involved in DNA damage repair: e.g. BRCA1 and BRCA2 genes in breast/ovarian cancer
Other mechanisms of oncogenesis:
- Epigenetic mechanisms of oncogenesis
- Chromosomal aberrations
Describe the basics of taking a family history.
- take a 3 generation family history
- ask about consanguinity
- ask about ethnic background (for e.g. Ashkenazi Jewish, other founder populations)
- ask about types and ages of all cancers
NB. Some individuals with a hereditary predisposition to cancer do not have a family history of cancer.
What are some decisions that can be made from taking a family history?
Is genetic testing indicated?
Or are other investigations required first?
- confirmation of cancer diagnoses
- testing of tumour samples (e.g. IHC)
Is increased screening indicated?
- for affected individual
- for unaffected relatives
What are some implications of undertaking genetic testing?
Implications for individual:
- recurrence risks
- risks of other cancers
Implications for relatives:
- how to share information
- concerns about children
- predictive testing
Insurance implications:
- current moratorium for predictive testing
Family planning options (e.g. prenatal, PGD)
Describe the BRCA 1 and BRCA 2 genes.
BRCA1 mutations - 0.11% population
BRCA2 mutations - 0.12% population
Their function is in repair of double stranded DNA breaks (homologous recombination).
It is responsible for
~ 16% familial breast cancers
~ 5% breast cancer
~ 10% ovarian cancer (also prostate, pancreatic, fallopian tube and peritoneal cancers)
What screening c an be undertaken for BRCA carriers?
BREAST SCREENING:
- 30-50y: annual MRI screening
- 30-50y: annual mammograms
- > 50: annual mammogram
OVARIAN SCREENING:
- unproven efficacy
- not currently recommended
