Lecture 39: Familial cancer predisposition Flashcards
True or false: All cancers are genetic but only a small proportion is caused by a high-risk hereditary cause.
True
Describe multi- stage carcinogenesis.
A series of genetic changes occur within cells leading to increasingly abnormal behaviour and histology
True or false: germ line mutations are more likely to enable cancer than somatic mutations
True
Is it more likely for cancer to develop after a primary somatic mutation or a secondary somatic mutation?
Secondary somatic mutation
What is Penetrance?
The percentage of individuals with a specific genotype who also express the expected phenotype
Name two ways Penetrance may be modified?
- May be modified by other genetic variations
- May be modified by environmental factors
What is the role of gatekeeper genes?
they directly regulate tumour growth by monitoring and controlling cell division and death while preventing the accumulation of mutations
What is the role of caretaker genes?
improving genomic stability (repairing mutations)
What is the role of landscaper genes?
they control the stromal surrounding environment
What does the likelihood of developing cancer depend on?
The importance of the gene function
A defect in which type of gene is associated with familial adenomatous polyposis?
Gatekeeper
A defect in which type of gene is associated with Lynch syndrome?
caretaker
What is another name for Lynch syndrome?
Hereditary nonpolyposis colorectal cancer (HNPCC)
A defect in which type of gene is associated with juvenile polyposis syndrome:
landscaper
What is the function of the tumour suppressor genes
Protects cells from becoming cancerous
Inhibit cell division, preventing the formation of tumours
What affect does loss of function of the tumour suppressor genes have?
Increases the risk of cancer.
What is the function of oncogenes?
Regulate cell growth and differentiation
Gain of function/activating mutations increase the risk of cancer
Give 5 examples of tumour suppressor genes:
1) APC
2) BRCA 1
3) BRCA 2
4) TP53
5) Rb
Give 2 examples of oncogenes:
1) growth and signal transduction factor genes
2) RET gene
What is the name of the theory that states that a cell requires both genes to be mutated for cancer to arise?
Knudson’s two hit hypothesis
What does Knudson’s two-hit hypothesis state?
for a cell to become cancerous, two hits are required on a specific gene in a single cell
Describe Knudson’s two hit hypothesis in inherited cancers:
one gene will already be affected due to inheritance meaning just one is required for cancer
What mode of inheritance do most familial cancers follow?
autosomal dominance
Give three examples of autosomal recessive familial cancers:
1) MUTYH associated polyposis
2) Fanconi anaemia
3) ataxia telangiectasia
Each parent is a carrier of one mutated copy, usually without the disease (but may have a different phenotype e.g. BRCA2)
¼ of children inherit both mutated copies and the cancer risk
Give 6 mutation types associated with carninogenesis:
1) missense
2) nonsense
3) frame shift
4) splice site mutations
5) large deletions and duplications
6) translocations
Do sporadic cancer mutations arise at young or old ages?
Old
Do familial cancer mutations appear at young or old ages?
Young
Name 6 ways of finding familial cancer genes
Disease-causing translocations may give locations
Studying sporadic cancer
Family studies – linkage analysis
Candidate gene analysis
Newer technologies e.g. whole exome sequencing
Focus now on ‘moderate risk’ genes and genetic modifiers
Name the stages of a taking a family history
Include maternal and paternal sides
Consanguinity? Diagnoses in apparently unrelated people may be linked
At least 3 generations
Children, siblings, parents, uncles, aunts, nephews, nieces, grandparents, cousins
Types of cancer, age of diagnosis
Confirm if possible – medical records, cancer registries, death certificate
Do sporadic cancer mutations commonly have one primary cancer or many?
One
Do familial cancer mutations commonly have one primary cancer or many?
Many
What gene is retinoblastoma associated with?
Rbl
What are the purposes of genetic assessment?
Diagnosis/explanation of family history
Counselling of advantages and disadvantages of testing
Risk of further cancers for affected cases
Risk of cancer for unaffected relatives
Screening
Prevention
Treatment
Research
What are the disadvantages of genetic assessment?
‘Can of worms’
Anxiety/unhappiness – self, children, other relatives
Genetic discrimination - ?? Not so much in UK
Results may not lead to any change in management
Financial costs to NHS (though has to be viewed as a whole)
When is diagnostic testing used?
Initial diagnostic testing (mutational analysis) usually performed on DNA from a relative affected with cancer to try to identify the familial mutation
When is predictive testing used?
If a mutation is identified in the family, predictive testing for the specific mutation may then be offered to other relatives to determine whether or not they are at risk
What causes bilateral retinoblastoma?
germline mutations
How many children are diagnosed with retinoblastoma a year in the UK?
30-50
What is familial adenomatous polyposis?
the presence of hundreds of bowel polyps that appear from the teens onwards, giving a very high risk of bowel cancer
Describe the presentation of retinoblastoma
Childhood ocular cancer
Very rare: 1 in 15,000-30000 live births
~30-50 children/year in UK
Classic example following Knudson 2-hit hypothesis
Retinoblastoma (Rb1) gene
What 3 other cancers is famliial adenomatous polyposis associated with?
1) CHRPE (retinal disease)
2) desmoid tumour
3) osteomas
What gene is familial adenomatous polyposis associated with?
APC (tumour suppressor gene)
Describe the features of FAP
Hundreds of bowel polyps (adenomas) from teens onwards
Accounts for ~1% of bowel cancers
High risk (up to 100%) of bowel cancer if untreated (note attenuated form)
Other features – CHRPE, desmoid tumours, osteomas
APC tumour suppressor gene
Autosomal dominant inheritance
Colonoscopies, total colectomy late teens/early 20s
What is Lynch syndrome?
Hereditary non-polyposis colorectal cancer
What 5 mismatch repair genes is Lynch syndrome associated with?
1) MLH1
2) MSH2
3) MSH6
4) PMS2
5) EPCAM
What other 4 cancers is Lynch syndrome associated with?
1) endometrial
2) ovarian
3) stomach
4) urinary tract
What criteria is often used to diagnose familial Lynch syndrome in the family?
Modified Amsterdam Criteria
How is Lynch sydnrome managed? (3)
1) colonoscopy every 2 months
2) removal of any polyps
3) aspirin
What cancers are BRCA 1 and 2 mutations associated with? (5)
1) breast
2) ovarian
3) male breast cancer
4) pancreas
5) prostate
What is the name of the surgery used to remove both ovaries and fallopian tubes?
bilateral salpingo-oopherectomy
What gene mutation causes Li Fraumeni syndrome?
P53
What is Li-Fraumeni syndrome?
Germline mutation of one copy of p53 causing a 100% lifetime risk of cancer
What cancers is Li-Fraumeni syndrome associated with? (4)
1) breast
2) sarcomas
3) brain
4) leukaemia
What is CHEK2 syndrome?
a mutation of the CHEK2 syndrome, giving a 22% lifetime risk of breast cancer
How often should patients with Lynch syndrome have a colonoscopy?
every 24 months from age ~25 or 35 (gene dependent
(Removal of polyps/early detection of cancer improves survival
Role of aspirin in preventing polyps)
How often should women get a breast screening?
annual MRI 30-50, annual mammography from 40 onwards (some eligible for screening from 25)
What is the benefit of breast screenings?
Risk-reducing mastectomies +/- reconstruction
Risk-reducing BSO (ovarian screening probably no use)
Lifestyle changes
Pharmacological prevention BRCA2 (limited evidence)
What are your risk of cancers with BRCA1 and BRCA 2 genes?
Risk of breast cancer 70%; ovarian BRCA1 – 44%; BRCA2 – 10-20%
Some increased risk of other cancers – e.g. prostate, male breast cancer, pancreas
What are the function of BRCA1 and BRCA2 genes?
BRCA1&2 are involved in DNA repair
