L5- Familial Cancer Flashcards
Caretaker genes do what tasks?
DNA repair
Carcinogen metabolism
improve genomic stability e.g. repair of mutations
Cancer e.g: HNPCC
Gatekeeper genes do what?
Cell cycle control
Programmed cell death
Directly regulate tumour growth: monitor and control cell division and death, preventing accumulation of mutations
cancer e.g: FAP
Macroenvironments involves what?
Chemical
viruses
radiation
physical agents
Microenvironments involves what?
Oxyradicals
Hormones
Growth factors
What is the two hit hypothesis theory
You need changes in both copies of a gene for cancer to develop. If one of the genes is hit in a germ line mutation , a second somatic one is more likely to occur to enable cancer
Recessive at the cellular level (i.e. both copes of the gene inactivated to have effect).
Autosomal dominant pattern of inheritance of the cancer risk
What is cancer
A series of genetic changes occur within cells leading to increasingly abnormal behaviour and histology
What is Penetrance?
Percentage with a gene change who develop the condition
- May be modified by other genetic variations
- May be modified by environmental factors
Landscapers do what?
Control the surrounding stromal environment
Cancer e.g: JPS, UC
What do Tumour Suppressor genes do?
Protects cells from becoming cancerous
- Loss of function increases the risk of cancer
- e.g. APC, BRCA1/2, TP53, Rb
What do Oncogenes do?
Regulate cell growth and differentiation
- Gain of function/activating mutations increase the risk of cancer
- e.g. Growth and signal transduction factors, RET gene
A few cancer syndromes show autosomal recessive inheritance pattern, which ones?
.MYH associated polyposis, Fanconi anaemia, Ataxia telangiectasia
Mutation types
Splice site mutations
Large deletions and duplications
Translocations
How to find familial cancers?
Disease-causing translocations may give locations
Family studies – linkage analysis
Candidate gene analysis
New technologies e.g. whole exome sequencing
What would you include in a family history?
Include maternal and paternal sides
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
Sporadic vs Familial Cancers
Sporadic
- Onset at older age
- One cancer in individual
- Unaffected family members
- Cancers that are rarely genetic e.g. Cervix, lung
Familial
- Onset at younger age
- Multiple primaries in individual
- Other family members affected
- Same type/genetically-related cancers
Purpose 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
Diagnostic versus predictive genetic testing
Initial diagnostic testing (mutational analysis) usually performed on DNA from a relative affected with cancer to try to identify the familial mutation
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
Retinoblastoma
Childhood ocular cancer
Follows the Knudson two hit hypothesis
- Retinoblastoma (Rb1) gene
-Both genes mutated/lost in the tumour
-Genetic cases – one mutation is present in germline
-Inherited cases occur at younger average age
-Bilateral cases almost always germ line
15% of apparently sporadic unilateral cases are germline (high new mutation rate)
Other cancer risks e.g. osteosarcoma
Early screening for children at risk
Familial Adenomatous Disease (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
Other features – CHRPE, desmoid tumours, osteomas
APC tumour suppressor gene
Colonoscopies, total colectomy late teens/early 20s
-Autosomal dominant inheritance
Hereditary Non-Polyposis Colorectal Cancer (NHPCC)
Accounts for ~2-3% of bowel cancers
Polyps are common, but not polyposis
60-80% risk of bowel adenomas or cancer from ~mid 20s onwards
Other cancer risks e.g. endometrial/ovarian/stomach/GU
Mismatch repair genes
MLH1 (50%), MSH2 (40%), MSH6 (10%), PMS1/2 (rare)
-Autosomal dominant inheritance
HNPCC – Amsterdam Criteria
- One member diagnosed with colorectal cancer before age 50 years
- Two affected generations
- Three affected relatives, one of them a first-degree relative of the other two
- FAP should be excluded
- Tumours should be verified by pathologic examination
BRCA1 & BRCA2 genes
- BRCA1&2 are involved in DNA repair
- ~10% of cases of breast cancer under 40 and ~25% of those with strong FH
- Common mutations in Jewish and some other founder populations
- Autosomal dominant inheritance
- Risk of breast cancer 80%; ovarian BRCA1 – 40%; BRCA2 – 10-20%
- Some increased risk of other cancers – e.g. prostate, melanoma, male breast cancer
Options for BRCA1 & BRCA2 gene carriers
Breast screening – annual MRI 30-50, annual + mammography from ~35-40
Risk-reducing mastectomies +/- reconstruction
Risk-reducing BSO (ovarian screening probably no use)
Lifestyle changes
Pharmacological prevention studies
Li Fraumeni Syndrome
-P53 mutations. Rare
-Autosomal dominant
50% risk of cancer by age 40, close to 100% lifetime
Breast, sarcoma, brain, adrenocortical, leukaemia
Avoid radiotherapy – risk of inducing cancers
Limited screening
Poor prognosis
More syndromes at the end of the lecture
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