Lecture 5 GiM Flashcards
What are the factors that lead to cancer?
Various gene and environment factors.
What is two-hit hypothesis?
Knudson suggested that multiple “hits” to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the first insult was inherited in the DNA, and any second insult would rapidly lead to cancer. In non-inherited retinoblastoma, two “hits” had to take place before a tumor could develop, explaining the age difference.
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
What is the function of gatekeepers gene?
monitor and control cell division and death, preventing accumulation of mutations
directly regulate tumour growth
What is the function of caretakers gene?
Improve genomic stability eg repair of mutations
What is the function of landscapers gene?
Control the surrounding stromal environment
What is the function of tumour suppressor genes?
- Protect cells from becoming cancerous
- Loss of function increase the risk of cancer
What is the function of oncogenes?
-Regulate cell growth and differentiation
What is oncogenes?
A gene that has potential to cause cancer
What is the function of oncogenes?
Regulate cell growth and differentiation
What are the examples of tumour suppressor genes?
APC, BRCA1/2, TP53, Rb
What are the examples of oncogenes?
Growth and signal transduction factors, RET gene
What is the type of inheritance for the most of cancer syndromes?
Autosomal dominant
What are the examples of cancer syndromes with autosomal recessive disorder?
MYH associated polyposis, Fanconi anaemia, Ataxia telangiectasia
What are the characteristics of cancer syndromes with autosomal recessive disorder?
Each parent is a carrier of one faulty copy, usually without the disease
¼ of children inherit both mutated copies and the cancer risk
Appears to skip generations and may account for some sporadic cases
What are the ways to find familial cancer genes?
- Disease-causing translocations may give locations of the gene
- Family studies (linkage analysis)
- Candidate gene analysis
- New technologies e.g. whole exome sequencing
What are the differences between Sporadic vs Familial cancer?
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
Why diagnostic testing are performed?
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 a family, what is the next step that should be taken?
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 are the characteristics of Retinoblastoma condition?
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 are the general information of Retinoblastoma genetically?
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 germline
15% of apparently sporadic unilateral cases are germline (high new mutation rate)
Other cancer risks e.g. osteosarcoma
Early screening for children at risk
What are the characteristics of Familial Adenomatous Polyposis(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
Autosomal dominant inheritance
Colonoscopies, total colectomy late teens/early 20s
What are the characteristics of Hereditary Non-Polyposis Colorectal Cancer?
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
What is the Amsterdam Criteria?
The Amsterdam criteria are a set of diagnostic criteria used by doctors to help identify families which are likely to have Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC)
What are the benefits of colonoscopic screening in HNPCC?
Patients with HNPCC should have colonoscopy ~every 18-24 months from age ~25
Removal of polyps/early detection of cancer improves survival
?Role of aspirin in preventing polyps
What is the percentage of people with breast cancer has mutation of BRCA1/2 genes?
~10% of cases of breast cancer under 40 and ~25% of those with strong FH
What are the characteristics of BRCA1/2 genes mutation?
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
What are the options for BRCA1/2 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
What are the characteristics of 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 - ?MRI for breast
Poor prognosis
Value of genetic testing less clear
