Familial Cancer Flashcards
Genetic and environmental contributions to cancer
Progressive model for colon carcinogenesis
What are somatic mutations? Can they be inherited?
Occur in a single body cell and cannot be inherited
What are germline mutations? Can they be inherited?
Occur in gametes and can be passed onto offspring (every cell in the entire organism will be affected)
How can germline mutations affect your predisposition to cancer?
Can be born with inherited mutation that leaves you more susceptible to cancer e.g. mutations in the BRCA1 and BRCA2 genes which predispose to breast and ovarian cancer
What type of cancer does a mutation in MLH1 predispose you to?
hereditary non-polyposis colorectal cancer
What is the ‘two hit hypothesis’?
This hypothesis serves as the basis for the understanding of how mutations in tumor suppressor genes drive cancer.
Most loss-of-function mutations that occur in tumor suppressor genes are recessive in nature. Thus, in order for a particular cell to become cancerous, both of the cell’s tumor suppressor genes must be mutated.
What is a classic example of the ‘two hit hypothesis’?
Retinoblastoma
What is retinoblastoma?
Normally, retinoblasts stop growing and dividing during embryogenesis and differentiate. Typically, these differentiated cells do not divide very often, if ever. In the case of retinoblastoma, however, the retinoblasts fail to differentiate; thus, these cells continue to divide, forming tumors in the retina.
How does retinoblastoma prove the ‘two hit hypothesis’?
- Knudson’s combined data itself showed that retinoblastoma was caused by a germ-line mutation in approx 40% of cases
- BUT some children with an affected parent were disease-free BUT had children with retinoblastoma
- Suggests that an individual could inherit a germ-line mutation but not have the disease
- Both copies of the gene would need to be mutated in order for retinoblastoma to occur
- Individuals who inherited a mutation in one allele of the gene would only need to accumulate a single mutation in the remaining normal allele of any retinoblast in order for cancer to occur (more likely)
- However, without an inherited mutation, the same cell would need to accumulate two mutations—one in each allele of the gene (less likely)
What is penetrance?
Penetrance measures the proportion of individuals in a population who carry a specific gene and express the related trait. E.g. complete penetrance is a mutation that will cause symptoms in 100% of people who carry it
What are gatekeeper genes?
Directly regulate tumour growth: monitor and control cell division and death, preventing accumulation of mutations
What are caretaker genes?
improve genomic stability e.g. repair of mutations
What are landscaper genes?
Control the surrounding stromal enviroment
what is stroma?
the supportive tissue of an epithelial organ, tumour, gonad, etc., consisting of connective tissues and blood vessels.
The likelihood of developing cancer depends on the importance of the gene function. What is the risk of developing colorectal cancer if the mutation occurs; a) sporadically b) in gatekeeper (FAP) c) in caretaker (HNPCC) d) in landscaper (JPS, UC)?
What are tumour suppressor genes (TSG)?
- Protects cells from becoming cancerous
- Loss of function increases the risk of cancer
- e.g. APC, BRCA1/2, TP53, Rb
Autosomal dominant inheritance:
What type of inheritance pattern do most cnacer syndromes show?
A few cancer syndromes show autosomal recessive inheritance pattern. What is the chance of the child being affected?
- Each parent is a carrier of one mutated 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 needs to be included when taking a family history of cancer?
- 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
Difference in typical onset age between sporadic and familial cancer?
Sporadic - onset at older age
Familial - onset at younger age
Sporadic vs familial cancers
Diagnostic vs predictive 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
What are the BRCA1&2 genes involved in?
DNA repair
What is the inheritance pattern of mutations in BRCA1&2?
Autosomal dominant
How do mutations in BRCA1&2 affect the risk of breast and ovarian cancer?
- 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 40 onwards
- Risk-reducing mastectomies +/- reconstruction
- Risk-reducing BSO (ovarian screening probably no use)
- Lifestyle changes
- Pharmacological prevention studies
What is lynch syndrome?
Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC), is the most common cause of hereditary colorectal (colon) cancer.
what mutations are involved in Lynch syndrome?
Alterations in several genes involved in DNA mismatch repair that have been linked to Lynch syndrome. They include the genes of MLH1 (50%), MSH2 (40%), MSH6 (10%), PMS2 (rare), and EPCAM.
Inheritance of Lynch syndrome?
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 (all criteria need to be met):
- 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
With Lynch syndrome, how often should patients have a colonoscopy?
- Patients should have colonoscopy ~every 18-24 months from age ~25
- Removal of polyps/early detection of cancer improves survival
How can taking aspirin affect risk of bowel cancer in lynch syndrome?
Aspirin taken daily for more than two years could reduce the risk of bowel cancer in people with Lynch syndrome
