Familial Cancer Flashcards
Define Gain of Function mutation.
Mutation of a gene that enhances the activity of the product of the mutant gene.
Define Loss of Function mutation.
Mutation of a gene that diminishes the activity of the product of the mutant gene or reduce the amount of transcription of the mutant gene.
What is a proto-oncogene?
Proto-oncogene is a gene that has the potential to become an active oncogene.
It normally controls the cell cycle.
What is an Oncogene?
A gene that is involved in cancer directly or indirectly by altering the cell cycle. A gain of function mutation - one copy of the gene is sufficient enough to over ride the function of the normal copy. Thus, increasing the risk of Cancer.
What is a Tumour Suppressor Gene?
A gene that directs the production of a protein that is involved in regulating cell division, for example by promoting apoptosis of defective cells : Tp53, BAX gene
- A loss of function mutation: cell division becomes disorganised
- Both copies of Tumour Suppressor Genes must be loss for a neoplasia to form
- TS gene functions as stability gene
Examples of Tumour Suppressor Gene?
Tp53, Rb gene, BAX gene, NF1, MEN1
What is a stability gene?
A gene that maintains the structure and integrity of DNA & repair DNA through its product
- a type of TS gene
- if inactivated, TS gene and proto oncogenes are prone to mutation
- account for hereditary cancer predisposition syndromes
What is the Knudson’s Two-Hit Hypothesis?
2 events of mutation is required to increase the chance of developing cancer in 2 normal wild type alleles. If there is a predisposed mutation inherited, only 1 event of mutation is sufficient to trigger cancer.
Comparison between sporadic & familial cancers.
Sporadic :
- Common (90-95%)
- later onset
- single primary tumour with metastases
Familial
- Uncommon (5-10%)
- Early onset
- Multiple primary tumour
What are the essential information that aid a diagnosis of familial cancer?
- Family history : More than 1 members in the family are affected by a similar cancer
- Age of patient
- Multiple foci of primary tumours
What are the common genetic causes of Familial Breast Cancers?
BRCA-1 (more common - suspect if relatives have ovarian cancer) , BRCA-2, Tp53, PTEN, RAD51
Male Breast Cancer is associated with the mutation of what gene?
BRCA-2
What are BRCA-1 and BRCA-2?
BRCA-1 and BRCA-2 are DNA repair genes using homologous recombination.
What are the associated features of Familial Breast Cancers?
Ovarian cancer, Peritonial cancer
What is the interaction between BRCA-1 and BRCA-2?
DNA damage – phosphorylation of small BRCA-1 gene product – binds to the large BRCA-2 gene product – this complex binds to RAD51 – repair DNA breaks through homologous recombination
What is the factor that is associated with ovarian cancer in BRCA-2 breast cancer?
Mutation of Ovarian Cancer Cluster Region in exon 11
Where are BRCA-1 and BRCA-2 found?
BRCA-1 : chromosome 17
BRCA-2 : chromosome 13 ( also ATP7B in Wilson’s disease)
How are BRCA-1 and BRCA-2 tested?
Testing the blood for the relevant exons.
- WAVE machine for screening each section for mutation
- Sanger sequencing
What is the scoring system used to identify BRCA-1 and BRCA-2 mutation?
Manchester Scoring system
Preventive measures for BRCA-1 and BRCA-2 mutation carriers?
- Prophylactic bilateral mastectomies
- Prophylactic oophorectomy + fallopian tube resection
Management of breast cancer?
- Masectomy + sampling of regional lymph nodes for prognostic information
- radiotherapy if lymph nodes are involved and multiple foci of tumours are found
- If tumour is Oestrogen and Progesterone receptors sensitive : 1. Anti-oestrogen therapy : Tamoxifen 2. Aromatase-inhibitor : Anastrozole
- Her2/neu +ve (more rapid growth) : trastuzumab
What are the genes implicated in Familial Colon Cancer Syndromes?
MLH1, MSH2, MSH6, APC, MYH
What are the different familial colorectal cancer syndromes?
- Hereditary Non-Polyposis colon cancer
- Familial Adenomatous Polyposis
- MYH-associated polyposis
Genetic mutation implicated in Hereditary Non-polyposis Colon Cancer
MLH1, MSH2. MSH6
