Inherited and familial cancer Flashcards
What is the difference between inherited and familial cancers?
Inherited cancers are genetically inherited in a Mendelian fashion and contribute to 5-10% of all cancers
While familial cancers are cancers which are clustered in familys, which include inherited cancers but also those cancers which are likely due to common environmental exposure these account for 10-30% of all cancer
What is the difference in phenotype of genetic and sporadic tumours?
Genetic tumours often result in multiple tumours which are present bilaterally and have an early onset
Sporadic tumours however often result in single tumours which are unilateral and have a later onset
What is the cause of most hereditary cancer syndromes?
The inheritance of a mutant copy of a tumour suppressor gene
What are the features of an inherited cancer syndrome?
Several close family members with a common cancer
Several close relatives with related cancers
Two family members with the same rare cancer
Early age at diagnosis
Bilateral tumours in paired organs
Synchronous or successive tumours
Tumours in two different organ systems in one individual
Presentation of cancer in the less usually affected sex
How is ovarian cancer a good example of an inherited cancer?
Inherited cancers account for 5-10% of ovarian cancer and the degree of risk is related to both the strength of the family history and the number of affected first degree relatives
What inherited syndromes are related to ovarian cancer?
Hereditary site specific ovarian syndrome (BRCA1, BRCA2)
Hereditary breast ovarian syndrome (BRCA1, BRCA2)
Hereditary non-polyposis colorectal cancer syndrome (Lynch II) due to the HNPCC genes which includes a predisposition to non-polyposis colorectal cancer as well as ovarian, endometrial, stomach and pancreatic cancers
How is breast cancer an inherited cancer?
Inherited cancers make up 55 of breast cancer and 25% of all early onset breast cancers
Bilateral involvement is common with a 40% chance of developing contralateral breast cancer within 10 years
What genes are associated with inherited breast cancer?
Hereditary breast ovarian syndrome (BRCA1, BRCA2)
Li-Fraumeni Syndrome (p53)
Ataxia telangiectasis gene (ATM)
CHK2 gene
What factors must be considered before determining if a family is likely to have an inherited cancer syndrome?
Age of onset, this could simply be happening due to the person becoming old or could early onset could be due to increased vigilance
What is unusual about Li-Fraumeni Syndrome?
Several kinds of cancer are involved
Cancer often occurs at a young age and cancer often occurs several times throughout the life of an affected person
What is the significance of the BRCA 1 and BRCA2 genes?
These are responsible for most cases of early onset of breast and ovarian cancer
They are tumour suppressor gene inherited as an autosomal dominant trait, but in somatic cells it behaves like a recessive gene
What are the functions of BRCA1 and BRCA 2?
Murine BRCA 1 is expressed widely during development and expression in human breast cancer cells is regulated by sex steroids
Knockouts of BRCA1 and 2 both show embryonic lethality
They function in DNA repair as a protein scaffold which interact with RAD 51 a recombination and DNA repair protein of double stranded breaks
BRCA1 transactivates p21 expression which is a cyclin dependent kinase inhibitor
They also have functions in protein ubiquitination and chromatin remodelling
How can a mutated copy of BRCA1 or BRCA 2 lead to cancer?
This is a caretaker tumour suppressor gene which maintain genomic integrity while not a traditional gate keeper gene, loss of this caretaker gene probably permits the accumulation of other mutations which are directly responsible for cancer
What are the types of mutations that are seen in the BRCA1/2 genes?
80% of mutations are truncations caused by frame shift, nonsense or splice mutations
Missense mutations make up the remain 20% and present clinical problems as we are unable to distinguish polymorphic mutants with disease associated mutations
BRCA2 has an ovarian cancer cluster region where mutations lead to a highly elevated risk of ovarian cancer
What treatments are available for gene carriers of the BRCA1/2 mutations?
Primary prevention such as a changes in lifestyle, chemoprevention with things such as PARP inhibitors, tamoxifen which has been shown to reduce the risk of breast cancer in high-risk women or the oral contraceptive which has been shown to greatly reduce the risk of ovarian cancer
and prophylactic surgery such as a prophylactic mastectomy which greatly reduces the risk of breast cancer or prophylactic oophorectomy which not only reduces the risk of ovarian cancer but also breast cancer
Increased screening
