Genetic Predisposition to Cancer Flashcards
what actually is cancer
a genetic disease of somatic cells - happens by chance or due to environmental factors
what are a small proportion of cancers due to
an increased inherited predisposition to cancer
somatic mutations
(as opposed to germline mutations)
- occur in nongermline tissues
- are nonheritable
- cell not in germline develops some genetic alteration
germline mutations
(as opposed to somatic mutations)
- Present in egg or sperm
- Are heritable
- Causes cancer family syndromes
- in all cells of the body
what type of mutations are heritable
germline mutation
what are 3 genetic processes associated with cancer
- oncogenes
- tumour suppressor genes
- DNA damage-response genes
proto-oncogene
normal gene that codes for proteins to regulate cell growth and differentiation
what can mutations do to a proto-oncogene
change it into an oncogene
what can oncogenes do
accelerate cell division —> cancer
cancer arises when stuck in “on” mode
Tumour suppressor genes
function/role etc…
- Cell’s brake for cell growth
- genes inhibit cell cycle or promote apoptosis or both
- cancer arises when both brakes fail - Two-hit hypothesis
two-hit hypothesis
in order for a particular cell to become cancerous, both of the cell’s tumor suppressor genes must be mutated
if the two-hit hypothesis is true, what does that make tumour suppressor genes
recessive genes in effect
Two-hit hypothesis - explain each mutation
Normal genes (prevent cancer)
1st mutation (susceptible carrier)
2nd mutation or loss (leads to cancer)
what are DNA damage-response genes
the repair mechanics for DNA (DNA repair mechanics)
when does cancer arise in DNA damage-response genes
when both genes fail, speeding the accumulation of mutations in other critical genes
what does mismatch repair failure lead to
microsatellite instability (MSI)
Explain microsatellite instability (MSI)
- MMR (mismatch repair) - corrects erros that spontaneously occur during DNA replication (e.g. single base mismatches or short insertions/deletions)
- cells with anormally functioning MMR tend to accumulte errors
- MSI is the phenotypic evidence that MMR is not functioning normally - genetic hypermutability
benign
lacks ability to metastasize - rarely/never become cancerous
Dysplastic
benign but could procress to malignancy - pre-malignant
malignant
able to metastasize
what are 2 other, less common, causes of cancer
- autosomal recessive syndromes
- multiple modifier genes of lower genetic risk
features of retinoblastoma
- occurs in heritable and nonheritable forms
- Identifying at-risk ingants substantially reduces morbidity and mortality
- most common eye tumour in children
compare nonheritable vs heritable retinoblastoma (germline mutations in RB1 gene) - difference
Nonheritable - unilateral
Heritable - bilateral
Give some risk factors for breast cancer
- ageing
- family history - heritability
- early menarche, late menopause, nulliparity
- Estorgen use
- Diatery factors (e.g. alcohol)
- Lack of exercise
common genes contributing to familial breast cancer
BRCA1 and BRCA2
also contribute to familial ovarian cancer
what else cann contribute to familial ovarian cancer
other than BRCA1 and BRCA2
mis-match repair genes
Risk factors for colorectal cancer (CRC)
- ageing
- personal history of CRC or adenomas
- High-fat, low-fibre diet
- Inflammatory bowel disease
- Family history of CRC
what does HNPCC (CRC) result from
failure of mismatch repair (MMR) genes
what can commonly cause an adenoma to transform to a carcinoma in CRC
p53 mutation
Give 2 hereditary colorectal cancer (CRC) syndromes
- Non-polyposis (few to no adenomas) - HNPCC
- Polyposis (multiple adenomas) - FAP (familial adenomatous polyposis), AFAP (attenuated FAP), MAP (MYH associiated polyposis)
Clinial features of HNPCC
- tumour site throughout colon rater than descending colon
- extracolonic cancers: e.g. ovary, stomach…
clinical features of FAP
- estimated penetrance for adenomas > 90%
- Risk of extracoolonic tumors (e.g. upper GI, thyroid, brain..)
- CHRPE (congenital hypertrophy of the retianl pigment epithelium) may be present
- Untreated polyposis leads to 100% risk of cancer
Attenuated FAP
- few colonic adenomas
- not associated with CHRPE
- upper GI lesions
- associated with mutations at 5’ and 3’ ends of APC (tumour supressor) gene
recessive MYH polyposis
similar clinical features to attenuated FAP
what can explain families with history of cancer but not mutation, and differences in cancer penetrance in families with same mutation
multiple modifier genes of lower genetic risk
wayse to manage cancer risk in adenomatous polyposis syndromes
- surveillance
- preventative surgery
- chemoprevention
what do inherited mutations normally cause
an increased predisposition to cancer
what is now being carried out routinely on certain cancers to identify familail mutations and to target therapies
mutation testing
nature of tumour supressor genes (dominant or recessive)
are recessive and require 2 alleles to have a mutation
