genetic predisposition to cancer Flashcards
cancer arises from …
gene mutations
somatic/germline
somatic mutation
occur in non-germline tissues, non inheritable
germline mutations
mutation in gametes, all cells affected in offspring, heritable and cause family cancer syndromes
genetic processes associated with cancer
oncogenes
tumour suppressor genes
DNA damage response genes
mismatch repair genes
oncogenes
proto-oncogenes: normal gene that codes for proteins to regulate cell growth and differentiation
mutations can change a proto-oncogene into an oncogene
oncogenes accelerate cell division
1 mutation is sufficient for role in cancer development
tumour suppressor genes
cell’s brakes for cell growth
genes inhibit cell cycle/promote apoptosis or both
cancer arises when both brakes fail (2 hit hypothesis) - 1st mutation: susceptible carrier, 2nd mutation: leads to cancer
DNA damage response genes
repair mechanics for DNA
Cancer arises when both genes fail, speeding the accumulation of mutations in other critical genes
mismatch repair genes
MMR corrects errors that spontaneously occur during DNA replications
HNPCC results from failure of mismatch repair genes
Mismatch repair failure leads to micro-satellite instability - MSI is the phenotypic evidence that MMR is functioning abnormally, these cells tend to accumulate errors
benign vs malignant
benign - lacks ability to metastasise, rarely/never become cancerous, can still cause -ve health effects
dysplastic: benign but could progress to malignancy, cells show abnormalities in appearance and cell maturation - sometimes referred to as premalignant
malignant: not benign, able to metastasise
dominantly inherited cancer syndromes
oncogene: MEN2 and familial medullary thyroid cancer; RET gene
tumour suppressor gene: breast/ovarian cancer, FAP, Li-Fraumeni syndrome, retinoblastoma; BRCA1/2, APC, P53, RB
DNA repair: HNPCC/Lynch syndrome; MLH1, MSH2/6, PMS1/2
Other causes of cancer
autosomal recessive syndromes
multiple modifier genes of lower genetic risk
de novo mutations
new mutation occurs in germ cell of parent
no family history of hereditary cancer syndrome
common in: FAP, multiple endocrine neoplasia, hereditary retinoblastoma 2B
what does FAP stand for
familial adenomatous polyposis
most cancer susceptibility genes are …
dominant with incomplete penetrance
retinoblastoma
1/20 000 children
most common eye tumour in children
occurs in hereditable and non-hereditable forms
identifying at risk infants reduces morbidity and mortality
nonheritable retinoblastoma
unilateral tumour
no family history
~2/o at diagnosis
no increased risk of 2nd primaries
heritable retinoblastoma
usually bilateral tumours
family history in 20% of cases
<1y/o at diagnosis
increased risk of 2nd primaries: osteosarcoma, other sarcomas, melanoma and others
risks factors for breast cancer
age family history dietary factors e.g. alcohol lack of exercise early menarche late menopause nulliparity estrogen use
genetic causes of hereditary susceptibility to breast cancer
BRCA1 BRCA2 TP53 PTEN other undiscovered genes
BRCA1 functions
checkpoint mediator
DNA damage signalling and repair
chromatin remodelling
transcription
BRCA2 functions
DNA repair by homologous recombination
BRCA1 associated cancers: lifetime risks
breast cancer: 50-85% (often early age at onset)
2nd 1y breast cancer: 40-60%
ovarian cancer: 15-45%
possible increased risk of other cancers
BRCA2 associated cancers: lifetime risk
breast cancer: 50-85%
male breast cancer: 6%
ovarian cancer: 10-20%
increased risk of prostate, laryngeal and pancreatic cancers
hereditary colorectal cancer syndromes
- Non-polyposis (few to no adenomas): HNPCC (hereditary non-polyposis colon cancer/lynch syndrome), CRC and/or endometrial cancer
- Polyposis (multiple adenomas): FAP (severe colonic polyposis +/- CRC), AFAP (less severe colonic polyposis +/- CRC), MAP (varying degrees of colonic polyposis +/- CRC)
○ Clinical features of FAP
Estimated penetrance for adenomas >90%
Risk of extracolonic tumours (upper GI, desmoid, osteoma, thyroid, brain, other)
CHRPE (congenital hypertrophy of the retinal pigment epithelium) may be present
Untreated polyposis leads to 100% risk of cancer
what does AFAP stand for
attenuated FAP
what does MAP stand for
MYH associated polyposis
AFAP characteristics
late onset few colonic adenomas not associated with CHRPE Upper GI lesions associated with mutations at 5' and 3' ends to APC gene
recessive MYH polyposis features
similar clinical features to attenuated FAP
common mutations in mut-MYH gene
recessive inheritance
multiple modifier genes of lower genetic risk
may explain families with history of cancer and no identified mutation
may explain differences in cancer penetrance in families with the same mutation
managing cancer risk in adenomatous polyposis syndromes
improved outcomes with proven clinical interventions
surveillance
surgery
chemoprevention: NSAID, slows rate of polyp formation
aspiring: HNPCC carriers, reduces rate of polyp formation and transition to cancer
predictive gene tests
gene testing isnt always possible
mutation segregating with disease - test affected relatives
problems of gene variants of unknown significance
surveillance can be offered without having a gene test
for adult onset cancers, predictive gene test not offered until adulthood
polymorphisms, mutations and variations of unknown significance
- Normal code message, benign
- Polymorphism, probably benign
- Variant of unknown significance
- Probable pathogenic variant
- Pathogenic variant
breast cancer diagnosis
- Breast cancer: triple -ve (oestrogen, progesterone and HER2 -ve)
- Sporadic testing under age 50-60y, or any age where there is a family history
- Identify germline mutations for family
- For therapy: platinum based meds, PARP2 inhibitors, immunotherapies
ovarian cancer diagnosis
- All non-mucinous epithelial cancer
- Excluding borderline tumours
- Identify germline mutations for family
- For therapy: platinum based meds, PARP2 inhibitors, immunotherapies
