genetic predisposition to cancer Flashcards
alteration in single/several base(s)
non-functional protein
reduced function
shorten protein due to premature stop codon
causes disease
hereditary
strong genetic predisposition
familial clusters
polygenic inheritance or genetic susceptibility factors accumulating within family
tumours are clonal expansion
tumours are caused by clonal expansion of cell with mutations in its DNA
mutations accumulate
high rate of growth with metastatic potential
germline mutations
inherited from single alteration in ova/sperm
present in all cells in offspring
heritable
causes familial cancer syndromes
somatic mutations
occur in non-germline tissues
non-heritable
vast majority cancers
what part of cell cycle to oncogenes control
first part
what part of cell cycle due tumour suppresor genes and DNA repair genes work
second part where we have DNA synthesis
oncogenes normally
regulate cell growth
oncogene 1st mutation
leads to accelerated cell division
1 mutation sufficient for role in cancer development
tumour suppressor genes normally
prevent cancer
tumour suppressor genes 1st mut and 2nd mut/loss
1st: susceptible to cancer
2nd/loss: leads to cancer
multistep carcinogenesis e.g. colon cancer
normal epithelium which proliferates
adenoma
molecular events accumulate and more dysplasia
carcinoma which can metastasis
faulty DNA mismatch repair
main mechanism for familial cancers
mean DNA with mistake is not repair, mistake can persist and trigger multistep process
HNPCC/Lynch Syndrome
mutation in mismatch repair genes: germline predisposition to mismatch repair
excess colorectal, endometrial, urinary tract and gastric cancers
clinical features HNPCC
early but variable age at CRC diagnosis
tumour site in proximal colon predominates
BRCA 1 + 2 assoc cancer risks
breast: 60-80%
2nd 1ry breast: 40-60%
ovarian: 20-50%
BRCA2 in men
inc risk prostate and breast cancer
autosomal dominant inheritance
each child has 50% chance inheriting mutation
no skipped generations
equally transmitted by men and women
when to suspect hereditary cancer syndrome
cancer 2+ close relatives, same side F early age diagnosis multiple 1ry tumours bilateral/multiple rare Ca characteristic pattern of tumours e.g. breast and ovary evidence autosomal dominant transmission
cancer genetic interventions
- inc awareness symptoms/signs
- lifestyle: smoking, diet, exercise
- prevention: oestrogen, aspirin use
- screening
- prophylactic surgery
breast cancer surveillance options
breast awareness early clinical surveillance 5yrs < age 1st FH Ca -annual breast exams -mammography -MRI highest risk
when to do genetic testing for breast and ovarian cancer
all non-mucinous ovarian cancer
triple negative breast cancer under 60 with FH
BCRA under 40
genetic tests breast cancer
BCRA 1 and 2 PALB2 PTEN P53 CHEK2
genetic testing ovarian cancer
BRCA 1 and 2
Lynch genes
RAD51C
RAD51D
surveillance for CRC
colonoscopy
- 2yrly from 25 if gene carrier
- high-mod riks 5yrly from 50
- low-mod once 50
also prophylactic aspirin
screening for lynch syndrome
IHC for mismatch repair gene proteins
microsattelite instability testing
benefits of genetic testing
id highest risk
id non-carriers in families w known mutation
allows early detection and prevention strategies
may relieve anxiety
risks/limitations of genetic testing
doesn’t detect all mutations
continued risk sporadic cancer
efficacy of interventions variable
may result in psychosocial/economic harm
