Genetic lectures 1-3 Flashcards
% of breast and ovarian cancer which is sporadic, hereditary and breast cancer family clusters
Breast - 15/20% clusters and 5-10% hereditary
ovarian is 5-10% hereditary
colorectal cancer % of each cause
65-85% sporadic
10-30% familial
5% HNPCC, FAP
oncogenes problem
problem leads to uncontrolled cell growth
where do oncogenes, DNA repair genes and tumour suppressor genes work in the cell cycle?
oncogenes between G1 and G0
TSG - between GO and S
DNA - between S and G2
Germline mutations
mutation in sperm or egg which are heritable
cancer family syndromes
all cells affected in offspring
somatic mutations
occur in non germline tissues and are nonheritable
eg breast
oncogene mutations
1st mutation leads to accelerated cell division and 1 mutation is sufficient for role in cancer development
Example of diseases with oncogene mutations
leukaemia oncogene ABL - BCR ABL fusion protein
retinoblastoma
tumour suppressor genes mutation
susceptible carrier and 2nd mutation or loss of normal genes leads to cancer
HNPCC - what is the mutation?
mismatch repair genes
HNPCC
excess of CRC, endometrial, ovarian, gastric and urinary tract cancers
adenoma carcinoma sequence
Tumours in HNPCC
proximal colon
BRCA 1 and 2 and lifetime risk of breast and ovarian ca
breast: 60-80%
secondary primary breast: 40-60%
ovarian: 20-50%
Males and BRCA2
prostate and breast cancer
when to suspect hereditary cancer syndrome?
autosomal dominant early age at diagnosis more than 2 close relatives multiple and rare cancers - bilateral characteristic pattern eg breast or ovarian
Cancer genetics process
obtain detailed accurate FH confirm diagnoses of cancer risk estimation counselling interventions eg signs/lifestyle/prophylaxis genetic testing
Breast cancer surveillance options
breast awareness
early clinical surveillance 5yrs less than 1st age of cancer in the family
- annual breast exams
- mammography 2yrs 35-40, 1yr 40-50
high risk mammography 18monthly from 50-64
MRI at highest risk
prophylactic mastectomy
removes most but not all breast tissue
decreases breast cancer risks
total removes more than subcutaneous
prophylactic oophorectomy
eliminates risk of primary ovarian cancer
peritoneal carcinomatosis may occur
laparascopic, HRT until 50
benefits of genetic testing
identifies highest risk
identify non-carriers
early detection and prevention
may relieve anxiety
Risks and limitations of genetic testing
does not detect all mutations
sporadic cancer
efficacy for interventions
psychosocial/economic
li-fraumenti syndrome
TP53 mutations
soft tissue sarcoma, leukaemia, brain tumour
whole body MRI, breast screening
modes of inheritance for multisystem disorders
new mutations or inherited
chromosomal
single gene disorders
multifactorial
numerical and structural chromosomal mutations
numerical eg trisomy 21
structural eg translocation
single gene disorders
AD
AR
x-linked
multifactorial genetic conditions
polygenic
environmental
Common problems of multisystem disorders
variable expression
large variety of specialities
FH easily missed
NF1, TS and mytonic dystrophy inheritance
Autosomal dominant
criteria for NF1 diagnosis and how many are needed?
café au lait spots - 6 or more neurofibromas axillary freckling lisch nodules, optic gliomas thinning long bone cortex FH
Further features of NF1
macrocephaly, learning difficulties, epilepsy
short stature, noonan look
high bp - renal artery stenosis, phaechromocytoma
CNS and endocrine neoplasia
pseudoarthritis of tibia
diagnosis of NF1
clinical
managing NF1
annual review - bp, spine, eyes, tibia
Genetics of NF1
variable expression - 17q (tumour suppressor genes)
50% due to new mutation
NF1 and NF2
NF2 has acoustic neuroma, CNS and spinal tumours
chromosome 22
classic triad of TS
epilepsy
learning disability
skin lesions
genes in TS
1 in 700 - AD
variable expression
TSC1 and TSC2
almost full penetrance - on scans
Clinical features of TS
multisystem
variable expression - asymptomatic
40% learning difficulty
seizures - infantile spasms, myoclonic
Other features of TS
skin lesions eg depigmented macules, angiofibromas, shagreen patches, fibrous plaques forehead, subungual fibroma
kidney - cysts and angiomyolipomata
phakomas in eye - benign unless on macula
rhabdomyomas in heart
Screening at risk of TS relatives
skin, woods lamp, nails, cranial MRI, echo, Renal USS
myotonic dystrophy genetics
AD, CTG repeat on chromosome 19, anticipation
myotonic dystrophy signs
bilateral late onset cataracts
muscle weak, stiff, myotonia
decreased motivation, IBS, DM
heart block
Why are adults referred to genetics?
diagnosis predictive testing carrier test cascade screening FH fetal loss or recurrent miscarriage
what prediction testing can and must not be used for
usable to prevent or treat disease
3rd parties no access
children only tested if it benefits them
counselling
SOD enzyme
catalyses intracellular superoxide radicals conversion which damage nerve cells
motor neurons express this enzyme highly
Where are SO1-3 found and what metals?
1= cytoplasm and 3 = extracellular --> Cu, Zn 2 = mitochondria --> manganese
Huntingtons genetics
CAG expansion
advantages of predictive testing
uncertainty removed
if -ve = concerns reduced
if +ve = plan, surveillance, inform children
disadvantages of predictive testing
if +ve = remove hope, when?, risk to offspring
if -ve = survivor guilt
