Cancer genetics + Metabolic disease Flashcards
how do most cancers occur
sporadic - not due to hereditable gene mutation
combination of genetic, environment, hormones
what are 2 types of DNA repair paths
homologous recombination repair
mismatch repair
what is penetrance
penetrance = likelihood that specific gene mutation will cause disease in an individual
what is penetrance for breast cancer
although AD inheritance, incomplete penetrance
BRCA1 inheritance = 75% lifetime risk of breast Ca in women
men = 15% lifetime risk of prostate Ca
what are high + low risk susceptibility genes
high = TP53, BRCA/2, PTEN, CDH1, STR11
(rare gene variants that greatly increase the risk of a small proportion of cancers)
ascertained from FH
low = SNP single nucleotide polymorphisms, ATM, CHEK2
(relatively common gene variants that slightly increase risk of cancer)
multiple low risk variants combine to increase overall risk
ascertained from population studies
what are cancer red-flags in terms of
age
ethnicity
inheritance pattern
tumour type
age = premenopausal
ethnicity = jewish, east europe
inheritance = AD
tumour type = triple -ve cancer, high grade serous cancer, MMR deficient tumours
what are the cancer risk assessment tools
Manchester scoring system - finds probability of BRCA1/2 mutation
BODICEA/CanRisk
what are 4 criteria for MODY
young onset 6month-25yr
non-insulin dependent
beta cell dysfunction
autosomal dominant inheritance - single gene defect
what are 3 main types of MODY and how do they differ
GCK - lifelong mild, stable fasting hyperglycaemia, no treatment necessary
HNF1A - treat with SU
HNF4A - treat with SU, presents with macrosomia + hypoglycaemia at birth
what is GCK function and how does it differ to other hexokinases
GCK - acts as rate limiting step (glucose sensor in pancreatic B cell)
since lower affinity for glucose than other hex-kinases, so lacks feedback inhibition
how common are micro/macro-vascular complications in GCK
minimal
what MODY are babies born macrosomia
HNF4A only
when is GCK treated
only in pregnancy if foetus doesn’t have the AD mutation
test directly with CVS/amniocentesis, or cell free DNA
otherwise don’t treat with insulin as large amount needed to overcome regulatory response
why is HNF1A/HNFA4A sensitive to SU
low renal threshold for glucose
how is HNF1A/HNF4A treated
initially diet, then SU
after eating high carb food, post prandial hyperglycaemia seen
what is the pathophysiology of IEM (internal errors of metabolism)
lack of feedback
causes high levels of precursor
as enzyme deficient, product not made - so alternate pathway used instead, creating toxic products
how are IEM inherited
IEM = autosomal recessive
MODY = autosomal dominant
what IEM diseases are screened for
congenital hypothyroidism. sickle cell disease, cystic fibrosis
what exacerbates IEM
diet, intercurrent illness
what are neo/pre-natal screening tests
neo = blood prick test
pre = maternal fetal blood DNA analysis, CVS
CVS (tests for genetic abnormalities and common mutations)
which IEM is treated by inserting genetic material
mitochondrial
when do different carb IEM disorders present
glucose = from birth, fasting hypoglycaemia from birth
lactose (glu + gala) = during breast feeding
sucrose (flu + fru) = when weaning to solid food
what is the most common glycogen storage disease
G6PD deficiency = glycogen storage disease 1
deficient of G6P enzyme, so less gluconeogenesis
causes hypoglycaemia
present: hypoglycaemia, hepatomegaly, lactic acidosis, hyper urea+TG
what is McArdle disease
glycogen storage disease 5 - lack of glycogen phosphorylase
causes rhabdomyolysis (high CK + myoglobin in urine)
less extreme - muscle cramps, exercise intolerance
muscle wasting contractures
diagnose: genetic test, lactate not made on ischaemic exercise
treat: aerobic exercise
how do galactokinase + gala-1PO4UT deficiencies differ
galactokinase causes cataracts as build-up of galacterol
gala-1PO4UT deficiency (galactosemia = Irish) causes hepatotoxic effects (jaundice, hepatomegaly) as build-up of gal-1-PO4
when do IEM develop
within 24-48hr to 1st week of life
present with:
HYPOglycaemia
cataracts
hepatomegaly (+ spleno), jaundice
metabolic acidosis - lactic acidosis causing raised anion gap
cabbage smell as AA transport disorder causes AA aciduria
when do IEM develop
within 24-48hr to 1st week of life
present with:
why are IEM babies born full-term with NO physical abnormalities
they are protected during the pregnancy
what are lab findings of IEM
hypoglycaemia
hyperammonia
metabolic acidosis
present with:
HYPOglycaemia
cataracts
hepatomegaly (+ spleno), jaundice
metabolic acidosis - lactic acidosis causing raised anion gap
cabbage smell as AA transport disorder causes AA aciduria
how do galactokinase + gala-1PO4UT deficiencies differ
galactokinase causes cataracts as build-up of galacterol
gala-1PO4UT deficiency (galactosemia = Irish) causes hepatotoxic effects (jaundice, hepatomegaly) as build-up of gal-1-PO4
