Cancer genetics + Metabolic disease

Question 1

how do most cancers occur

Answer 1

sporadic - not due to hereditable gene mutation
combination of genetic, environment, hormones

Question 2

what are 2 types of DNA repair paths

Answer 2

homologous recombination repair
mismatch repair

Question 3

what is penetrance

Answer 3

penetrance = likelihood that specific gene mutation will cause disease in an individual

Question 4

what is penetrance for breast cancer

Answer 4

although AD inheritance, incomplete penetrance

BRCA1 inheritance = 75% lifetime risk of breast Ca in women
men = 15% lifetime risk of prostate Ca

Question 5

what are high + low risk susceptibility genes

Answer 5

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

Question 6

what are cancer red-flags in terms of
age
ethnicity
inheritance pattern
tumour type

Answer 6

age = premenopausal
ethnicity = jewish, east europe
inheritance = AD
tumour type = triple -ve cancer, high grade serous cancer, MMR deficient tumours

Question 7

what are the cancer risk assessment tools

Answer 7

Manchester scoring system - finds probability of BRCA1/2 mutation
BODICEA/CanRisk

Question 8

what are 4 criteria for MODY

Answer 8

young onset 6month-25yr
non-insulin dependent
beta cell dysfunction
autosomal dominant inheritance - single gene defect

Question 9

what are 3 main types of MODY and how do they differ

Answer 9

GCK - lifelong mild, stable fasting hyperglycaemia, no treatment necessary
HNF1A - treat with SU
HNF4A - treat with SU, presents with macrosomia + hypoglycaemia at birth

Question 10

what is GCK function and how does it differ to other hexokinases

Answer 10

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

Question 11

how common are micro/macro-vascular complications in GCK

Answer 11

minimal

Question 12

what MODY are babies born macrosomia

Answer 12

HNF4A only

Question 13

when is GCK treated

Answer 13

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

Question 14

why is HNF1A/HNFA4A sensitive to SU

Answer 14

low renal threshold for glucose

Question 15

how is HNF1A/HNF4A treated

Answer 15

initially diet, then SU
after eating high carb food, post prandial hyperglycaemia seen

Question 16

what is the pathophysiology of IEM (internal errors of metabolism)

Answer 16

lack of feedback
causes high levels of precursor
as enzyme deficient, product not made - so alternate pathway used instead, creating toxic products

Question 17

how are IEM inherited

Answer 17

IEM = autosomal recessive
MODY = autosomal dominant

Question 18

what IEM diseases are screened for

Answer 18

congenital hypothyroidism. sickle cell disease, cystic fibrosis

Question 19

what exacerbates IEM

Answer 19

diet, intercurrent illness

Question 20

what are neo/pre-natal screening tests

Answer 20

neo = blood prick test
pre = maternal fetal blood DNA analysis, CVS

CVS (tests for genetic abnormalities and common mutations)

Question 21

which IEM is treated by inserting genetic material

Answer 21

mitochondrial

Question 22

when do different carb IEM disorders present

Answer 22

glucose = from birth, fasting hypoglycaemia from birth
lactose (glu + gala) = during breast feeding
sucrose (flu + fru) = when weaning to solid food

Question 23

what is the most common glycogen storage disease

Answer 23

G6PD deficiency = glycogen storage disease 1

deficient of G6P enzyme, so less gluconeogenesis
causes hypoglycaemia

present: hypoglycaemia, hepatomegaly, lactic acidosis, hyper urea+TG

Question 24

what is McArdle disease

Answer 24

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

Question 25

how do galactokinase + gala-1PO4UT deficiencies differ

Answer 25

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

Question 26

when do IEM develop

Answer 26

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

Question 27

when do IEM develop

Answer 27

within 24-48hr to 1st week of life

present with:

Question 28

why are IEM babies born full-term with NO physical abnormalities

Answer 28

they are protected during the pregnancy

Question 29

what are lab findings of IEM

Answer 29

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

Question 30

how do galactokinase + gala-1PO4UT deficiencies differ

Answer 30

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