Genetics Flashcards
(35 cards)
1
Q
what are the 2 main types of mutation (heritable and not heritable), which of these is the main one and what are some of the differences between them?
A
- somatic mutation (MAIN): mutation arising in a single cell in the body, not heritable
- germline mutation: mutation in the gamete –> all the cells in the child affected, multisystemic, and heritable
2
Q
what is the autosomal dominant pattern of inheritance and why does cancer presentation not always follow this?
A
- no carrier, if you have the gene then you will have the disease
- no skipped generations
- 50% chance of inheriting it from one parent
cancer presents differently because some are more common in females (like breast), and not everyone with the gene will actually have the disease
3
Q
3-step prevention of mutation in cells. What kinds of cancer (sporadic or familial) occurs with each mutation?
which is the main type of mutation in familial cancer?
A
- oncogene: single gene controlling cell growth whose mutation is sufficient to drive accelerated cell division and cancer development
- tumor suppressor gene (TP53, 18q, Kras): germline base mutation where 1 mutation is already inherited and an additional mutation or deletion of the remaining copy will result in cancer.
- DNA repair genes: MAIN mutation in familial cancers - there is a mismatch during DNA repair
- mutation in only the oncogene: sporadic cancer
- mutation in all three or the remaining 2: familial cancer
4
Q
what are some of the cancers belonging to either oncogene, tumor suppressor, or DNA mismatch repair mutations?
A
- oncogene:
- leukemia: BCR-ABL fusion during crossing over
- retinoblastoma: (can also be familial)
- breast: BRCA 1/2 (can also be familial) - tumor suppressor gene:
- CRC
- retinoblastoma - DNA mismatch repair gene:
- Lynch syndrome (hereditary nonpolyposis colon cancer - HNPCC): MLH1/MSH2, MSH6, PMS2
- BRCA 1/2 syndromes:- familial breast cancer: 60-80% chance of breast cancer + 40-60% chance of developing new primary
- familial ovarian cancer: 20-50% chance of ovarian cancer (BRCA 1>2)
- breast + prostate cancer in men: (BRCA 2>1)
5
Q
describe Lynch syndrome/HNPCC
A
- autosomal dominant mismatch repair (MLH1/MSH2)
- <= 45 yrs (early diagnosis, 80% by 30 yrs)
- adenoma-carcinoma polyp formation (starts with adenoma before becoming cancer)
- develop other cancers (78% colon, 60% ovarian, stomach, biliary tract, ovarian, urinary tract, sebaceous gland, CNS)
6
Q
when to suspect hereditary cancer syndromes (5)
A
- autosomal dominant pattern of inheritance
- > = 2 close relatives with the condition
- multiple primaries
- bilateral, or multiple rare cancers
- recognizable cancer syndromes (Lynch, BRCA 1/2)
7
Q
surveillance program for breast cancer - normal, moderate-high risk, high risk
at what age does all breast screening stop?
A
ALL BREAST SCREENING STOPS AT 71 YRS
- normal:
- mammo 3 yrly from 50-70 yrs - moderate-high risk:
- annual breast exam by experts
- mammo 2 yrly from 35-40 –> 1 yrly from 40-50 –> return to normal 3 yrly routine from 50-70 yrs - high risk: start surveillance 5 yrs before the earliest diagnostic age of affected family members
- annual review by experts
- mammo doesn’t return to normal routine, and continue at 18 monthly from 50-70 yrs
- MRI screening (stop at 50 yrs since mammo better with old breasts)
8
Q
what are the chances of finding the mutation when doing genetic testing?
A
10%
9
Q
when is genetic testing offered in breast cancer?
A
- all non-mucus ova
- triple negative breast cancer < 60 yrs + FH
- BRCA 1/2 cancer < 40 yrs
10
Q
benefits of genetic testing (4)
A
- identify those with high risk (counseling, interventions)
- identify those with low risk (reassurance)
- relieves anxiety
- offer early help, family planning, and prophylactic treatment
11
Q
limitations of genetic testing (4)
A
- not all mutations are detected, though improving
- sporadic mutations can still happen regardless
- prophylactic treatment not 100% effective
- socioeconomic impact (insurance, mortgages, etc.)
12
Q
prophylactic interventions for BRCA 1/2 cancer (3) - which of these is GOLD standard?
A
- prophylactic mastectomy (GOLD standard): reduces risk to 5%
- HRT until 50 before oophorectomy: avoid surgical menopause
- laparoscopic oophorectomy after HRT: reduces chance of primary ovarian ca + reduce breast ca chance by 50%
13
Q
surveillance program for CRC and Lynch syndrome for normal gene carrier, low moderate, and high moderate risk
A
- normal:
- 2 yrly colonoscopy from 25 yrs - low moderate: no obvious mutation, 1 relative with cancer at < 50 yrs
- 1 colonoscopy at 55 yrs - high moderate: >= 2 relatives with cancer at < 55yrs or 3 relatives with later diagnosis
- 5 yrly colonoscopy from 50-70 yrs
14
Q
prophylactic treatment for Lynch syndrome (2)
A
- prophylactic oophorectomy (for endometrial ca)
2. prophylactic aspirin (colon + endometrial ca) - use omeprazole concurrently if experienced gastric ulcers
15
Q
what are the 2 methods used in genetic testing for CRC - and what is the purpose of genetic testing here?
A
- IHC for MLH1/MSH2, MHS6, PMS2 (Lynch genes)
2. microsatellite instability (MSI) detects footprints in mismatch repair genes
16
Q
modes of inheritance (types of mutation) in multisystem disorder (4), their subtypes, and some example diseases for each - chromosomal (2), single gene (3), multifactorial (2), mitochondrial (1)
A
- chromosomal:
- numerical: trisomy, duplications
- structural: translocation, deletions, microdeletions - single gene
- autosomal dominant: neurofibromatosis 1 (NF1), tuberous sclerosis, myotonic dystrophy
- autosomal recessive: CF
- X-linked: duchenne muscular dystrophy - multifactorial
- polygenic
- environmental: DM (multiple genes + environment), haemochromatosis (single gene + environment) - mitochondrial: mutation in the mitochondria of every cell, gets progressively worse as mutation accumulates with cell division
17
Q
differences between genetic and environmental cause of disease.
A
- genetic: less common, simple, unifactorial, high recurrence, penetrance easy to predict.
- environmental: more common, complex, multifactorial, low recurrence, penetrance variable
18
Q
diagnostic criteria for neurofirbomatosis 1 (NF1) - (7)
A
> =2 of the following:
- > = 6 cafe au late (CAL) spots, each >= 2 cm
- axillary/groin spotting
- > = 2 neurofibromas
- Lish spots (benign specks in the iris)
- optic glioma
- bone cortex thinning –> pseudoarthrosis (false joint)
- FH
19
Q
other presentations of NF1 (8)
A
- macrocephaly/encephaly (enlarged head)
- short stature
- Noonan’s facial dysmorphia (prominent and hooded eyes, wide-based nose + upturned bulbous tip, cupid bow lips)
- minor learning difficulties (10% need special schooling, 3% have moderate mental health disorder)
- scoliosis (common)
- epilepsy (uncommon, due to lesion in the brain)
- HTN (watch out for 1. renal aa stenosis, 2. phaechromocytoma)
- neuroplasty (optic glioma, endocrine, neural sheath tumors)
20
Q
what mode of inheritance is NF1, which gene is the mutation in, penetrance?
A
- autosomal dominant
- variable expression (intra/interfamilial)
- 17 q tumor suppressor gene (50% new paternal germline mutation)
- genetic testing is expensive but useful in children whose parents are affected to rule out NF1
21
Q
management of NF1 (7)
A
constant monitoring until diagnosis can be confirmed with genetic testing
- scoliosis monitoring
- checks for bp
- education monitoring
- check for angulation of the tibia
- visual changes
- ask parents to report unusual symptoms, since a rapidly growing tumor can occur anywhere in the body
- new MEK inhibitor selumetinib for malignant lesions
22
Q
what are some of the differences between NF1 and NF2? (5)
A
mainly more CNS affected then peripheral
- chromosome 22
- acoustic neuromas (CN VIII) which needs early intervention since it might affect CN VII
- cataracts
- CAL spots
- CNS + spinal cord tumors + meningioma
23
Q
classic triad of tuberous sclerosis
A
- epilepsy, starts in childhood and hard to treat (some have seizures - either 1. infantile spasms, 2. myoclonic seizure)
- learning difficulty (40%), autistic feature common
- benign skin lesions
24
Q
what are some of the benign skin lesions for TS (5)
A
- angiofibromas - across the nose and maxilla, mistaken for acne
- depigmented macules (ash leaf spots) - best seen under woodlamp
- fibrous plaque on forehead
- uncal fibromas of the nails
- shagreen patches - little raised patches of skin
25
what are some of the other presentations of TS? (5) - are these benign or malignant? what are some of the modes of investigation for these?
- hamartomas (tumors that are made with the same tissue that they grow from)
- angiofobrolipoma (potentially malignant tumor of the kidneys) - renal USS
- phakoma (benign tumor of the retina, unless on the macula), mistaken for retinonblastoma
- rhamdomyoma (benign tumor of the heart) - echo
- tumors of the brain (cortical tumors, sub-epndymal tumors, astrocytoma) - cranial MRI
26
what mode of inheritance is TS, which gene is the mutation in, penetrance?
- autosomal dominant
- 2 genes on different chromosomes for the same phenotype (TSC1/2) + 60% due to new sporadic mutation
- almost complete penetrance, but presentation variable
- genetic counseling and surveillance offered to the rest of the family
27
presentation of myotonic dystrophy (7)
- severe muscle dystrophy, death, severe learning disability at birth
- weak peripheral muscles + diaphragm (anesthesia risk)
- myotonic facial features (ptosis, saggy mouth, weak facial muscles)
- bilateral late onset cataracts
- heart block --> early death
- stiffness, myotonia
- low motivation, DM, bowel issues
28
what mode of inheritance is myotonic dystrophy, what is the type of the mutation?
- autosomal dominant
- CGT base repeats --> increasing with every passing generation
- testing for parents and termination of pregnancy offered in severe cases
29
predictive testing vs susceptibility testing. Who should not be offered predictive testing for late onset disease (yet) and why?
predictive testing: genetic testing of asymptomatic person to find out future risk of the disease
susceptibility testing: inherited increased risk of developing the disease
- children and adolescents should not be offered predictive testing unless there is a real benefit for the early knowledge of their potential condition
30
presentation of amyotrophic lateral sclerosis (6)
- around 55 yrs, younger in familial disease
- upper + lower neuron signs (progression weakness, muscle wasting, hyperreflexia)
- pure motor signs (fasciculations)
- cognition spared
- death from respiratory failure
- no cure
31
what mode of inheritance is amyotrophic lateral sclerosis, what is the type of the mutation?
- autosomal dominant (MAIN) or recessive
- Cu/Zn superoxide dismutase (SOD) gene mutation - 20% of familial disease and 2% of all cases
- penetrance incomplete, hard to predict even with mutation testing
32
what is the function of SOD gene, the 3 different SOD genes and which of these is the main one
SOD normally catalyzes the superoxide produced as part of normal metabolism - mutation of this gene results in accumulation of radical damage to the cell + loss of protection from DNA damage + cell degradation
- SOD 1: (MAIN) found in the cytoplasm, contains Cu/Zn, chromosome 21
- SOD2: found in mitochondria, contains Mg, chromosome 6
- SOD3: found in ECF, contains Cu/Zn, chromosome 4
33
what is the mode of transmission of Beck's muscular dystrophy?
- X-linked recessive (only in males)
| - gets progressively worse with each generation (presents earlier)
34
What is the mode of transmission of Huntington's disease, the mutation, and penetrance?
- autosomal dominant
- CAG base repeats in the exon 1 of HTT gene
- full penetrance, no cure
35
presentation of Huntington's (5)
- onset 30-40 yrs and presents for 15-20 yrs before death (now increasingly later onset)
- movement disorder like chorea-athetosis but gentler (type of movement depends on the balance of chemicals in the basal ganglia)
- cognitive changes (poor planning and memory) - subcortical dementia
- personality changes like apathy, irritability, self-centered, disinhibition (may be aware of the changes)
- psychiatric disease like aggression, depression, paranoia, psychosis
