genetic predisposition to cancer Flashcards

1
Q

cancer arises from …

A

gene mutations

somatic/germline

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2
Q

somatic mutation

A

occur in non-germline tissues, non inheritable

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3
Q

germline mutations

A

mutation in gametes, all cells affected in offspring, heritable and cause family cancer syndromes

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4
Q

genetic processes associated with cancer

A

oncogenes
tumour suppressor genes
DNA damage response genes
mismatch repair genes

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5
Q

oncogenes

A

proto-oncogenes: normal gene that codes for proteins to regulate cell growth and differentiation
mutations can change a proto-oncogene into an oncogene
oncogenes accelerate cell division
1 mutation is sufficient for role in cancer development

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6
Q

tumour suppressor genes

A

cell’s brakes for cell growth
genes inhibit cell cycle/promote apoptosis or both
cancer arises when both brakes fail (2 hit hypothesis) - 1st mutation: susceptible carrier, 2nd mutation: leads to cancer

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7
Q

DNA damage response genes

A

repair mechanics for DNA

Cancer arises when both genes fail, speeding the accumulation of mutations in other critical genes

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8
Q

mismatch repair genes

A

MMR corrects errors that spontaneously occur during DNA replications
HNPCC results from failure of mismatch repair genes
Mismatch repair failure leads to micro-satellite instability - MSI is the phenotypic evidence that MMR is functioning abnormally, these cells tend to accumulate errors

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9
Q

benign vs malignant

A

benign - lacks ability to metastasise, rarely/never become cancerous, can still cause -ve health effects

dysplastic: benign but could progress to malignancy, cells show abnormalities in appearance and cell maturation - sometimes referred to as premalignant
malignant: not benign, able to metastasise

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10
Q

dominantly inherited cancer syndromes

A

oncogene: MEN2 and familial medullary thyroid cancer; RET gene
tumour suppressor gene: breast/ovarian cancer, FAP, Li-Fraumeni syndrome, retinoblastoma; BRCA1/2, APC, P53, RB
DNA repair: HNPCC/Lynch syndrome; MLH1, MSH2/6, PMS1/2

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11
Q

Other causes of cancer

A

autosomal recessive syndromes

multiple modifier genes of lower genetic risk

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12
Q

de novo mutations

A

new mutation occurs in germ cell of parent
no family history of hereditary cancer syndrome
common in: FAP, multiple endocrine neoplasia, hereditary retinoblastoma 2B

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13
Q

what does FAP stand for

A

familial adenomatous polyposis

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14
Q

most cancer susceptibility genes are …

A

dominant with incomplete penetrance

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15
Q

retinoblastoma

A

1/20 000 children
most common eye tumour in children
occurs in hereditable and non-hereditable forms
identifying at risk infants reduces morbidity and mortality

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16
Q

nonheritable retinoblastoma

A

unilateral tumour
no family history
~2/o at diagnosis
no increased risk of 2nd primaries

17
Q

heritable retinoblastoma

A

usually bilateral tumours
family history in 20% of cases
<1y/o at diagnosis
increased risk of 2nd primaries: osteosarcoma, other sarcomas, melanoma and others

18
Q

risks factors for breast cancer

A
age
family history
dietary factors e.g. alcohol 
lack of exercise
early menarche
late menopause
nulliparity 
estrogen use
19
Q

genetic causes of hereditary susceptibility to breast cancer

A
BRCA1 
BRCA2
TP53
PTEN 
other undiscovered genes
20
Q

BRCA1 functions

A

checkpoint mediator
DNA damage signalling and repair
chromatin remodelling
transcription

21
Q

BRCA2 functions

A

DNA repair by homologous recombination

22
Q

BRCA1 associated cancers: lifetime risks

A

breast cancer: 50-85% (often early age at onset)
2nd 1y breast cancer: 40-60%
ovarian cancer: 15-45%
possible increased risk of other cancers

23
Q

BRCA2 associated cancers: lifetime risk

A

breast cancer: 50-85%
male breast cancer: 6%
ovarian cancer: 10-20%
increased risk of prostate, laryngeal and pancreatic cancers

24
Q

hereditary colorectal cancer syndromes

A
  • Non-polyposis (few to no adenomas): HNPCC (hereditary non-polyposis colon cancer/lynch syndrome), CRC and/or endometrial cancer
  • Polyposis (multiple adenomas): FAP (severe colonic polyposis +/- CRC), AFAP (less severe colonic polyposis +/- CRC), MAP (varying degrees of colonic polyposis +/- CRC)

○ Clinical features of FAP
Estimated penetrance for adenomas >90%
Risk of extracolonic tumours (upper GI, desmoid, osteoma, thyroid, brain, other)
CHRPE (congenital hypertrophy of the retinal pigment epithelium) may be present
Untreated polyposis leads to 100% risk of cancer

25
Q

what does AFAP stand for

A

attenuated FAP

26
Q

what does MAP stand for

A

MYH associated polyposis

27
Q

AFAP characteristics

A
late onset 
few colonic adenomas
not associated with CHRPE
Upper GI lesions
associated with mutations at 5' and 3' ends to APC gene
28
Q

recessive MYH polyposis features

A

similar clinical features to attenuated FAP
common mutations in mut-MYH gene
recessive inheritance

29
Q

multiple modifier genes of lower genetic risk

A

may explain families with history of cancer and no identified mutation
may explain differences in cancer penetrance in families with the same mutation

30
Q

managing cancer risk in adenomatous polyposis syndromes

A

improved outcomes with proven clinical interventions
surveillance
surgery
chemoprevention: NSAID, slows rate of polyp formation
aspiring: HNPCC carriers, reduces rate of polyp formation and transition to cancer

31
Q

predictive gene tests

A

gene testing isnt always possible
mutation segregating with disease - test affected relatives
problems of gene variants of unknown significance
surveillance can be offered without having a gene test
for adult onset cancers, predictive gene test not offered until adulthood

32
Q

polymorphisms, mutations and variations of unknown significance

A
  1. Normal code message, benign
  2. Polymorphism, probably benign
  3. Variant of unknown significance
  4. Probable pathogenic variant
  5. Pathogenic variant
33
Q

breast cancer diagnosis

A
  • Breast cancer: triple -ve (oestrogen, progesterone and HER2 -ve)
  • Sporadic testing under age 50-60y, or any age where there is a family history
  • Identify germline mutations for family
  • For therapy: platinum based meds, PARP2 inhibitors, immunotherapies
34
Q

ovarian cancer diagnosis

A
  • All non-mucinous epithelial cancer
  • Excluding borderline tumours
  • Identify germline mutations for family
  • For therapy: platinum based meds, PARP2 inhibitors, immunotherapies