genetic predisposition to cancer

Question 1

cancer arises from …

Answer 1

gene mutations

somatic/germline

Question 2

somatic mutation

Answer 2

occur in non-germline tissues, non inheritable

Question 3

germline mutations

Answer 3

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

Question 4

genetic processes associated with cancer

Answer 4

oncogenes
tumour suppressor genes
DNA damage response genes
mismatch repair genes

Question 5

oncogenes

Answer 5

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

Question 6

tumour suppressor genes

Answer 6

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

Question 7

DNA damage response genes

Answer 7

repair mechanics for DNA

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

Question 8

mismatch repair genes

Answer 8

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

Question 9

benign vs malignant

Answer 9

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

Question 10

dominantly inherited cancer syndromes

Answer 10

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

Question 11

Other causes of cancer

Answer 11

autosomal recessive syndromes

multiple modifier genes of lower genetic risk

Question 12

de novo mutations

Answer 12

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

Question 13

what does FAP stand for

Answer 13

familial adenomatous polyposis

Question 14

most cancer susceptibility genes are …

Answer 14

dominant with incomplete penetrance

Question 15

retinoblastoma

Answer 15

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

Question 16

nonheritable retinoblastoma

Answer 16

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

Question 17

heritable retinoblastoma

Answer 17

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

Question 18

risks factors for breast cancer

Answer 18

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

Question 19

genetic causes of hereditary susceptibility to breast cancer

Answer 19

BRCA1 
BRCA2
TP53
PTEN 
other undiscovered genes

Question 20

BRCA1 functions

Answer 20

checkpoint mediator
DNA damage signalling and repair
chromatin remodelling
transcription

Question 21

BRCA2 functions

Answer 21

DNA repair by homologous recombination

Question 22

BRCA1 associated cancers: lifetime risks

Answer 22

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

Question 23

BRCA2 associated cancers: lifetime risk

Answer 23

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

Question 24

hereditary colorectal cancer syndromes

Answer 24

• 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

Question 25

what does AFAP stand for

Answer 25

attenuated FAP

Question 26

what does MAP stand for

Answer 26

MYH associated polyposis

Question 27

AFAP characteristics

Answer 27

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

Question 28

recessive MYH polyposis features

Answer 28

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

Question 29

multiple modifier genes of lower genetic risk

Answer 29

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

Question 30

managing cancer risk in adenomatous polyposis syndromes

Answer 30

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

Question 31

predictive gene tests

Answer 31

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

Question 32

polymorphisms, mutations and variations of unknown significance

Answer 32

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

Question 33

breast cancer diagnosis

Answer 33

- 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

Question 34

ovarian cancer diagnosis

Answer 34

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