Genetic Predisposition to Cancer

Question 1

what actually is cancer

Answer 1

a genetic disease of somatic cells - happens by chance or due to environmental factors

Question 2

what are a small proportion of cancers due to

Answer 2

an increased inherited predisposition to cancer

Question 3

somatic mutations

(as opposed to germline mutations)

Answer 3

• occur in nongermline tissues
• are nonheritable
• cell not in germline develops some genetic alteration

Question 4

germline mutations

(as opposed to somatic mutations)

Answer 4

• Present in egg or sperm
• Are heritable
• Causes cancer family syndromes
• in all cells of the body

Question 5

what type of mutations are heritable

Answer 5

germline mutation

Question 6

what are 3 genetic processes associated with cancer

Answer 6

• oncogenes
• tumour suppressor genes
• DNA damage-response genes

Question 7

proto-oncogene

Answer 7

normal gene that codes for proteins to regulate cell growth and differentiation

Question 8

what can mutations do to a proto-oncogene

Answer 8

change it into an oncogene

Question 9

what can oncogenes do

Answer 9

accelerate cell division —> cancer

cancer arises when stuck in “on” mode

Question 10

Tumour suppressor genes

function/role etc…

Answer 10

• Cell’s brake for cell growth
• genes inhibit cell cycle or promote apoptosis or both
• cancer arises when both brakes fail - Two-hit hypothesis

Question 11

two-hit hypothesis

Answer 11

in order for a particular cell to become cancerous, both of the cell’s tumor suppressor genes must be mutated

Question 12

if the two-hit hypothesis is true, what does that make tumour suppressor genes

Answer 12

recessive genes in effect

Question 13

Two-hit hypothesis - explain each mutation

Answer 13

Normal genes (prevent cancer)
1st mutation (susceptible carrier)
2nd mutation or loss (leads to cancer)

Question 14

what are DNA damage-response genes

Answer 14

the repair mechanics for DNA (DNA repair mechanics)

Question 15

when does cancer arise in DNA damage-response genes

Answer 15

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

Question 16

what does mismatch repair failure lead to

Answer 16

microsatellite instability (MSI)

Question 17

Explain microsatellite instability (MSI)

Answer 17

• MMR (mismatch repair) - corrects erros that spontaneously occur during DNA replication (e.g. single base mismatches or short insertions/deletions)
• cells with anormally functioning MMR tend to accumulte errors
• MSI is the phenotypic evidence that MMR is not functioning normally - genetic hypermutability

Question 18

benign

Answer 18

lacks ability to metastasize - rarely/never become cancerous

Question 19

Dysplastic

Answer 19

benign but could procress to malignancy - pre-malignant

Question 20

malignant

Answer 20

able to metastasize

Question 21

what are 2 other, less common, causes of cancer

Answer 21

• autosomal recessive syndromes
• multiple modifier genes of lower genetic risk

Question 22

features of retinoblastoma

Answer 22

• occurs in heritable and nonheritable forms
• Identifying at-risk ingants substantially reduces morbidity and mortality
• most common eye tumour in children

Question 23

compare nonheritable vs heritable retinoblastoma (germline mutations in RB1 gene) - difference

Answer 23

Nonheritable - unilateral
Heritable - bilateral

Question 24

Give some risk factors for breast cancer

Answer 24

• ageing
• family history - heritability
• early menarche, late menopause, nulliparity
• Estorgen use
• Diatery factors (e.g. alcohol)
• Lack of exercise

Question 25

common genes contributing to familial breast cancer

Answer 25

BRCA1 and BRCA2 | also contribute to familial ovarian cancer

Question 26

what else cann contribute to familial ovarian cancer | other than BRCA1 and BRCA2

Answer 26

mis-match repair genes

Question 27

Risk factors for colorectal cancer (CRC)

Answer 27

* ageing * personal history of CRC or adenomas * High-fat, low-fibre diet * Inflammatory bowel disease * Family history of CRC

Question 28

what does HNPCC (CRC) result from

Answer 28

failure of mismatch repair (MMR) genes

Question 29

what can commonly cause an adenoma to transform to a carcinoma in CRC

Answer 29

p53 mutation

Question 30

Give 2 hereditary colorectal cancer (CRC) syndromes

Answer 30

* Non-polyposis (few to no adenomas) - HNPCC * Polyposis (multiple adenomas) - FAP (familial adenomatous polyposis), AFAP (attenuated FAP), MAP (MYH associiated polyposis)

Question 31

Clinial features of HNPCC

Answer 31

* tumour site throughout colon rater than descending colon * extracolonic cancers: e.g. ovary, stomach...

Question 32

clinical features of FAP

Answer 32

* estimated penetrance for adenomas > 90% * Risk of extracoolonic tumors (e.g. upper GI, thyroid, brain..) * CHRPE (congenital hypertrophy of the retianl pigment epithelium) may be present * Untreated polyposis leads to 100% risk of cancer

Question 33

Attenuated FAP

Answer 33

* few colonic adenomas * not associated with CHRPE * upper GI lesions * associated with mutations at 5' and 3' ends of APC (tumour supressor) gene

Question 34

recessive MYH polyposis

Answer 34

similar clinical features to attenuated FAP

Question 35

what can explain families with history of cancer but not mutation, and differences in cancer penetrance in families with same mutation

Answer 35

multiple modifier genes of lower genetic risk

Question 36

wayse to manage cancer risk in adenomatous polyposis syndromes

Answer 36

* surveillance * preventative surgery * chemoprevention

Question 37

what do inherited mutations normally cause

Answer 37

an **increased predisposition** to cancer

Question 38

what is now being carried out routinely on certain cancers to identify familail mutations and to target therapies

Answer 38

mutation testing

Question 39

nature of tumour supressor genes (dominant or recessive)

Answer 39

are recessive and require 2 alleles to have a mutation