genetics: predisposition to cancer

Question 1

what do disease associated mutations do to DNA?

Answer 1

alter protein function:

• functional
• non-functional or missing
• reduced function

Question 2

how much breast cancer is hereditary

Answer 2

5-10%

Question 3

how much ovarian cancer is hereditary?

Answer 3

5-10%

Question 4

causes of hereditary susceptibility to colorectal cancer

Answer 4

familial

HNPCC (hereditary nonpolyposis colorectal cancer)

familial adenomatous polyposis (FAP)

rare CRC syndromes

Question 5

what is hereditary nonpolyposis colorectal cancer also known as

Answer 5

lynch syndrome

Question 6

stages in the cell cycle

Answer 6

M (mitosis)

G1 (cell growth)

G0 (resting)

S (synthesis)

G2

Question 7

where do oncogenes act in the cell cycle

Answer 7

1st part of cell cycle
G1-G0
(cell growth)

Question 8

where do tumour suppressor genes act in the cell cycle?

Answer 8

2nd part of cell cycle
G0-S
(synthesis)

Question 9

where do DNA repair genes act in the cell cycle?

Answer 9

second part of cell cycle
S-G2
(synthesis)

Question 10

what are tumours?

Answer 10

clonal expansions

Question 11

what do cancers arise from?

Answer 11

gene mutations

Question 12

features of germline mutations?

Answer 12

• mutation in egg or sperm
• heritable
• cause cancer family syndromes

Question 13

features of somatic mutations

Answer 13

• nongermline tissues eg breast

- nonheritable

Question 14

roles of oncogene in cancer development

Answer 14

normal genes regulate cell growth

a single mutation in an oncogene leads to an accelerated cell division

Question 15

what oncogene is implicated in leukaemia?

Answer 15

oncogene ABL

coding for BCR-ABL fusion protein

Question 16

role of tumour suppressor genes in cancer development

Answer 16

normal genes prevent cancer

first mutation makes you a susceptible carrier

second mutation leads to cancer

Question 17

using colon cancer, give an example of multi-step carcinogenesis.

Answer 17

normal epithelium proliferates to become an adenoma

adenoma becomes more dysplastic with the accumulation of genetic events

develops into a carcinoma which can then metastasize

Question 18

DNA mismatch repair

Answer 18

main mechanism for familial cancer

accumulation of unprepared DNA can be a trigger for cancer

Question 19

hereditary non-polyposis colon cancer (Lynch Syndrome)

Answer 19

mutation in mismatch repair genes leads to adenoma-carcinoma sequence for polyp formation

early but variable age at CRC diagnosis (~45 years)

tumour site in proximal colon predominates

Question 20

what cancers are BRCA1 and BRCA2 associated with?

Answer 20

breast cancer (60-80%)

ovarian cancer (20-25%)

males: prostate, breast (BRCA2)

Question 21

autosomal dominant inheritance

Answer 21

each child has 50% chance of inheriting the mutation

no “skipped generations”

equally transmitted by men and women

Question 22

when to suspect a hereditary cancer syndrome?

Answer 22

family: cancer in >2 close relatives, autosomal dominant transmission evidence
tumours: multiple, characteristic pattern
diagnosis: early age, bilateral or multiple rare cancers

Question 23

breast cancer surveillance options

Answer 23

early clinical surveillance 5 years before the age of the 1st cancer in family

• annual or clinical breast exams
• mammography
• MR screening those at highest risk

Question 24

features of prophylactic mastectomy

Answer 24

removes most but not all breast tissue

reduces breast cancer risk in women with a family history

Question 25

features of prophylactic oophorectomy

Answer 25

eliminates risk of primary ovarian cancer

induces surgical menopause

Question 26

surveillance for CRC?

Answer 26

colonoscopy

• high risk 2 yearly from 25 years old
• moderate risk: 55 years old

Question 27

surveillance for endometrial cancer?

Answer 27

symptom awareness: PMB

surgery

Question 28

benefits of genetic testing?

Answer 28

identifies

• highest risk
• non-carriers in families with a known mutation
• early detection and prevention strategies

relieves anxiety

Question 29

risks and limitations of genetic testing

Answer 29

• does not detect all mutations
• continued risk of sporadic cancer
• efficacy of interventions variable

Question 30

what is the future of genetic testing

Answer 30

polygenic risk scores: decide screening in families without a highly penetrant mutation

increasing role of germline and tumour genetic profile in determining treatment of cancer