Genetic Predisposition to Cancer

Question 1

How much of breast cancer is hereditary?

Answer 1

Sporadic (majority) 70-80%
Family clusters = 15-20%
Hereditary 5-10%

Question 2

How much of ovarian cancer is hereditary?

Answer 2

Hereditary 5-10%

Sporadic 90-95%

Question 3

How much of colorectal cancer is due to hereditary susceptibility?

Answer 3

Sporadic 65-85%
Rare CRC syndromes < 0.1%
Familial 10-30%
Familial adenomatous polyposis (FAP) = 1%
Hereditary nonpolyposis colorectal cancer (HNPCC) 5%

Question 4

The cell cycle involves…

Answer 4

Oncogenes 
GO - resting 
Tumour suppressor genes 
DNA repair genes 
S (synthesis)
G2 
M - mitosis 
G1 - cell growth

Question 5

What are tumours?

Answer 5

Clonal expansions

Question 6

What does cancer arise from?

Answer 6

Gene mutations

Question 7

What kind of gene mutations can cancer arise from?

Answer 7

Germline mutations

Somatic mutations

Question 8

Features of germline mutations

Answer 8

mutation in egg or sperm of the parent which affects all cells in the offspring
are heritable
cause cancer family syndromes

Question 9

Features of somatic mutations

Answer 9

e.g. in breast
occur in non germline tissues
are non heritable

Question 10

Normal gene oncogenes do what?

Answer 10

Regulate cell growth

Question 11

What does a 1st mutation in an oncogene do?

Answer 11

Leads to accelerated cell division

1 mutation sufficient for role in cancer development

Question 12

Tumour suppressor genes

Answer 12

Normal genes - prevent cancer
1st mutation - susceptible to cancer
2nd mutation or loss - leads to cancer

Question 13

DNA base pair mismatch can lead to either…

Answer 13

Normal DNA repair OR

Mutation induced by unrepaired DNA

Question 14

Pathology of HNPCC / lynch syndrome

Answer 14

Mutation in mismatch repair genes

excess of colorectal, endometrial, urinary tract, ovarian and gastric cancers

Question 15

What sequence for polyp formation is in HNPCC / lynch syndrome?

Answer 15

Adeno-carcinoma

Question 16

Clinical features of HNPCC / lymph syndrome

Answer 16

early but variable age at CRC diagnosis (approx. 45 years)

Tumour site in proximal colon predominates

Question 17

Lifetime associated risks of the BRCA1 and 2 genes

Answer 17

Breast cancer 60-80% (often early age at onset)
Secondary breast cancer 40-60%
Ovarian cancer = 20-50% (1>2)
males ; increased risk of prostate cancer and breast cancer especially in BRCA2

Question 18

In autosomal dominant inheritance, what chance does the child have of inheriting the mutation?

Answer 18

50%

Question 19

Features of autosomal dominant inheritance

Answer 19

child has 50% chance of inheriting the mutation
no “skipped” generations
equally transmitted by men and women

Question 20

Features of Mendelian risk

Answer 20

Dominant, high penetrance syndrome

can have a 25-50% chance of carrying the mutation

Question 21

When to suspect a hereditary cancer syndrome

Answer 21

cancer in 2 or more close relatives or same side of family
early age at diagnosis
multiple primary tumours
bilateral or multiple rare cancers
characteristic pattern of tumours (breast and ovary)
Evidence of autosomal dominant transmission

Question 22

Breast cancer surveillance options

Answer 22

breast awareness
early clinical surveillance 5yr < age 1st Ca in family 
- annual clinical breast exams 
- mammography 
- MR screening those at highest risk

Question 23

How often is a mammogram done depending on your risk of breast cancer?

Answer 23

Moderate / high 
- 2 yearly from 35-40, 
- yearly from 40-50 
High 
- 18 monthly from 50-64

Question 24

Effects of a mastectomy on chances of breast cancer

Answer 24

Significantly reduces breast cancer risk in women with FH

BRCA1 mutation positive women breast cancer incidence reduced to 5%

Question 25

Effects of a prophylactic oophorectomy on chances of ovarian cancer

Answer 25

Eliminates risk of primary ovarian cancer
- however peritoneal carcinomatosis may still occur
Induces surgical menopause but HRT until 50 does not change until BRCA risk
Risk of subsequent BRCA halved in mutation positive women

Question 26

Surveillance for colorectal cancer

Answer 26

Colonoscopy
High risk 
- 2 yearly from 25
Moderate risk 
- 35 - 55

Question 27

Effects of colorectal screening

Answer 27

Reduces risk of colorectal cancer in HNPCC families

Question 28

Screening for Endometrial cancer

Answer 28

Look for

• PMB
• transvaginal USS
• surgery

Question 29

Benefits of genetic testing

Answer 29

Identifies highest risk
Identifies non carriers in families with a known mutation
Allows early detection and prevention strategies
may relieve anxiety

Question 30

Risks and limitations of genetic testing

Answer 30

does not detect all mutations
continued risk of sporadic cancer
efficacy of interventions variable
may result in psychological or economic harm

Question 31

Examples of a 1st degree relative

Answer 31

Sister
Child
Parent

Question 32

Examples of a 2nd degree relative

Answer 32

Aunt / uncle (on either side)

Grandparent (on either side)

Question 33

Examples of a 3rd degree relative

Answer 33

First cousin