Genetic predisposition to cancer

Question 1

How Much Breast Cancer Is Hereditary?

Answer 1

Hereditary = 5-10%

Family clusters = 15-20%

Question 2

How Much Ovarian Cancer Is Hereditary?

Answer 2

5-10%

Question 3

Causes of hereditary colorectal cancer?

Answer 3

1) Familial = 10-30%
2) Lynch syndrome (Hereditary nonpolyposis colorectal cancer, HNPCC) = 5%
3) Familial adenomatous polyposis (FAP) = 1%
4) Rare CRC syndormes = 0.1%

Question 4

Which type of mutation is heritable?

Answer 4

Germline mutations

Question 5

Which type of mutation is non-heritable?

Answer 5

Somatic mutations

Question 6

Which type of mutation leads to all cells being affected?

Answer 6

Germline mutation

Question 7

Which type of mutation leads to a particulate site being affected?

Answer 7

Somatic mutation

Question 8

Which type of mutation leads to cancer family syndromes?

Answer 8

Germline mutation

Question 9

Which type of mutation is inherited from single alteration in egg or sperm?

Answer 9

Germline mutation

Question 10

Which part of the cell cycle are oncogenes?

Answer 10

Between G1 (cell growth) and G0 (Resting)

Question 11

Which part of the cell cycle are tumour suppressor genes?

Answer 11

Between G0 (Resting) and S (Synthesis)

Question 12

Which part of the cell cycle are DNA repair genes?

Answer 12

Between S (Synthesis) and G2

Question 13

Which oncogene is linked to Leukaemia?

Answer 13

Oncogene ABL - ACR-ABL Fusion protein

Question 14

What is the oncogene BCR-ABL linked to?

Answer 14

CML and ALL

Question 15

What is the tumour suppressor gene Rb linked to?

Answer 15

Retinoblastoma and osteosarcoma

Question 16

How does an oncogene work?

Answer 16

1) Needs damage to only one allele

2) Leads to a gain of function

Question 17

How does an tumour suppressor gene work?

Answer 17

1) Needs damage to both (two) alleles

2) Leads to loss of function

Question 18

1st mutation/loss versus 2nd mutation/loss in tumour supressor genes?

Answer 18

1st = Susceptible carrier
2nd = Leads to cancer

Question 19

Multi-step carcinogenesis of colon cancer?

Answer 19

1) Loss of APC = Hyper-proliferative epithelium and then Early adenoma
2) Activation of K-ras = Intermediate adenoma
3) Loss of 18q = Late adenoma
4) Loss of TP53 = Carcinoma
5) Other alterations = Metastasis

Question 20

What does mutation/loss of APC tumour suppressor gene lead to ?

Answer 20

Coloractal cancer (Associated with FAP)

Question 21

What does activation of K-Ras oncogene lead to?

Answer 21

> Colorectal cancer
Lung cancer
Pancreatic cancer

Question 22

What does loss/mutation of TP53 tumour suppressor gene lead to?

Answer 22

> Most human cancers

> Li-Fraumeni syndrome

Question 23

What is the main mechanism for familial cancer?

Answer 23

Faulty DNA mismatch repair

Question 24

What is Lynch syndrome (Hereditary non-polyposis colon cancer) caused by?

Answer 24

Mutation in mismatch repair genes

Question 25

Where is the tumour site usually in Lynch syndrome (HNPCC)?

Answer 25

Proximal colon

Question 26

What is the common age of diagnosis in Lynch syndrome/HNPCC related colorectal cancer?

Answer 26

Early but variable (45 years)

Question 27

Which types of cancers caused by Lynch syndrome/HNPCC?

Answer 27

1) Colon (78%) 2) Endometrial (60%) 3) Stomach (19%) 4) Biliary tract (18%) 5) Ovarian (11%) 6) Urinary tract (10%) 7) Sebaceous gland (9%) 8) CNS (4%)

Question 28

Within women what is the lifetime risk of breast cancer in BRCA1 and BRCA2 tumour suppressor genes?

Answer 28

1) Breast cancer (60-80%) - Often early age at onset | 2) Second primary breast cancer (40-60%)

Question 29

Within women what is the lifetime risk of ovarian cancer in BRCA1 and BRCA2 tumour suppressor genes?

Answer 29

20-50% (BRCA1 increased risk versus BRCA2)

Question 30

Within men what cancers in BRCA1 and BRCA2 tumour suppressor genes are they at risk of?

Answer 30

Increased risk of prostate, breast cancer and pancreatic cancer Especially in BRAC2 mutations/loss

Question 31

In autosomal dominant inheritance what is the chance of a child inheriting the mutation?

Answer 31

50% chance in an unaffected individual

Question 32

In autosomal dominant inheritance what is the chance of a skipped generation?

Answer 32

There is no skipped generation

Question 33

If a grandmother had an autosomal dominant condition and the mother of the grandson wasn't affected by the mutation what is the chance of the grandson being a carrier?

Answer 33

25%

Question 34

When should inheritors cancer syndrome be suspected?

Answer 34

> Cancer in 2 or more close relatives (on same side of family) > Early age at diagnosis > Multiple primary tumors > Bilateral or multiple rare cancers > Characteristic pattern of tumours (e.g. breast and ovary) > Evidence of autosomal dominant transmission

Question 35

What is the cancer genetics process?

Answer 35

1) Obtain family history 2) Confirm diagnosis of cancer 3) Risk estimation 4) Counselling

Question 36

Aspects of clinical genetics consultation?

Answer 36

1) Family history 2) Risk estimation 3) Explanation of basis of risk 4) Interventions: - Increased awareness of symptoms/signs - Lifestyle = Diet, smoking, exercise - Prevention = Oestrogen, aspirin use - Screening - Prophylactic surgery 5) Genetic testing

Question 37

Surveillance option is breast cancer?

Answer 37

Early clinical surveillance (Mammography): - Moderate/High = 2 yearly from 35-40yrs and yearly 40-50yrs - High = 18 months

Question 38

What is the option in BRCA1 and BRCA2 carriers?

Answer 38

Prophylactic mastectomy - In BRCA1 mutation positive women incidence is reduced to 5% Prophylactic Oophorectomy

Question 39

What is the advantage of prophylactic oophorectomy in BRCA1/BRCA2 carriers?

Answer 39

1) Eliminates risk of primary ovarian cancer; however; peritoneal carcinomatosis may still occur 2) Risk of subsequent BRCA halved

Question 40

What is the advantage of laparoscopic oophorectomy in BRCA1/BRCA2 carriers?

Answer 40

Laparoscopic approach reduces postsurgical morbidity

Question 41

Which drug may be given prophylactically in high risk individuals for colorectal cancer?

Answer 41

Aspirin

Question 42

When an individual is a gene carrier for colorectal cancer when should screening be carried out?

Answer 42

Colonoscopy should be performed every 2 years from 25 years old

Question 43

When an individual is a moderate risk for colorectal cancer when should screening be carried out?

Answer 43

Colonoscopy should be performed every five years from 50yrs or yearly from 55yrs

Question 44

How can you genetically test for Lynch syndrome?

Answer 44

IHC for mismatch repair gene proteins or micro satellite instability testing (MSI)

Question 45

What are the benefits of genetic testing?

Answer 45

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

Question 46

What are the risks/limitations of genetic testing?

Answer 46

> Does not detect all mutations > Continued risk of sporadic cancer > Efficacy of interventions variable > May result in psychosocial or economic harm

Question 47

In terms of family history who is important to test in hereditary disease?

Answer 47

1st degree relatives = Father, mother, siblings and children 2nd degree relatives = Aunt, uncle, grandparents 3rd degree relatives = First cousin

Question 48

Which mutation is associated with Li-Fraumeni syndrome?

Answer 48

TP53 tumour suppressor gene mutation/loss