Genetic Predisposition to Cancer

Question 1

How does disease-associated mutations alter protein function?

Answer 1

Results in non-functional or missing protein
Protein with reduced function

Question 2

How much is breast and ovarian cancer hereditary?

Answer 2

5-10%
In breast cancer 15-20% is family clusters

Question 3

What are the causes of hereditary susceptibility to colorectal cancer?

Answer 3

Sporadic
Familial
Rare CRC syndromes
Lynch syndrome
Familial adenomatous

Question 4

What are germline mutations?

Answer 4

Inherited from single alteration in egg or sperm
Are heritable
Cause cancer family syndromes

Question 5

What are somatic mutations?

Answer 5

Occur in non-germline tissues
Are non-heritable

Question 6

What is involved in the cell cycle?

Answer 6

G0
S -synthesis
G2
M -mitosis
G1 - cell growth
Oncogenes, tumour suppressor genes and DNA repair genes

Question 7

What is an ocogene?

Answer 7

A gene with the potential to cause cancer
1st mutation leads to accelerated cell division

Question 8

How can tumour suppressor genes?

Answer 8

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

Question 9

Describe multi-step carcinogenesis

Answer 9

Normal epithelium - hyper-proliferative epithelium - early adenoma - inter-mediate adenoma - late adenoma - carcinoma - metastasis

Question 10

Describe Lynch syndrome/ HNPCC (hereditary non-polyposis colon cancer)

Answer 10

Mutation in mismatch repair genes
Excess colorectal, endometrial, urinary tract, ovarian and gastric cancers
Adenoma - carcinoma sequence for polyp formation

Question 11

What are the clinical features of HNPCC?

Answer 11

Early but variable age of CRC diagnosis
Tumour site is proximal colon predominates

Question 12

What are the BRCA1 and 2 associated cancers?

Answer 12

Breast cancer
Secondary primary breast cancer
Ovarian cancer
Males - prostate cancer and breast cancer

Question 13

What is mendelian risk?

Answer 13

Dominant
High penetrance syndrome

Question 14

When is hereditary cancer syndrome suspected?

Answer 14

Cancer in 2 or more close relatives, early age at diagnosis, multiple primary tumours, bilateral or rare cancer, characteristic pattern and evidence of autosomal dominant transmission

Question 15

What is the cancer genetic process?

Answer 15

Obtain detailed FH
Confirm diagnosis of cancer
Risk estimation
Counselling

Question 16

What are the breast counselling surveillance options?

Answer 16

Breast awareness
Early clinical surveillance every 5 years
Annual or clinical breast exams
Mammography
MR screening is very high risk

Question 17

Describe prophylactic mastectomy

Answer 17

Removes most but not all breast tissue
Significantly reduced breast cancer risk in women
BRCA1 mutation positive women - breast cancer incidence reduced to 5%

Question 18

Describe prophylactic oophorectomy

Answer 18

Eliminates risk of primary ovarian cancer - peritoneal carcinomatosis may still occur
Induces surgical menopause
Risk of subsequent BRCA halved

Question 19

Describe genetic testing for Lynch syndrome

Answer 19

IHC for mismatch repair gene proteins or microsatellite instability testing
Determine if gene is implicated
Recommended for CRC management

Question 20

What are the benefits of genetic testing?

Answer 20

Identifies highest risk, non-carriers in families, allows early detection and prevention strategies

Question 21

What are the risks and limitations of genetic testing?

Answer 21

Does not detect all mutations, continued risk of sporadic cancer, efficacy of interventions variable and may result in psychosocial or economic harm