Genetic Predisposition to Cancer

Question 1

how much breast and ovarian cancer is hereditary?

Answer 1

breast cancer: 5-10% hereditary with 15-20% family clusters
ovarian cancer: 5-10% hereditary

Question 2

what are the causes of hereditary susceptibility to colorectal cancer?

Answer 2

familial: 10-30% of colorectal cancers
- Lynch syndrome aka. hereditary nonpolyposis colorectal cancer (HNPCC) (5%)
- familial adenomatous polyposis (FAP) (1%)
- rare CRC syndromes (<0.1%)

Question 3

what type of mutations are inheritable?

Answer 3

Germline mutations:
- inherited from single alteration in egg or sperm
- cause cancer family syndromes

Question 4

what is an oncogene?

Answer 4

An oncogene is a mutated gene that has the potential to cause cancer by causing cells to grow and divide uncontrollably.
- 1 mutation is sufficient for role in cancer development.

mutated version of a gene that regulates cell growth (proto-oncogene)

Question 5

what is a tumour suppressor gene?

Answer 5

A tumor suppressor gene is a normal gene that controls cell growth and division, and prevents cells from growing out of control (causing cancer).
- 1st mutation in a tumour suppressor gene makes a person a susceptible carrier.
- 2nd mutation or loss of tumour suppressor gene leads to cancer.

Question 6

what is the main mechanism for familial cancer?

Answer 6

faulty DNA mismatch repair

Question 7

What causes Lynch syndrome/HNPCC? and what does this result in?

Answer 7

• mutation in mismatch repair genes.
• excess of colorectal, endometrial, urinary tract, ovarian and gastric cancers.
• adenoma to carcinoma sequence for polyp formation.
• early but variable age at CRC diagnosis (45 years).

Question 8

what tumour site is most common in HNPCC?

Answer 8

proximal (ascending) colon

Question 9

BRCA1 and BRCA2 associated cancers and their lifetime risk

Answer 9

• breast cancer 60-80% (often early age at onset)
• second primary breast cancer 40-60%
• ovarian cancer 20-50% (1 > 2)
• males: increased risk of prostate and breast cancer esp. BRCA2

Question 10

characteristics of autosomal dominant inheritance

Answer 10

• each child has 50% chance of inheriting the mutation
• no ‘skipped generations’
• equally transmitted by men and women

Question 11

When should you suspect hereditary cancer syndromes?

Answer 11

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

Question 12

do prophylactic mastectomies work?

Answer 12

• removes most but not all breast tissue.
• significantly reduces breast cancer risk in women with a family history.
• BRCA1 mutation-positive women breast cancer incidence reduced to 5%.

Question 13

do prophylactic oophorectomies work?

Answer 13

• eliminates risk of primary ovarian cancer; however, peritoneal carcinomatosis may still occur.
• induces surgical menopause but HRT till 50 does not change BRCA risk.
• risk of subsequent breast cancer halved in mutation-positive women.

Question 14

what surveillance is offered to those with risk of developing familial CRC?

Answer 14

Colonoscopy:
- gene carrier: 2 yearly from 25 years old
- moderate risk: one at 55 or every 5 years from 50 years old
- prophylactic aspirin for gene carriers

Question 15

what interventions are available for those at increased risk of developing endometrial cancer?

Answer 15

• symptom awareness
• surgery: TAH & BSO

Question 16

what genetic testing is available for Lynch Syndrome/HNPCC?

Answer 16

• immunohistochemistry (IHC) for mismatch repair gene proteins or microsatellite instability testing (MSI) are inexpensive ways of determining if a tumour is Lynch syndrome associated.
• if IHC/MSI high, genetic screen to determine if a gene is implicated (two somatic hits can mislead otherwise)
• IHC/MSI recommended CRC management useful for treatment too

Question 17

Describe the founder effect

Answer 17