Familiar Cancer

Question 1

What needs to occur for a cell to turn cancerous?

Answer 1

• Proliferation signalling,
• Avoidance of apoptosis,
• Bypassing replicative senescence

Question 2

What is the function of tumour suppressor genes

Answer 2

They can have different functions
- Inhibition of cell through cell cycle,
- Promote apoptosis,
- DNA repair genes

Question 3

What is the function of proto-oncogenes?

Answer 3

Regulate/activate cell growth and differentiation. If mutated, can become oncogenes (cancer causing)

Question 4

What is the common genetic causes of cancer?

Answer 4

Most are autosomal dominant inheritance of an altered tumour suppressor gene

Question 5

Explain the two hit hypothesis?

Answer 5

Both TSGs need to be inactivated to cause a phenotypic. 1 TSG mutation can be inherited, the second is acquired. Person with an inherited mutation is more likely to develop cancer at an earlier age as a second, sporadic mutation will result in no active TSGs left.

Question 6

What should be an alarm for genetic cancer when taking a history?

Answer 6

• More than one person in the same family affected by similar cancers with an early age of onset.
• Multiple primary tumours,
• Early age of onset

Question 7

What are two common mutations tested for with familial breast cancer?

Answer 7

BRCA1 and BRCA2. Less commonly TP53 and PALB2

Question 8

What are the cancers and risks associated with BRCA1 mutations?

Answer 8

• Breast (50-80% risk of cancer by 70)
• Ovarian (20-50%)
  (risks depend on family history and other genes)

Question 9

What are the cancers and risks associated with BRCA2 mutations?

Answer 9

• Breast (50-80%)
• Ovarian (10-20)
• Male breast cancer (5-6%)

Question 10

What is another genetic RF for development of breast cancer?

Answer 10

Many low-penetrance loci which offer an increased susceptibility for breast cancer.
There is about 72 different loci which are quite common but each only causes a small increased risk of BC.

Question 11

What is the normal function of BRCA1 and 2 genes?

Answer 11

They are DNA repair genes which repair double strand breaks via homologous recombination.

Question 12

When is DNA testing offered for identification of BRCA mutations?

Answer 12

If a person possesses at least a 10% risk. It is done via next generation sequencing

Question 13

What are possible preventative measures for breast cancer?

Answer 13

• Examinations and screenings via mammography or MRIs.
• If person has BRCA mutation then they are offered prophylactic bilateral mastectomies and prophylactic oophorectomies

Question 14

What are some additional genes which when mutated, can cause and increased risk of ovarian cancer

Answer 14

HNPCC genes (MLH1 or MLH2).

Question 15

Name a new possible treatment for ovarian cancer

Answer 15

Olaparib

Question 16

What is the most common cause of familial colon cancer?

Answer 16

Hereditary non-polyposis colon cancer. (most colon cancers are AD)

Question 17

Describe features of hereditary non-polyposis colon cancer (Lynch syndrome)

Answer 17

Occurs due to AD mutation in the DNA mismatch repair genes (important for accurate DNA replication)
- Usually only a few polyps (less than 10), which may or may not also be present on uterus, stomach and ovaries.

Question 18

What are the risks if a person has a MMR gene mutation?

Answer 18

Males - 80-90% lifetime risk of colon cancer.
Females - 40% of cc, 50% risk of endometrial cancer and 4% risk of ovarian

Question 19

What screening is offered for those with MMR gene mutations and are therefore at risk of HNPCC?

Answer 19

Colonoscopies.
- 2 yearly colonoscopies from age 25.
- 2 yearly endoscopies from age 50.
(NB: Aspirin mat reduce risk of colorectal cancer)

Question 20

What are the common mutations which cause HNPCC?

Answer 20

They are different DNA mismatch repair (MMR) genes
-MLH1 (50%)
- MLH2 (40%)
- MSH6 (7-10%)

Question 21

What is another autosomal dominant cause of genetic colon cancer and its features?

Answer 21

Familial Adenomatous Polyposis. It is caused by a mutation in the APC gene.
- 80% have congenital hypertrophy of the retinal pigment epithelium.
- Offered annual bowel screening from age 11

Question 22

What is an autosomal recessive cause of colon cancer

Answer 22

• MUTYH polyposis, an autosomal recessive (remember this!) disease which can result in the development of 15-200 polyps. (Mild FAP)
• High risk of carcinomas so offered 2 yearly colonoscopy