Inherited Predisposition to Cancer

Question 1

What are the requirements for cell transformation to a cancer cell?

Answer 1

• proliferative signalling
• avoidance of apoptosis
• bypassing of replication senescence

Question 2

What are the 2 cell cycle genes involved in most cancers?

Answer 2

• TSGs (mutation results in a loss of function)
• DNA repair genes

Question 3

What is the normal function of a TSG?

Answer 3

• some inhibit progression through the cell cycle
• some promote apoptosis
• some act as DNA repair genes

Question 4

What is the role of proto-oncogenes and the result of mutation?

Answer 4

• stimulate the normal cell cycle
• mutation activates the genes into oncogenes with a gain of function leading to overactivity of the protein (mutations are not usually inherited)

Question 5

Contrast sporadic with familial cancer

Answer 5

Sporadic: common, late onset with single primary tumour

Familial: uncommon, early onset with often multiple primary tumours

Question 6

Describe the 2 hit hypothesis

Answer 6

When an individual inherits a mutated gene (1st hit), in order to develop cancer they must also acquire a second mutation (2nd hit)

Question 7

What is the normal function of BRCA1 and BRCA2 genes?

Answer 7

DNA repair by homologous recombination of double strand breaks, cell cycle regulation and the regulation of transcription of other genes

Question 8

What genes are responsible for breast/ovarian cancer?

Answer 8

• BRCA1 (50-80% risk of breast, 20-50% risk of ovarian)
• BRCA2 (50-80% risk of breast, 10-20% risk of ovarian, 5-6% male breast)
• TP53
• PALB2

Question 9

What screening and prevention can be done against breast/ovarian cancer?

Answer 9

• screening: mammography/MRI
• prevention: prophylactic bilateral mastectomy/oophorectomy

Question 10

List the different colorectal cancer predisposition syndromes

Answer 10

• HNPCC (AD)
• FAP (AD)
• MYH-associated polyposis (AR)

Question 11

Which genes are responsible for HNPCC and what are their functions?

Answer 11

• mutation in MMR system genes responsible for accurate DNA replication
• usually MLH1 and MSH2 (mis-match repair genes)

Question 12

Describe the clinical aspects of HNPCC?

Answer 12

• few polyps (stomach, uterus, ovary)
• 80-90% risk in males, 40% in females
• screening can be done from age 25 through colonoscopies every 2 years
• from age 50 through upper GI endoscopies

Question 13

Which gene is responsible for FAP and its function?

Answer 13

Mutation in APC gene resulting in overactivity of WNT pathway

Question 14

Describe the clinical aspects of FAP

Answer 14

• lots of polyps which start as benign but confer risk of becoming malignant
• screening through annual bowel screening

Question 15

Which gene is responsible for MYH- associated polyposis?

Answer 15

base excision repair gene DNA glycosylase

Question 16

Describe the clinical aspects of MYH-associated polyposis

Answer 16

• many polyps (milder form of FAP)
• high risk of carcinoma
• screening done every 2 years by colonoscopy

Question 17

What virus is Kaposi’s sarcoma associated with?

Answer 17

HIV