Inherited Cancer Risk and Familial Cancer

Question 1

Which genetic defect is associated with myeloid leukaemia?

Answer 1

Translocation of chromosome 9 and 22

AKA Philadelphia chromosome

Question 2

Describe familial cancer?

Answer 2

Mutations in normal genes associated with cell growth, cell differentiation and cell death. Mutations:

1. Gain of function (oncogenes)
2. Loss of function (tumour suppressor genes)

Question 3

Describe oncogenes?

Answer 3

Promotes cellular proliferation - they are switched ON in embryonic life and during times of tissue repair
They are switched OFF in adult life = proto-oncogenes
Activating mutations switch them back ON
Behave in a DOMINANT manner

Question 4

Name the oncogene associated with the movement of neural crest cells in embryonic life and state the effects on this via activating mutations and inactivating mutations?

Answer 4

RET

1. Inactivating mutation = Hirschprung’s (deficient migration of NCC into the gut and therefore - sluggish part of the bowels w/o neuronal ganglions
2. Activating mutation (adult life) = MEN.2 syndrome

Question 5

Describe three features found with MEN.2A?

Answer 5

1. Malignant thyroid cancer (medullary)
2. Parathyroid cancer (benign)
3. Phaechromocytoma (benign)

Question 6

Describe four features found with MEN2B?

Answer 6

1. Mucosal neuromas
2. Ganglioneuroma of the gut
3. Tall and slim build
4. Thickened lips

Question 7

Name the tumour suppressor gene associated with retinoblastoma and state the genes three functions?

Answer 7

Mutated RB1 gene

1. Cell division
2. DNA replication
3. Cell death

Question 8

Name the tumour suppressor gene associated with Li Fraumeni syndrome and state the genes three functions?

Answer 8

Mutated TP53 gene (GERMLINE)

1. Cell division
2. DNA repair
3. Cell death

Question 9

Name three cancers associated with Li Fraumeni syndrome?

Answer 9

Brain tumours
Sarcomas
Leukaemias

Question 10

Name the tumour suppressor gene associated with familial adenomatous polyposis and state the genes five functions?

Answer 10

Mutated APC gene

1. Cell division
2. Damage
3. Migration
4. Adhesion
5. Death

Question 11

Name the tumour suppressor gene associated with Lynch syndrome and state the genes two functions?

Answer 11

Mutated MLH.1 and MSH.2

1. DNA MISMATCH REPAIR
2. Cell cycle regulation

Question 12

Name the tumour suppressor gene associated with breast and ovarian cancer and state the genes three functions?

Answer 12

Mutated BRCA1 and BRCA2

1. Double-stranded DNA repair of breaks
2. Cell division
3. Cell death

Question 13

Describe the ‘mutator pathway’ (mismatch repair pathway) as associated with colorectal cancer?

Answer 13

Mutation in a gene which functions to CORRECTLY COPY DNA - therefore introductions of mutations will be introduced in lots of other genes. This tends to happen at areas of the genome with repeated DNA sequences (microsatelites) and intragenic repeats

Question 14

Describe the ‘suppressor pathway’ as associated with colorectal cancer?

Answer 14

1st mutation - APC gene and once this is hit - other mutations occur in other cell-cycle control genes w/o mutator targets (checking machinery doesn’t work any more)

Question 15

Which cancer syndrome is associated with the mutator pathway?

Answer 15

Lynch syndrome (HNPCC) = accelerated adenoma progression
<100 adenomas
Increased colorectal cancer risk
Increased endometrial cancer risk

Question 16

Which cancer syndrome is associated with the suppressor pathway?

Answer 16

FAP - GERMLINE mutations of APC

Accelerated adenoma initiation

Question 17

Name and describe the two types of FAP?

Answer 17

Classical FAP = 1000s of colonic adenomas with 95% penetrance by 35 and 100% malignancy risk
Attenuated FAP = 10 - 100 adenomas

Question 18

Name the five extra-colonic features associated with FAP?

Answer 18

1. Gastric-fundus polyps
2. Duodenal polyps
3. Congenital hyperplasia of retinal pigmentation
4. Childhool hepatoblastoma
5. Thyroid cancer (papillary)

Question 19

Describe Gardener’s syndrome?

Answer 19

FAP +

1. Osteomas
2. Soft-tissue tumours (subacous cysts/fibromas/desmoid tumours)

Question 20

Describe Turcot’s syndrome FAP?

Answer 20

FAP +

Medulloblastoma

Question 21

Describe Muir-torr syndrome?

Answer 21

Lynch + subacous skin tumours (subacous adenomas/subacous epitheliomas/subacous carcinomas/keratocarcinoma

Question 22

Describe Turcot’s syndrome HNPCC?

Answer 22

Lynch +

Glioblastoma

Question 23

Name an investigative marker for Lynch syndrome and name one for sporadic crc?

Answer 23

Lynch = High MSI

Sporadic crc = BRAF V600E

Question 24

Describe the Amsterdam criteria for identifying is a patient is likely to have Lynch syndrome?

Answer 24

3 colorectal tumours
2 - over two generations
1 diagnosis under 50
- If (+ve) = colorectal tissue biopsy