Inherited cancer syndromes

Question 1

What are the two main classes of familial cancer genes?

Answer 1

Gatekeepers (tumour suppressors) and Caretakers (DNA repair genes)

Question 2

What do Gatekeeper genes control?

Answer 2

Cell proliferation, differentiation, death; respond to oncogenic damage (e.g., APC)

Question 3

What is the role of Caretaker genes?

Answer 3

DNA repair and maintenance; their loss leads to genomic instability (e.g., MLH1, MSH2)

Question 4

Which genes are mutated in Lynch syndrome (HNPCC)?

Answer 4

MLH1, MSH2, MSH6, PMS2

Question 5

What is the molecular hallmark of Lynch syndrome?

Answer 5

Microsatellite instability (MSI)

Question 6

What signalling pathway is affected by MSI in TGFβR2 gene in HNPCC?

Answer 6

TGFβ signalling pathway

Question 7

What genes are involved in Juvenile Polyposis Syndrome?

Answer 7

SMAD4 and BMPR1A

Question 8

What is the role of SMAD4 and BMPR1A?

Answer 8

TGFβ superfamily; transcriptional regulation and cell cycle control

Question 9

Which gene is mutated in Familial Adenomatous Polyposis (FAP)?

Answer 9

APC (tumour suppressor)

Question 10

What are the clinical features of FAP?

Answer 10

Numerous colonic adenomas, retinal lesions, osteomas, CNS tumours

Question 11

What condition results from defective nucleotide excision repair?

Answer 11

Xeroderma Pigmentosum (XP)

Question 12

What causes Hereditary Breast and Ovarian Cancer (HBOC)?

Answer 12

Germline mutations in BRCA1 or BRCA2

Question 13

What role do BRCA1 and BRCA2 play?

Answer 13

Double-strand DNA repair via RAD51 interaction

Question 14

Which tumour suppressor is linked to Retinoblastoma?

Answer 14

pRB (RB1 gene)

Question 15

What happens when pRB is phosphorylated?

Answer 15

It allows the cell cycle to proceed into S phase

Question 16

What gene is mutated in Li-Fraumeni syndrome?

Answer 16

p53 (tumour suppressor)

Question 17

What does p53 regulate?

Answer 17

DNA damage response: cell cycle arrest or apoptosis

Question 18

What disorder results from ATM mutation affecting p53 activation?

Answer 18

Ataxia Telangiectasia (AT)

Question 19

What gene is mutated in Familial Melanoma?

Answer 19

p16INK4a (CDKN2A) and sometimes CDK4

Question 20

What is the function of p14ARF from the same locus as p16INK4a?

Answer 20

Inhibits MDM2, stabilising p53

Question 21

What gene is mutated in Cowden Syndrome?

Answer 21

PTEN (dual phosphatase, tumour suppressor)

Question 22

What pathway does PTEN inhibit?

Answer 22

PI3K/Akt pathway → induces G1 arrest/apoptosis

Question 23

What syndrome is associated with retinal and CNS hemangioblastomas?

Answer 23

Von Hippel Lindau disease

Question 24

What does the VHL protein regulate?

Answer 24

HIF1α degradation; affects ECM formation and cell cycle exit

Question 25

What gene is mutated in MEN1?

Answer 25

MEN1 gene encoding menin

Question 26

What are the features of MEN1?

Answer 26

Tumours of parathyroids, pancreatic islets, anterior pituitary

Question 27

What gene is mutated in MEN2 syndromes?

Answer 27

RET proto-oncogene

Question 28

What mutation is associated with MEN2B?

Answer 28

RET M918T mutation (alters substrate specificity)

Question 29

What gene is mutated in Costello Syndrome?

Answer 29

H-Ras

Question 30

What tumours are seen in Costello Syndrome?

Answer 30

Rhabdomyosarcoma, neuroblastoma, bladder cancer