Cancer Bio - diseases

Question 1

Retinoblastoma

Answer 1

AR, familial (40%) or sporadic (60%)
Hudsons 2 hit hypothesis - 2 separate mutations, 1 in each of rb allele needed to prevent RB expression.
Rb TSG regulates transcription & cell cycle proliferation
Assoc. cancers - Retinoblastoma & SCLC

Question 2

Wilms Tumour

Answer 2

Mutation of Wt1 TSG (transcriptional regulator).
Associated cancers - Nephroblastoma

Question 3

FAP (Familial adenomatous polyposis)

Answer 3

AD - mutation of APC TSG gene

APC binds and regulates B-catenin activity, unregulated B-Catenin -> uncontrolled growth & proliferation

Assoc cancers - multiple polyps from adolesence - Increased risk of colorectal cancers.

Loss of APC (hyperplastic) -> DNA hypomethylation (early adenoma) -> K-ras activation (intermediate adenoma) -> LOH 18q ?TSG (late )-» loss of P53 (carcinoma)

Question 4

HNPCC (hereditary non polyposis colorectal carcinoma) - LYNCH syndrome

Answer 4

AD - defects in MSH2 & MLH1 account for 90% of cases also PMS1, PMS2, MSH6

Mech of A - loss of protein products coded by these genes -> loss of MMR -> reduces fidelity of DNA replication by orders of magnitude

Assoc cancers - colorectal cancer, endometrial, ovary.
Amsterdam II criteria: > 3 family members (1 first degree, other 2), 2 successive generations, >1 diagnosed <50 years, FAP excluded

Question 5

Familial breast cancer

Answer 5

BRCA 1 (17q) & BRCA 2 (13q)
Also PALB2, CHEk2, ATM, Ras 1
AD involved in HR pathway of DNA repair

In patients with mutated BRCA, normal tissues are heterozygous - no increased sensitivity. A spontaneous somatic mutation in other BRCA allele in later life causes cells to be deficient in HR repair -» genomic instability -» sensivity to DNA crosslinking agents (e.g Cisplatin).

Synthetic lethality:
PARP used in BER to repair SSBs. If left unrepaired (e.g. in context of PARPis) - replication converts to these to DSBs. BRCA used in HR to repair DSBs.
Normal cells treated with PARPis - functional HR - viable.
BRCA mutant tumour cells - treated with PARPis - loss of BER & HR - synthetic lethality - death.

Assoc cancers - breast, ovarian, prostate, fallopian tube, leukaemia/lympoma. BRCA2 also in fanconi anaemia.

Question 6

Li Fraumeni Syndrome

Answer 6

AD, germline p53 mutation, haploinsufficiency is sufficient for tumour formation.

P53 involved in multiple regulatory cellular processes e.g DNA damage repair, induction of G1 cell cycle arrest and apoptosis and transcription. 25 x increased risk <50 - multiple primaries at a young age.

Assoc cancers - breast, brain, sarcoma, leukaemia, adrenal cortex
(early onset breast, her 2+, bilateral, mixed lobular & ductal)

Question 7

Neurofibromatosis 1

Answer 7

NF1 gene mutation, AD
Involved in Ras-GAP activity
Associated cancers - neurofibromatosis, sarcomas, gliomas

Question 8

MEN1

Answer 8

Tumour suppressor
AD - TSG menin 1
Associated cancers = parathryoid, pancreatic, pituitary adenoma

Question 9

MEN 2A

Answer 9

AD - RET oncogene (TKR)
Associated cancers = medullary thyroid cancer, phaechromocytoma, parathyroid

Question 10

MEN 2B

Answer 10

AD = RET oncogene (TKR)
Associated cancers = Marfanoid and mucosal neuromas, parathyroid, phaechromocytoma

Question 11

Xeroderma pigmentosa

Answer 11

AR - involving 7 proteins XPA-G
M of A = Defective nucleotide excision repair, highly UV light sensitive - unable to repair SSBs
Associated cancers = 1000x risk of skin cancers (scc, bcc, melanoma), 20x risk of other malignancies, mental retardation, premature dementia

Question 12

Ataxia Telangiectasia

Answer 12

AR - Ataxia Telangiectasia Mutated kinase (ATM) mutation
ATM is an inactive homodimer -> activated by DSBs (ionising radiation) -> phosphorylated to active monomers -> phosphorylate p53 & CHk1 (G1/S checkpoint), CHk2 (G2/M checkpoint) causing either cell cycle arrest and DNA repair or if damage too severe apoptosis.

ATM deficient cells are therefore very radiosensitive and unable to repair DSBs

Associated cancers - progressive cerebellar ataxia from childhood, multiple telangiectasia (skin, conjuctiva). 100x increased risk of lymphoma, leukaemia, breast

Question 13

Peutz Jeghers

Answer 13

AD mutation of LKB1 / STK 11

Is a serine/threonine kinase involved in cell signalling

Assoc cancers = benign harmatomatous polyps, hyperpigmented macules on oral mucosa & lips, colorectal cancer, breast cancer

Question 14

Von Hippel Lindau

Answer 14

AR - VHL TSG

regulates proteolysis, stimulates HIF -» angiogenesis

Associated cancers - haemangioblastomas - cerebellum, spinal cord, kidney, retina (blindness common), RCC, phaechromocytoma

Question 15

Cowden Syndrome

Answer 15

AD - mutation of PTEN TSG (therefore PI3K/AKT pathway activated)

Associated cancers = breast, thyroid adenocarcinoma, skin SCC, colorectal, endometrial

Macrocephaly, mucocutaneous lesions.

Question 16

viral causes assoc with Liver Ca

Answer 16

HBV,HCV

Question 17

viral causes assoc with Cervix

Answer 17

HPV 16 & 18
E7 = degradation of Rb prevents E2F sequestration - cyclin A & E produced - drive for cell cycle progression
E6= forms complex with ubiquitin ligase, binds p53 and causes lysis of p53

Question 18

viral causes assoc with Stomach ca

Answer 18

H Pylori

Question 19

cancers assoc with HIV

Answer 19

kaposis, non hodgkins, lymphoma, hodgkins (HHV8)

Question 20

cancers assoc with EBV

Answer 20

Burkitts, nasopharyngeal