Molecular Carcinogenesis

Question 1

what are the specific hallmarks of cancer cells (10)

Answer 1

self sufficiency in positive growth signalling - eg in RAS always on

evading growth suppressors - mutations in Rb to stop prevention of proliferation

avoiding immune destruction - binding PD1/PDL1 stops T cells

enabling replicative immortality - stop telomere shortening

promoting inflammation

activating invasion and metastasis

inducing angiogenesis - nutrients for tumour

genome instability and mutation (Bcl2 overexpression in cancers = anti-apoptotic)

resisting cell death

deregulated metabolism

Question 2

what is a proto-oncogene

Answer 2

normal genes that promote cell proliferation, survival and angiogenesis

Question 3

what is an oncogene

Answer 3

mutation of protocol-oncogene causing cancerous cell - activity of expressed proteins

Question 4

why are oncogenes so powerful genetically

Answer 4

dominant gain in function

1 mutant copy of gene acts dominantly to the remaining normal parental gene

Question 5

what are some examples of oncogenes

Answer 5

RAS, myc, RAF, HER2 and EGFR

Question 6

what are the 4 steps mechanisms of oncogene activation

Answer 6

translocation
point mutation
amplification
insertion

Question 7

describe the specific 4 processes of oncogene activation

Answer 7

trasnlocaiton of oncogene from low to an active transcription site - aberrant expression of the oncogene
point mutation - substitution of single base within the amino acid sequence produces a hyperactive oncoprotein
amplification by insertion of multiple copies of an oncogene - increased expression
insertion for promoter or enhancing genes near an oncogene = increased expression

Question 8

what are the two types of tumour suppressor gene

Answer 8

gatekeeper - antioncogenes - negative regulators of the cell eye and proliferation - positive regulators of apoptosis

caretakers - maintain genetic stability

Question 9

what are some examples of tumour suppressor genes

Answer 9

APC, P53, BRCA1/2

Question 10

what is the mechanism of TSG loss

Answer 10

carcinogens induce molecular abnormalities in TSG/s which reduction protein function / expression
does this by inactivating point mutations, deletion, translocations, epigenetic silencing

Question 11

what are familial cancer syndromes

Answer 11

caused by inheritance of a mutant copy of TSG gene which increases risk by 70-90%

Question 12

how would familial transfer of a mutant caretaker gene lead to increased risk of cancer

Answer 12

genetic instability - predisposition to developing cancer - also needs to hit hypothesis

Question 13

what is required to turn a normal cell into a neoplastic cell

Answer 13

minimum of 3-6 genetic alterations

Question 14

describe the mutagenic pathway of colorectal cancer from normal epithelium to adenocarcinoma

Answer 14

normal (APC)
early adenoma (KRAS)
intermediate adenoma (SMAD4)
late adenoma (P53) 
adenocarcenoma

Question 15

what are the uses of tumour markers

Answer 15

diagnosis - identification of type or subtype
prognosis - some confer worse survival
therapy - predict therapeutic response
monitoring

Question 16

what are serum markers and what can they be used for

Answer 16

antigens of cancerous cells - not sensitive or specific enough for general screening but can be used as an adjunct (antra help)

Question 17

why types of cancerous cells can serum markers test for

Answer 17

AFP, hCG, PSA (prostate), CEA and thyroglobulin

Question 18

what marker is over expressed in 30% of breast cancers and how do we use this in treatment

Answer 18

HER2 - treat with herceptin

Question 19

what mutations do 50% of colorectal cancers have and how do we use this in treatment

Answer 19

KRAS mutation - permanently on from of RAS

therefore cannot give cetuximab or panitummuab

Question 20

what protein is over expressed in lung cancers

Answer 20

EGFR