Cancer development and spread (DONE)

Question 1

Historical context

Answer 1

Cancer known for many centuries- evidence from mummified remains, term cancer introduced by Hippocrates, relatively uncommon
Scientific advancement during 1800 and 1900s- better instrumentation to enhance understanding of cells and tissues
Early 1900s saw cancer emerging as medical diagnosis
Mid 1900s: advent of chemotherapy, cancer societies and significant government funding

Question 2

Cancer statistics

Answer 2

Cases: 360,000 in UK, 50% of these are breast, prostate, lung and bowel
Deaths: 164,000 in UK, lung cancer accounts for more than 20% of these, over 50% of deaths are in people 75 years or older
Survival: 50% survive cancer for 10 or more years
Preventable cases: 38% of cases in UK are preventable

Question 3

Cancers develop due to a build up of mutations in genes that control key cellular function

Answer 3

DNA damage (mutation) causes initiation
Proliferation (growth promoters) leads to promotion
Development of cancerous phenotype results in progression
Mutations build up over time until a cancerous phenotype occurs

Question 4

CRC adenoma-carcinoma sequence: Vogelstein’s model

Answer 4

Normal colon- APC, abnormalities
Hyperproliferative epithelium- methylation abnormalities
Adenoma- 18q deletion
Carcinoma- p53 deletion
Further accumulation of genetic abnormalities

Question 5

Cancer hallmarks definition

Answer 5

Protein product of tumour suppressor genes inhibits cellular processes central to cancer hallmarks
Hallmarks: defining features of a cancer cell

Question 6

Six cancer hallmarks

Answer 6

Self-sufficiency in growth signals
Insensitivity to antigrowth signals
Evading apoptosis
Limitless replicative potential
Sustained angiogenesis
Tissue invasion and metastasis

Question 7

Tumour suppressor genes

Answer 7

Protein product of tumour suppressor genes inhibits cellular process central to cancer hallmarks- mitosis, migration/invasion etc.
Tumour suppressor gene disruption requires LOH (loss of heterozygosity)- requires both alleles for loss of function (c.f. oncogenic activation)

Question 8

Many tumour suppressor genes regulate cell cycle progression

Answer 8

S: unreplicated or damaged DNA
G2/M: unreplicated or damaged DNA
M: chromosome misalignment
G1/s: damaged DNA

Question 9

Tumour suppressors: Rb

Answer 9

Retinoblastoma originally defined as a gene associated with the development of an inherited eye tumour
Bi-allelic Rb loss directly leads to retinoblastoma
Most common paediatric eye cancer
1:200,000 births
Accounts for 3% of cancers in children under 15 years

Question 10

Rb: MOA

Answer 10

Rb1 encodes 928aa protein that regulates E2F function

Question 11

Proto-oncogenes

Answer 11

Proto-oncogenes are normal genes that have the propensity to support cancer when mutated
Whereas tumour suppressor gene mutation is recessive, oncogenic mutation is dominant

Question 12

Oncogenes by location

Answer 12

Secreted
Membrane associated
Transmembrane
Cytosolic
Nuclear

Question 13

Oncogenes by function

Answer 13

Growth factors
Growth factor receptors
G proteins
Intracellular kinases
TxFs

Question 14

Mechanisms of proto-oncogene conversion

Answer 14

Chromosomal rearrangements (translocation and inversion)
Amplification
Point mutations

Question 15

erbB2 oncogenic amplification

Answer 15

Member of erbB (EGFR) family

Her2 overexpression/activation characterizes specific cancers e.g. breast, gastric, ovarian

Question 16

Smoking

Answer 16

90% of lung cancer is from smoking
32% of male cancer deaths are due to smoking
25% of female cancer deaths are due to smoking

Question 17

Diet

Answer 17

Western diet: high fat, high meat

Prostate and colon cancer association

Question 18

How does diet influence CRC development?

Answer 18

Nitrogen/ammonia: undigested remnants of dietary protein undergo bacterial degradation- production of ammonia, phenol, HA, ammonia absorbed by colonocytes
Presence of nitrate, nitrite and nitrosamines in processed meat: inflammation and mucosal damage, production of nitrogen leads to formation of N-nitroso compounds

Question 19

UVA/B radiation

Answer 19

80% of malignant melanoma caused by overexposure to sunlight

Photons are directly absorbed by DNA bases leading to mutagenic changes e.g. LOH, oncogene activation