Cancer basics

Question 1

what fraction of cancer in england can be prevented?

Answer 1

4/10

Question 2

What is cancer?

Answer 2

uncontrolled growth/proliferation of abnormal cells.

cancerous cells invade and destroy healthy tissue including organs

Question 3

what are the five broad stages of cancer?

histologically

Answer 3

cell with mutation
hyperplasia
dysplasia
in situ cancer
invasive cancer

Question 4

how does the intratumour heterogenity help survival of the cancer

Answer 4

selection pressures won’t elimintate all the cells
survival of resistant clones help repopulate the tumour making it more likely to spread

Question 5

whats the difference between intratumour heterogeneity, intertumour heterogeneity and intercancer heterogeneity

Answer 5

Intratumor heterogeneity - the presence of more than one clone of cancer cells within a given tumor mass
Intertumor heterogeneity - the presence of different genetic alterations in different metastatic tumors from a single patient
Intercancer heterogeneity - heterogeneity between cancer from different anatomical locations

Question 6

what are the two paths to cancer formation?

Answer 6

genetic origin
acquisition of a series of DNA mutations in the genome

but progression is influenced by cancer cell extrinsic factors (soluble

Question 7

what are the main points in tumour progression and metastatis?

8

Answer 7

• carcinogeneis/tumourigenesis
• angiogensis
• detachment/invasion
• intravasation
• migration/transport
• extravasation
• micrometastasis
• macrometastasis

Question 8

what type of cell intrinsic factors promote cancer?

Answer 8

• altered tumour suppressor or oncogene function
• deregulation of cell cycle proteins
• dysregulated signallign pathways
• chromosomal instability - leads to deletions or duplications within genes

Question 9

what type of cell extrinsic factors promote cancer?

Answer 9

• soluble factors
• immune cells
• angiogenesis
• extracellular matrix
• altered environmental conditions

Question 10

what ways can cancer be treated?
(5)
in terms of disrupting their mechanisms

Answer 10

• surgical removal or radiation directed at primary tumour
• limit spread of disease (chemotherapy, antiangiogenics)
• circumvent immune evasion (immunotherapy)
• correct dysregulated signlling pathways (targetted antibodies, small molecule)
• prevention of cell proliferation (chemotherapy, small molecule approaches, antibodies)

Question 11

what targetted therapies are used for HER2 breast cancer

Answer 11

Herceptin, monoclonal antibodies

Question 12

What targetted therapies are used in EGFR lung cancer?

Answer 12

Iressa, smallmolecule EGFR inhibitor

Question 13

what is the average cost and time frame that it taes to bring a drug to market

Answer 13

10-15 years
$1.3 - 2.8 billion

Question 14

give some evidence as to why cancer is a genetic disease

Answer 14

• most carcinogens are also mutagens
• no mini epidemics, not contagious (but see viral oncogenes)
• incidence increases with age as does damage to DNA
• some cancers segregate in families
• chromosomal instability is a common feature
• defects in DNA repair increase the probability of cancer

(>50 forms have some degree of inherited predisposition)

Question 15

what are the types of mutations that can occur?
(6)

Answer 15

• substitution (point mutations)
• insertions
• deletions
• duplication
• inversions
• translocations

Question 16

Is cancer a inherited disease if it is genetic?

Answer 16

all cancer arises from mutations in genes but not all cancer is inherited
most is not inherited, only 5-10% are due to inherited mutations (germline)

Question 17

what are germline mutations?

Answer 17

mutation in every cell of the body, including the reproductive cells (starting from a mutation in germline cells)
passed directly from a parent to a child

associated with inherited and familial forms of cancer - less common cau

Question 17

what are germline mutations?

Answer 17

mutation in every cell of the body, including the reproductive cells (starting from a mutation in germline cells)
passed directly from a parent to a child

associated with inherited and familial forms of cancer - less common cau

Question 18

cancer caused by germline mutations is called… _____________

Answer 18

inherited cancer

Question 19

cancer caused by somatic mutations is called…

Answer 19

sporadic cancer

Question 20

what are somatic mutations?

also known as acquired mutations

Answer 20

occur from damage to genes during a persons lifetime (eg by tobacco, ultraviolet radiation and age)
not passed from parent to child

most common cause of cancer

Question 21

what is the difference between somatic and germline mutations?

Answer 21

somatic: occur in nongermline tissues, cannot be inherited, mutation in tumour only, nonheritable
germline: present in egg or spern, can be inherited, cause cancer family syndrome, mutation in egg or sperm, all cells affected in offspring, heritable

Question 22

what is a ‘cancer gene’?

Answer 22

a gene with a normal biological function, but when mutated behave differently causing or contributing to cancer development.

Question 23

what are the two main groups of cancer gene?

Answer 23

oncogene and tumour suppressor gene

Question 24

give three features of oncogenes relating to inheritance

Answer 24

- tend to be dominanctly acting (gain of function) - mutations in these genes are not *usually* inherited - activated oncogene in the germline is often embryonically lethal

Question 24

give three features of oncogenes in terms of inheritance

Answer 24

- tend to be dominanctly acting (gain of function) - mutations in these genes are not *usually* inherited - activated oncogene in the germline is often embryonically lethal

Question 25

give three featuers of tumour suppressor genes

Answer 25

- recessivly acting - mutations in these genes inherited in family cancer syndrome - mutations cause loss of function

Question 25

give three featuers of tumour suppressor genes

Answer 25

- recessivly acting - mutations in these genes inherited in family cancer syndrome - mutations cause loss of function

Question 26

what is the normal function of tumou suppressor genes

Answer 26

normally function to prevent cell growth/ division

Question 27

what are the four major differences between oncogenes and tumour suppressor genes | normal function, mutations cause, allele acting, inheritance

Answer 27

oncogenes: normal function to promote cell growth/ division, mutations cause gain of function, dominantly acting, not usually inherited tumour suppressor genes: normal function to prevent cell growth/division, mutations cause loss of function, recessive at cellular level (two mutated alleles), seen in inherited cancers

Question 28

give three examples of inherited cancers linked to tumour suppressor genes

Answer 28

* Retinoblastoma - RB1 * Familial adenomatous polyposis (FAP) – APC * Li-Fraumeni syndrome - TP53

Question 29

what ways can oncogenes be activated | give examples for each (3)

Answer 29

* Amplification (e.g. Myc oncogene) * Translocation (e.g. gene fusion BCR-ABL) * Point mutations (e.g. Ras family genes– Kras, Nras, Hras)

Question 30

give two examples of family cancers linked to oncogenes

Answer 30

* Multiple endocrine neoplasia type 2 (MEN2) – RET * Isolated hereditary papillary renal cell cancer (HPRCC) – MET

Question 31

using the protooncogenic and oncogenic form of H-ras what did scientists find about whats causing oncogenesis in bladder carcinoma

Answer 31

mutation responsible for H-ras oncogene activation in bladder carcinoma narrowed to a 350bp region by recombining the protooncogene and oncogene this section was then sequenced and it was discovered that a point mutation - a single missence base pair change from glycine to vline was enough to give transforming function

Question 31

using the protooncogenic and oncogenic form of H-ras what did scientists find about whats causing oncogenesis in bladder carcinoma

Answer 31

mutation responsible for H-ras oncogene activation in bladder carcinoma narrowed to a 350bp region by recombining the protooncogene and oncogene this section was then sequenced and it was discovered that a point mutation - a single missence base pair change from glycine to vline was enough to give transforming function

Question 32

whats the resultant difference between a point mutation within a control element vs one within the gene

Answer 32

a point mutation within a control element results in normal growth stimulating protein in excess a point mutation within the gene will result in hyperactive or degradation resistant protein

Question 33

how do oncogenes and tumour suppressor genes differe in the distribution of mutations within them?

Answer 33

oncogenes: tend to have mutations in few codons affecting particular domains, very localised and with a bias towards missense mutations tumour suppressor genes: tend to have mutations more widely spread across the gene, more evenly missense mutations and mutations inducing premature termination codons (loss of function)

Question 34

cancer genes are further classified into what three groups | reflecting the nature of the function of the gene

Answer 34

gatekeepers, caretakers and landscapers

Question 35

what are gatekeeper genes | with examples

Answer 35

ones that act directly to restrain cell proliferation eg classical tumour suppressors (RB1) and *some oncogenes* (RET)

Question 36

what are caretaker genes | with examples

Answer 36

ones that act indirectly to maintain the integrity of the genome, and disruption leads to genomic instability eg DNA repair genes; a subgroup of tumour suppressor genes, (BRCA1, BRCA2)

Question 37

what are lanscaper genes? | with examples

Answer 37

ones that act indirectly to control the environment in which cells grow, creasting a microenvironment aiding cell gowth, (extracellular matrix genes)

Question 38

how do DNA repair genes act differently to classical tumour suppressor genes?

Answer 38

classical tumour suppressor genes are directly involved ingrowth inhibition or differentiation (gatekeeper function) DNA repair genes are indirectly involved in growth inhbition or differentiation (caretaker function) ## Footnote they are similar in the fact that they are targetted by loss of function mutations

Question 39

inactivation of DNA repair genes by mutations results in....

Answer 39

...DNA damage going unrepaired which leads to accumulation of mutations in other cellular genes increasing the likelihood of damagin mutations in other critical genes

Question 40

give 5 facts of retinoblastoma | prevalence, gender lean, signs/symptoms, treatments,

Answer 40

- most common eye tumour in children (approx 1 in 20000) - tumour of retinal stem cells - males and females equally affected - signs and symptoms include white pipul eye pain or redness - treatments include srgery, chemo, radiation therapy

Question 41

why do inherited forms of retinoblastoma occur earlier?

Answer 41

the sporadic cases needed two somatic mutations and the inherited cases only one (inherited cases already have one in the germline, need one sporadic) Retinal cells grow very rapidly in early life, likelihood of a second somatic mutation is very high when one gene is already out of action