Cancer basics Flashcards
what fraction of cancer in england can be prevented?
4/10
What is cancer?
uncontrolled growth/proliferation of abnormal cells.
cancerous cells invade and destroy healthy tissue including organs
what are the five broad stages of cancer?
histologically
cell with mutation
hyperplasia
dysplasia
in situ cancer
invasive cancer
how does the intratumour heterogenity help survival of the cancer
selection pressures won’t elimintate all the cells
survival of resistant clones help repopulate the tumour making it more likely to spread
whats the difference between intratumour heterogeneity, intertumour heterogeneity and intercancer heterogeneity
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
what are the two paths to cancer formation?
genetic origin
acquisition of a series of DNA mutations in the genome
but progression is influenced by cancer cell extrinsic factors (soluble
what are the main points in tumour progression and metastatis?
8
- carcinogeneis/tumourigenesis
- angiogensis
- detachment/invasion
- intravasation
- migration/transport
- extravasation
- micrometastasis
- macrometastasis
what type of cell intrinsic factors promote cancer?
- altered tumour suppressor or oncogene function
- deregulation of cell cycle proteins
- dysregulated signallign pathways
- chromosomal instability - leads to deletions or duplications within genes
what type of cell extrinsic factors promote cancer?
- soluble factors
- immune cells
- angiogenesis
- extracellular matrix
- altered environmental conditions
what ways can cancer be treated?
(5)
in terms of disrupting their mechanisms
- 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)
what targetted therapies are used for HER2 breast cancer
Herceptin, monoclonal antibodies
What targetted therapies are used in EGFR lung cancer?
Iressa, smallmolecule EGFR inhibitor
what is the average cost and time frame that it taes to bring a drug to market
10-15 years
$1.3 - 2.8 billion
give some evidence as to why cancer is a genetic disease
- 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)
what are the types of mutations that can occur?
(6)
- substitution (point mutations)
- insertions
- deletions
- duplication
- inversions
- translocations
Is cancer a inherited disease if it is genetic?
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)
what are germline mutations?
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
what are germline mutations?
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
cancer caused by germline mutations is called… _____________
inherited cancer
cancer caused by somatic mutations is called…
sporadic cancer
what are somatic mutations?
also known as acquired mutations
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
what is the difference between somatic and germline mutations?
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
what is a ‘cancer gene’?
a gene with a normal biological function, but when mutated behave differently causing or contributing to cancer development.
what are the two main groups of cancer gene?
oncogene and tumour suppressor gene
give three features of oncogenes
relating to inheritance
- 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
give three features of oncogenes in terms of inheritance
- 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
give three featuers of tumour suppressor genes
- recessivly acting
- mutations in these genes inherited in family cancer syndrome
- mutations cause loss of function
give three featuers of tumour suppressor genes
- recessivly acting
- mutations in these genes inherited in family cancer syndrome
- mutations cause loss of function
what is the normal function of tumou suppressor genes
normally function to prevent cell growth/ division
what are the four major differences between oncogenes and tumour suppressor genes
normal function, mutations cause, allele acting, inheritance
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
give three examples of inherited cancers linked to tumour suppressor genes
- Retinoblastoma - RB1
- Familial adenomatous polyposis (FAP) – APC
- Li-Fraumeni syndrome - TP53
what ways can oncogenes be activated
give examples for each (3)
- Amplification (e.g. Myc oncogene)
- Translocation (e.g. gene fusion BCR-ABL)
- Point mutations (e.g. Ras family genes– Kras, Nras, Hras)
give two examples of family cancers linked to oncogenes
- Multiple endocrine neoplasia type 2 (MEN2) – RET
- Isolated hereditary papillary renal cell cancer (HPRCC) – MET
using the protooncogenic and oncogenic form of H-ras what did scientists find about whats causing oncogenesis in bladder carcinoma
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
using the protooncogenic and oncogenic form of H-ras what did scientists find about whats causing oncogenesis in bladder carcinoma
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
whats the resultant difference between a point mutation within a control element vs one within the gene
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
how do oncogenes and tumour suppressor genes differe in the distribution of mutations within them?
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)
cancer genes are further classified into what three groups
reflecting the nature of the function of the gene
gatekeepers, caretakers and landscapers
what are gatekeeper genes
with examples
ones that act directly to restrain cell proliferation
eg classical tumour suppressors (RB1) and some oncogenes (RET)
what are caretaker genes
with examples
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)
what are lanscaper genes?
with examples
ones that act indirectly to control the environment in which cells grow, creasting a microenvironment aiding cell gowth, (extracellular matrix genes)
how do DNA repair genes act differently to classical tumour suppressor genes?
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)
they are similar in the fact that they are targetted by loss of function mutations
inactivation of DNA repair genes by mutations results in….
…DNA damage going unrepaired which leads to accumulation of mutations in other cellular genes increasing the likelihood of damagin mutations in other critical genes
give 5 facts of retinoblastoma
prevalence, gender lean, signs/symptoms, treatments,
- 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
why do inherited forms of retinoblastoma occur earlier?
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
