Path 2: Carcinogenesis Flashcards
What is carcinogenesis?
a multistep process resulting from the accumulation of multiple mutations
what is initiating mutation?
found in all progeny, begins the process towards malignant transformation
- essentially the first driver mutation
- often include loss-of-function mutations in genes that maintain genomic integrity
–leading to genomic instability
what is driver mutation?
mutation that increases malginant potential of the cell
what is passenger mutation?
mutation with low malignant effect
drive mutations fall into 4 main categories:
- proto-oncogenes
- tumour suppressor genes
- genes regulating apoptosis
- genes responsible for DNA repair
proto-oncogenes:
gain of function mutation = oncogenes
tumour suppressor genes:
generally loss-of-function mutations
gene regulating apoptosis:
can be gain- or loss- of function
genes responsible for DNA repair:
- generally loss of function
- affected cells acquire mutations at an accelerated rate
define oncogenes
promote excessive cell growth, even in absence of normal growth-promoting signals
- created by mutations in proto-oncogenes
- encode oncoproteins that participate in signaling pathways driving cell proliferation
Oncogenes: Ras
- downstream component of receptor tyrosine kinases signalling pathways
- point mutation of RAS family genes is the single most common abnormality of proto-oncogenes in human tumors
oncogenes: PI3K
part of PI3 family `
oncogenes: Myc
Myc is a transcription factor
- Immediate early response gene
○ Induced by Ras/MAPK signaling (among others)
- When activated:
○ Increases cell proliferation and growth
§ How was Myc involved in the cell cycle? They produce Cdk
○ Contributes of other hallmarks of cancer
§ Warburg effect (e.g. can upregulate glycolytic enzymes
§ Increased telomerase activity (contribute to endless replicative activity)
§ May also allow more terminally differentiated cells to gain characteristics of stem cells
- Implicated in cancers of breast, colon, lung
Which of the 2 cell cycle checkpoints regulated by cdk-cyclin complexes do you suppose is more important in cancer?
G1/S checkpoint
what happens when there is a gain-of-function mutations in cyclin D and Cdk 4, how would this affect progression through the G1/S checkpoint
increase cell division
explain tumour suppressor genes
products of tumour suppressor genes apply brakes to cell proliferation
what is RB?
is a key negative regulator of the G1/S checkpoints
what are the direct and indirect effects of RB being suppressed (tumour suppressor gene)
direct - loss of function involving both RB alleles
indirect -
- gain of function mutation upregulating CDK4/cyclin D
- loss of function mutation of CKIs
what does p53 do?
regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis
what gene is the most frequently mutated in human cancer?
p53
what happens when p53 is mutated?
DNA damage goes unrepaired and driver mutations accumulate in oncogenes and other cancer genes
what is p16 function?
inhibits Cdk4-cyclin D comple (G1-cdk complex) needed for progression through the cell cycle
what happens when there is a p16 mutation?
increased cell cycle progression
what are the 8 fundamental changes in all cancers
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Altered cellular metabolism
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Ability to invade and metastasize
Ability to evade the host immune system
