Cancer traits 1 Flashcards
Cancer is a disease of what?
genome
What do carcinogens do?
produce mutations
What do mutations in somatic cells cause?
transformation and carcinogenesis
What is initiation
initiation of cancer development is clonal
- mutation in one specific cell will give a rise to whole tumour
What is carcinogenesis?
normal cells transformed into cancerous cells
What is the process of tumour cells
continue accumulating mutations, can evolve -> sub-clonal selection offers growth advantage and explains cell heterogeneity in tumours
- cells get different mutations
mutations in germ cells can be inherited increasing cancer risk but rarely causing it immediately
What are the names if cells in processing to malignant tumour?
normal cell (initiation occurs)->initiated cell (promotion occurs)-> preneoplastic cell (progression occurs) -> neoplastic cell (metastasis occurs)-> malignant tumour
What is an abnormal cell cycle?
unreplicated, mutated or damaged DNA, blocks progression of cell cycle at checkpoints
What is the process of abnormal cell cycle?
initial mutation inactivates a negative cell cycle regulator -> next mutation over activates a positive cell cycle regulator -> third mutation inactivates a genome stability factor->additional mutations accumulate rapidly->cancer cell
What is the difference between a normal cell and a cancer cell during DNA damage?
normal cell will lead to apoptosis whereas cancer cell will continue dividing
What is missense mutation?
change of single DNA base resulting in change in amino acid sequence & change of protein function
What is frameshift mutation
addition or removal of DNA bases shift DNA & amino acid sequence; results in different protein
what is nonsense mutation
change of single DNA base creates stop codon that terminates translation; results in shorter protein with no or abnormal function
what are chromosome rearrangements?
piece of chromosome breaks & is lost entirely (deletion), moves to different location (translocation), flips direction (inversion), or is repeated (duplication)
Can alter several genes at once, generating fusion genes
What is proto-oncogenes
normal cellular genes which regulate cell growth &/or division & differentiation
What is an oncogene
a proto-oncogene that has been activated by mutation or over expression - results in deregulated cell division
what are the sequences of stop codon in mRNA
UAA, UAG, UGA
What are the features of sense DNA
DNA is responsible for storing & transferring genetic information
One strand of DNA is called the sense strand because when you read it in the right direction, it provides the code to make a protein
The sense strand is bonded to an opposite DNA strand that is called the antisense/noncoding strand
Antisense doesn’t carry the translatable code, but serves as a template during transcription
What are the stop codon sequences in sense DNA
TAG, TGA, TAA
What is HER2 + function
encodes human epidermal growth factor receptor 2, has tyrosine kinase activity
= breast cancer
What is the cause of oncogene activation
- gene mutation: results in different oncoprotein than normal protein
- point mutations: in proto-oncogene or in promoter/regulatory element
- chromosomal translocation: fusion in proteins or disruption of regulatory elements - oncoprotein are same as normal protein but overexpressed
- gene amplification
one alteration in one copy of protocol-oncogene is enough to convert it into an oncogene
proto-oncogene mutation mainly affect somatic cells
What are the examples of oncogenes?
HER2
KRAS
BCR-ABL1
MYC
What is KRAS + function
GTPase (converts GTP->GDP)protein involved in signal transduction, controls cell growth and differentiation downstream of receptor tyrosine kinases, point mutation -> protein permanently active -> continuous proliferation
=lung cancer
what is BCR-ABL1 + Function?
philadelphia chromosome: fusion protein due to reciprocal chromosomal translocation between chromosomes 9 & 22
- has consituitave (unregulated) tyrosine kinase activity
=chronic myeloid leukemia
What is MYC and function?
family of photo-oncogenes that code for transcription factors
- pathogenic alterations in MYC involved activation, amplifications and translocations
= lymphoma (c-MYC)
= neuroblastoma (n-MYC)
TSG function ?
-Encode proteins that maintain cell cycle checkpoints & control genome stability
-Inhibit replication & proliferation of damaged cells by:
-Repair of DNA damage (e.g. BRCA1/2)
-Apoptosis (TP53)
What happens if TSG is inactivated?
Knudson’s 2-hit hypothesis: loss of function mutations in TSG are recessive in nature–> one normal allele is sufficient for cellular control
“Second hit” affecting normal allele–> disrupts gene function
Familial (heritable) cancers develop after additional loss of normal functional allele (loss of heterozygosity)
What is heterozygous state?
indicates absence of a functional TSG copy - but people remain healthy as there is still one functional gene left on the other chromosome of the pair
- the other copy can be inactivated by point mutation or other mechanisms -> results in loss of heterozygosity event and leaving no TSG to protect the body
loss of heterozygosity doesn’t imply a homozygous state (which would require presence of 2 identical alleles in the cell)
What is TP53 + function?
a TSG example
- codes for tumour protein p53
- detects cellular stress (DNA damage) -> cell cycle arrest -> damage repair or apoptosis
- over 50% of dancer contain TP53 gene mutations (missense)
What is Li-fraumeni syndrome
people who inherit only one functional tp53 allele -> most likely will develop cancer
What is RB1 + function?
- example of TSG
- codes for RB (retinoblastoma) protein
- prevents cell growth by inhibiting cell cycle
- when cells are ready to divide, RB is phosphorylated (inactivation) -> cell cycle progresses
- RB mutation, gene deletion or loss of heterozygosity lead to retinoblastoma (eye cancer) -> affects young children
40% germinal, 60% non
What occurs if there are mutation in DNA repair gene?
accumulation of mutation -> genomic instability, activation of oncogenes and loss of tumour supressors
What is BRCA and
an example of DNA repair gene
-BRCA1/2 inherited mutations increase risk of breast, prostate, ovarian cancers
sustaining proliferative signalling in normal cells?
require growth factors to proliferate
- GF bind to cell-surface receptors, typically with intracellular tyrosine kinase domains
TKDs send intracellular signals regulating
- cell cycle progression
- cell growth
- cell survival
- energy metabolism
What occurs in cancer cells in proliferative signalling
synthesise of GF’s/ligands -> autocrine proliferative signalling (positive feedback loop)
b. unregulated receptor expression -> increased sensitivity to ligand
c. stimulate normal cells to supply GF’s
d. constitutively activate signalling pathways downstream of receptors -> no need
How do normal cells evade growth supressors
use antigrowth signals to maintain quiescence & homeostasis
- these signals block proliferation by forcing cells:
- to enter quiescent G0 state -> cell cycle arrest
- permanently lose their proliferative potential -> interim post-mitotic state, senescence, apoptosis
cells can re-emerge from G0 state on some future occasion when extracellular signals permit
How do cancer cells evade growth supressors?
circumvent antigrowth programs (evade TGF-beta anti proliferative signalling)
- many antigrowth programs depend on tsg (tp53, PTEN &RB)
- complete loss of TSG
- accumulation of mutations that render genes inactive
What can cancer cells become in growth signals?
self sufficient in growth signals
also become insensitive to antigrowth signals
What are the different types of genetic mutations in cancer?
missense
frameshift
nonsense
chromosome rearrangements
