Overview of cancer and genetics Flashcards
types of cancers
sporadic
familial
hereditary
sporadic cancers
accounts for 70% of cancers
random chance/event
familial cancers
20% of cancers
shared environmental exposure
similar genetic background
hereditary cancers
10% of cancers
inherited genetic mutation
increased risk of cancer development
cancer as a disease of multiple steps
most develop form a single abnormal cell
a cell acquiring a mutation becomes abnormal
further mutations accumulate in some of the descendants of this first abnormal cell
allows descendant cells to acquire certain capabilities allowing them to gain advantages to outgrow the normal cells
known as clonal evolution
as tumours get bigger so does the genomic instability
intra-tumour heterogeneity
actual tumour progression doesn’t follow a linear path of clonal evolution
multiple independent mutations arise triggering parallel clonal expansions
tumour mass has several genetically distinct signatures
hallmarks of cancer
evading growth suppressors
avoiding immune destruction
enabling replicatie immortality
tumour-promoting inflammation
activating invasion and metastasis
inducing angiogenesis
genome instability and mutation
resisting cell death
deregulating cellular energetics
sustaining proliferative signalling
deregulation of tissue homeostasis drives cancer
loss of balance between cell proliferation and apoptosis gives rise to cancers
deregulation of genes that control these pathways drive cancer progression
genes are collectively known as cancer critical genes
2 main classes of cancer critical genes
porto-oncogenes
tumour suppressor genes
proto-oncogenes
normal genes which promote cellular proliferation
cell proliferation is tightly regulated, expression and activity of proto-oncogens is also tightly related
when mutated they-re expressed as oncogenes
leads to gain of function of corresponding proteins
mechanisms producing oncogenes
translocation- new promoter, normal growth stimulating protein in excess
gene amplification- multiple copies of the gene, normal growth stimulating protein in excess
mutation in control region- normal growth stimulating protein in. excess
mutation within the gene- hyperactive or degradation resistant protein
BCR-Abl tyrosine kinase
Bcr-Abl fusion gene found in chronic myeloid leukaemia and acute lymphoblastic leukaemia
reciprocal translation between chromosome 9 and 22
Abl-tyrosine kinase under the BCR promoter
new BCR-Abl fusion with protein with increase tyrosine kinase activity and is constitutively active
increases cell proliferation 30% in adult ALL and 90% in CML
amplification of proto-oncogene
excess protein produced can have numerous consequences
hyperactive cell proliferation signalling
rapid cell cycle transition
doesn’t respond to tumour suppressor genes
inactivation of tumour suppressor genes
levels exceed regulation threshold
results in hyperactive protein leading to a proliferative surge in the cell
tumour suppressor genes TSG
normally negatively regulate and suppress cell proliferation
involved in diverse cellular functions:
- inhibition of proliferative cell signalling
-DNA repair
-cell cycle arrest
-regulation of apoptosis
TSGs frequently inactivate by mutation and deletion
loss of function of corresponding protein
what is the loss of tumour suppressor genes normally
recessive
loss of tumour suppressor genes
normal cell 2 TSG alleles
mutational event
inactivation of 1st allele, cell still functions
second mutational event
inactivation of 2nd allele
loss of gene (protein) function
tumour q
retinoblastoma
Rb
most common eye cancer in children
caused by germline mutation in retinoblastoma Rb gene
knudsons observations on Rb
sporadic cases
-late onset single tumours, unilateral tumours, risk of recurrence same as normal population, no other areas of the body affected
familial cases
-early onset, multiple, bilateral, increased risk of recurrence, eyes and other areas
led to 2 hit hypothesis
2 hit hypothesis
familial Rb cases
1. hereditary germline mutation in one allele so all cells are “primed”
2. somatic mutation
therefore tumours develop early and form at multiple sites
sporadic Rb cases
two this in the same cell lineage, tumours form at one site
1. somatic mutation
2. somatic mutation
mechanism of TSG inactivation
loss of function mutations to both alleles
deletion of both alleles- homozygous deletion
loss of function mutation to one allele, deletion of another “ loss of heterozygosity”
post translational mechanism- binding to viral oncoproteins
gene silencing (epigenetics)
modification of gene expression rather than alteration of the genetic code itself
epigenetic mechanism for TSG suppression, switched on
active chromatin/ open
unmethylated cytosines, white circles
acetylated histones
transcription possible
epigenetic mechanism for TSG suppression, switched off
silenced chromatin/ condensed
methylated cytosines, red circles
deactylated histones
transcription not possible
germline mutation to TSG in genetic predisposition to cancers
retinoblastoma, Rb
breast/ovary, BRCA1
colorectal cancer:
-familial adenomatous polyposis (FAP)- APC
-hereditary non-polyposis colorectal cancer (HNPCR)- MLH1
hereditary breast cancers
autosomal dominant inherited condition
mutation in BRCA1 or BRCA2
10% of all breast cancer
role of BRCA proteins
maintain genomic integrity by repairing double strand DNA breaks
homozygous mutation of BRCA1 in mice leads to death in early embryogenesis due to chromosomal aberrations
loss of BRCA1 results in unprepared DNA damage= genomic instability
targeting BRCA mutant breast cancers
normal cells can rely on BRXA2 and PARP (poly ADP-ribose polymerase) for DNA repair
BRA mutant breast cancers are addicted to PARP BER (base excision repair)
BRCA mutant breast cancers are particularly sensitive to PARP inhibition
synthetic lethality
