Overview of cancer and genetics

Question 1

types of cancers

Answer 1

sporadic
familial
hereditary

Question 2

sporadic cancers

Answer 2

accounts for 70% of cancers
random chance/event

Question 3

familial cancers

Answer 3

20% of cancers
shared environmental exposure
similar genetic background

Question 4

hereditary cancers

Answer 4

10% of cancers
inherited genetic mutation
increased risk of cancer development

Question 5

cancer as a disease of multiple steps

Answer 5

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

Question 6

intra-tumour heterogeneity

Answer 6

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

Question 7

hallmarks of cancer

Answer 7

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

Question 8

deregulation of tissue homeostasis drives cancer

Answer 8

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

Question 9

2 main classes of cancer critical genes

Answer 9

porto-oncogenes
tumour suppressor genes

Question 10

proto-oncogenes

Answer 10

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

Question 11

mechanisms producing oncogenes

Answer 11

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

Question 12

BCR-Abl tyrosine kinase

Answer 12

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

Question 13

amplification of proto-oncogene

Answer 13

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

Question 14

tumour suppressor genes TSG

Answer 14

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

Question 15

what is the loss of tumour suppressor genes normally

Answer 15

recessive

Question 16

loss of tumour suppressor genes

Answer 16

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

Question 17

retinoblastoma

Answer 17

Rb
most common eye cancer in children
caused by germline mutation in retinoblastoma Rb gene

Question 18

knudsons observations on Rb

Answer 18

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

Question 19

2 hit hypothesis

Answer 19

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

Question 20

mechanism of TSG inactivation

Answer 20

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

Question 21

epigenetic mechanism for TSG suppression, switched on

Answer 21

active chromatin/ open
unmethylated cytosines, white circles
acetylated histones
transcription possible

Question 22

epigenetic mechanism for TSG suppression, switched off

Answer 22

silenced chromatin/ condensed
methylated cytosines, red circles
deactylated histones
transcription not possible

Question 23

germline mutation to TSG in genetic predisposition to cancers

Answer 23

retinoblastoma, Rb
breast/ovary, BRCA1
colorectal cancer:
-familial adenomatous polyposis (FAP)- APC
-hereditary non-polyposis colorectal cancer (HNPCR)- MLH1

Question 24

hereditary breast cancers

Answer 24

autosomal dominant inherited condition
mutation in BRCA1 or BRCA2
10% of all breast cancer

Question 25

role of BRCA proteins

Answer 25

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

Question 26

targeting BRCA mutant breast cancers

Answer 26

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