BIOL 239

Cancer Genetics
Chapter 16
pg 545-551, 554-560, 562-564, 567
(16.1-16.5)

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2011
Pulitzer
Prize

2
The Immortal Life of Henrietta Lacks

-origin of HeLa cells

3
 2014 males

New cases
(incidence)
of Cancer

Canadian Cancer
Society
Line is Age-standardized females
Incidence rate
-corrected to account for age
structure in Canada

http://www.cancer.ca/~/media/cancer.ca/CW/publicatio
ns/Canadian%20Cancer%20Statistics%202014/Canadi
an-Cancer-Statistics-2014-EN.pdf 4
http://www.cancer.ca/~/media/cancer.ca/CW/publica
tions/Canadian%20Cancer%20Statistics%202014/C
anadian-Cancer-Statistics-2014-EN.pdf 5
Cancer is a genetic disorder
involving mutations in cells.

Cancer is not inherited, but

certain inherited mutations
can predispose one to cancer

6
Cancer (oncogenesis)
-begins with loss of cell cycle control
= tumor
-tumor (transformed) cells undergo
further changes that allow them to
invade and disrupt other tissues
= cancer

Exhibit an abnormal phenotype

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Cancer
Types of cancer - FYI

Carcinoma: epithelial origin e.g. skin

Sarcoma: connective tissue
(e.g., bone, cartilage)
Leukemia: blood-forming tissue
(e.g., marrow)
Lymphoma: cells of the immune
system (e.g., B-cells)
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Cancer arises when controls
over cell division no longer
function properly
-2 groups of genes

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Tumor-suppressor genes
-involved in cell cycle control
-act recessively

genes TP53 and RB

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11
e.g., TP53 product is p53 protein -gatekeeper
-regulates G1 to S Checkpoint:

-normally, when DNA is damaged in G1 phase,

entry into S phase is delayed to allow repair
before DNA replication proceeds.

-in mammals, the S phase delay is initiated

by activation of the p53 pathway.

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p53 is a transcription factor how it works:

cell cycle control…..

Cyclin-dependent kinase (CDK)
- when active, CDK commits the cell to S phase
- induces promoters of genes needed for DNA
synthesis

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p53 is a transcription factor how it works:

p53 induces expression of protein p21

-p21 inactivates CDK

p21

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p53 regulates G1 to S Checkpoint:

-p53 induces expression of p21

® p21 inactivates CDK
® stops movement into S phase
® cell cycle arrest

-if the damage cannot be repaired, then apoptosis

is initiated by p53 protein

end result is prevention of cell division

(checkpoint)®apoptosis if damage not repaired
-p53 protein acts as a tumor suppressor

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-homozygosity for mutations in the TP53 gene
have the ability to disrupt this checkpoint
(acts recessively)

-consequently, the damaged DNA gets replicated

and strand breaks occur that cause serious
chromosomal abnormalities
-cells with mutations in TP53 may allow a cell to
rapidly acquire further gene mutations

-approx 50% of all cancers are associated

with mutations in TP53
e.g., colon, breast, liver, lung, ovarian,
and pancreatic cancers
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 DNA damage (e.g. breaks)

S phase must be stopped!

p53 activated
No entry into S phase

repair can’t repair

S phase continues apoptosis

Tumor formation suppressed
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Driver Mutations:

-those mutations resulting in cancer

initiation and/or progression

-these mutations have the potential to

increase net cell growth

=mutations in TP53, RB, BRACA

-they are the ‘achilles’ heel’ of tumors

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A near-tetraploid cell line from mammary gland: breast; duct; primary
ductal carcinoma, cells are homozygous for a frameshift mutation in
BRCA1, held at ATCC, included in the Cancer Genome Project at the
Sanger Institute.
Departments of Pathology and Oncology, University of Cambridge
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A near-diploid cell line from lung, metastatic site, bone marrow
carcinoma, held at ATCC. Karyotyped in collaboration with the
Sanger Institute.
Departments of Pathology and Oncology, University of Cambridge
20
Remember………

It takes more than just disruptions

in TP53 to cause cancer, but this is a
common “first strike” leading down
the road to cancer

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e.g., Rb - brake
-recall CDK inactivated by p21
-stops movement to S phase

How?
-CDK acts on Rb

Rb
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E2F is a transcription
factor needed for
expression of genes for
DNA synthesis

-Rb binds and

inactivates E2F
-CyclinD/CDK complex
phosphorylates Rb
(pRb) to begin S phase

-pRb releases E2F

-transcription of genes
for DNA synthesis
begins
Fig 16.15
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Rb - brake
-in absence of functional Rb, S phase
cannot be prevented =uncontrolled cell
growth

-normally p53 will become activated to induce

apoptosis and prevent this cell from
replicating

Rb
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-“Two-hit” mutational model for some
cancers supported by studies of
retinoblastoma
-tumor of the eye
-can be hereditary or sporadic
-both involve mutation in tumor suppressor
gene RB

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hereditary
-one mutant RB copy is inherited from a
parent = first hit
-mutation present in germ line (passed on)
-if good RB becomes mutated (second hit),
then retinoblastoma begins in that eye
(somatic)
-recessive allele, but end effect is dominant

sporadic
-requires 2 independent mutations of RB
to begin oncogenesis
-somatic mutation not passed on
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 Inheritance of one copy of the RB allele
predisposes individuals to cancer of the retina

Germline
inherited Not inherited

Incomplete penetrance
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75% chance tumor develops
-autosomal dominant
because there
exists a strong
likelihood that
another mutation
in the normal
allele will
eventually
occur
-incomplete penetrance,
variable expression

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Mutant tumor-suppressor alleles
release a brake on cell division,
and can decrease the accuracy of
cell division in homozygotes

-act recessively
-mutations inactivate

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BRCA1 and BRCA2 genes are tumor-
suppressor genes

-products are part of a surveillance

system needed for repairing DNA breaks
-if mutations occur in these genes, then
damaged DNA may get replicated
-heterozygotes are at higher risk for
acquiring mutation in remaining copy

-promotes mutations in other genes

leading to cancer = dominant
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Oncogenes
-mutant alleles that act dominantly
to stimulate cell proliferation
-mutations activate

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Studying tumor-causing retroviruses
(oncoviruses) has lead to the discovery of
oncogenes

Mouse
Mammary
Tumor
virus

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Proto-oncogenes and Normal allele
oncogenes involved in
stimulating cell
proliferation

Proto-oncogene
is now under
control of a viral
promoter
= oncogene

Gets transcribed along

with virus genome and
gets packaged into
progeny virus particles,
which then insert it into
other cells/hosts
Fig 16.20 33
Some DNA viruses carry oncogenes
e.g., some strains of human papilloma
virus (genital warts)

->90% of cervical cancer in women is

associated with strains of HPV
carrying oncogenes that inactivate the
p53 and Rb – why?

-is the first step in tumorigenesis

(other mutations must follow to develop
cancer)
34
 Some HPV strains are carcinogens

35
Wikimedia commons: Laboratory of Tumor Virus Biology - NIH-Visuals Online# AV-8610-3067
-vaccine Gardasil 9 – recombinant vaccine containing
recombinantly made capsids (Virus-Like Particles;VLPs) of
7 oncogenic strains (16, 18, 31, 33, 45, 52, 58) and 2 non-
oncogenic strains (6, 11)

-Ontario, licenced for males and females. Free for grade 7

girls and boys

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37
-accidental integration of viral DNA
disruption of cell cycle, but no virus
cells aren’t killed, continue to replicate
increases probability of mutations
cancer

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Note:
Only oncogenic strains, like 16 and 18,
destroy p53 and Rb proteins.

Non-oncogenic strains cannot bind p53.

They bind Rb, but do not destroy it.

When they integrate, they do not

continue to disrupt cell cycle.

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HeLa karyotype – a transformed cell line
isolated from Henrietta Lacks (cervical cancer)

From J. Landry et al. The Genomic and Transcriptomic Landscape of a HeLa Cell Line. Genes Genomes Genetics. March 112013 online

HPV 18 inserted here 40

Normally…….
-cells with damaged DNA are caught by
p53®repair or apoptosis (tumor suppressed)

Mutations in TP53 (2 hits)…..

-cell can’t detect damage and DNA gets
replicated
-leads to many chromosomal abnormalities
e.g., RB mutated, cells divide in uncontrolled
manner = tumor

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but, normally……..
-most such cells will only undergo a limited
number of replication rounds as telomers
shorten each time, then die

Mutations in genes controlling telomerase

expression…….
-allows telomers to be repaired and cells become
immortalized
(could have happened as a result of mutations
of TP53 gene)

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Mutations in genes that induce cell
proliferation (proto-oncogenes ®oncogenes)…
-causes cell to reproduce rapidly

-excessive proliferation enhances the potential

for mutation

-mutations are more likely to occur in a large

clone of rapidly growing cells

-every round of DNA replication enhances

the potential for new mutations to occur to lead
to cancerous state
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Typically, multiple mutations must occur to
change a normal cell to a cancerous one

e.g., analysis of cells from human colon cancers,

show that these cells contain mutations in at
least 5-10 genes

pancreatic
cancer cell

® 44
 Cancer develops over time

The incidence of cancer rises with

age. Supports idea that cancer is
generally caused by a series of
mutations.

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Cancer is thought to arise by successive
mutations in a clone of proliferating cells

Fig 16.6

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Phenotypes for cancer include
many types of cellular
abnormalities

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 Fig 16.2
-autocrine stimulation

-contact inhibition
(loss of cell-cell
communication)

-resistance to = apoptosis
irradiation
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-disruption of local tissue and invasion of
distant tissues

Fig 16.5

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 -angiogenesis

Fig 16.5

http://www.hhmi.org/biointeractive/angiogenesis

Posted on LEARN
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Recommendations to Keep Cancer at Bay
American Cancer Society

5 points

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