Transcript Slides for cancer talk BME1450 Oct 2006

Cancer genetics and treatment
BME1450
David Hogg
RJ 47 year male
• Presented to family doctor Dec 2003 with
pigmented lesion on scalp
• Told lesion of no significance
Melanoma Types
Superficial spreading melanoma
Lentigo maligna melanoma
Nodular melanoma
Acral lentiginous melanoma
RJ 47 year male
• Lesion began to bleed two months late
• Biopsy showed nodular melanoma
• Referred to Princess Margaret Hospital
melanoma clinic for opinion March 2004
RJ 47 year male
• Sent for wide local excision of melanoma
• Sentinel node biopsy revealed melanoma in 2/6
regional lymph nodes
• Radical neck dissection April 2004: no positive nodes
RJ 47 year male
• Treated with Interferon-
• While on treatment, developed severe
headaches in July 2004
RJ 47 year male
• Treated with radiotherapy to brain plus
Temozolomide
• Died of disease August 2004
The art of medicine lies in amusing the patient
while the disease runs its course.
Sir William Osler
Cancer – questions and problems
1.
2.
3.
4.
What is Cancer?
What causes the disease?
Why is cancer so difficult to treat?
Where are we going?
Cancer – questions and problems
1.
2.
3.
4.
What is Cancer?
What causes the disease?
Why is cancer so difficult to treat?
Where are we going?
Normal cells - characteristics
1. Proliferate only when they receive positive
growth signals from the environment
2. Cease growing or die in the absence of such
signals
3. Cease growing or die when they receive
growth-inhibitory or death signals
Normal – characteristics: cont…
4. Differentiate or enter senescence (old age)
during their lifetime.
5. Respect local anatomic boundaries – will not
cross tissue barriers unless specifically told to
do so.
6. Do not spread to other areas of the body
(metastasize).
Genetic targets
Programs/responses
Growth
factor
Growth
+
No growth
Growth Factor
receptor
+
Signal transduction
pathways
DNA (genes)
Inputs
Tumor suppressor
Death
Differentiation
Metastasis
Inhibitory
factor
Cancer is a genetic disease I
•
•
•
Cancer cells are derived from normal cells
To progress from a normal cell to a malignant
one, a series of changes in the DNA of the cell
must occur
These changes alter the behaviour of the cell.
Cancer is a genetic disease II
•
•
•
In almost all cases, a cell must suffer multiple
genetic ‘hits’ to become fully malignant.
The number of hits is thought to number about 5-7
in most types of cancer
In many cases, at least some of these genetic lesions
are known, and may differ between different types
of cells (and hence cancer types).
Tumor progression – sequential mutations
s1
s2
s3
s4
Timing of genetic changes
•
•
There is not always a set pattern of genetic
changes as a cell progresses to malignancy.
In other words, although 5-7 changes must
occur to make a cell fully malignant, the
order and timing of these alteration may be
flexible.
Implications of progressive genetic
alterations
•
•
•
Cancers are not cells with “uncontrolled
growth”!
Loss of growth control occurs very slowly over
several years, in a stepwise fashion.
Therefore, defining the genetic changes in a
tumor will become as important as histological
study.
Melanoma Types
Superficial spreading melanoma
Lentigo maligna melanoma
Nodular melanoma
Acral lentiginous melanoma
Melanoma: a multistage process
Normal Skin
Benign Nevus
Dysplastic Nevus
(DN)
Radial Growth
Phase
melanoma
Vertical Growth
Phase
melanoma
Derived in part from Chin et al. (1998) Genes Dev. 12: 3467-3481
Timing of genetic lesions in melanoma
APC (FAP)
Normal colon
DN gene?
(DNS)
Normal melanocyte
Kras
SMAD4
DCC
MMR
(HNPCC)
p53
Adenocarcinoma
c-src/Cox2
CDKN2A
(Familial melanoma)
Ras? - 10q 6p
p53
Invasive melanom
Cancer – questions and problems
1.
2.
3.
4.
What is Cancer?
What causes the disease?
Why is cancer so difficult to treat?
Where are we going?
What causes genetic changes?
•
Environment
–
•
Radiation, drugs (eg: chemotherapy); infections;
etc
Genetic background
–
–
Inherited (germline) mutations
Tendency to develop genetic lesions (DNA repair
deficiencies).
Tumour Formation
Genotype
Environment
Somatic
Mutations
But remember throughout that no external
cause is efficient without a predisposition of
the body itself. Otherwise, external causes
which affect one would affect all...
Galen, 200 A.D.
Familial Cancer
• Now known to occur in many tumor types egs:
– Breast (BRCA1; BRCA2)
– Colon (APC; MLH1; MSH2; PMS1; PMS2)
– Melanoma (CDKN2A)
– Retinoblastoma (RB)
– Li-Fraumeni Syndrome (p53)
Familial Cancer - Characteristics
Compared to the corresponding sporadic cancers:
1. Age at first presentation is lower
2. Tumors may present at multiple sites in the same
tissue
3. Tumors may occur in different tissues
4. There may be a family history
Melanoma family - example
I:1
melanoma
II:1
multiple
myeloma
II:2
melanoma
II:3
brain
II:4
I:2
II:5
melanoma
Dx33
2 primaries
II:6
II:7
melanoma
Loss of a functional tumor suppressor gene
g
A1
A2
Normal
s
A1
A2*
Mutation of
one allele
A2*
Loss of remaining
normal allele
LOH of the wild-type CDKN2A allele in sorted
BM obtained from multiple myeloma patient
I:1
melanoma
II:1
multiple
myeloma
II:2
melanoma
II:3
brain
II:4
I:2
II:5
melanoma
Dx33
2 primaries
II:6
II:7
melanoma
Heteroduplex
Mutant
Germline DNA
Unsorted BM
Sorted BM (myeloma)
Wild-type
Knudson’s Two-Hit Model
Mendelian
Sporadic
Germline mutation
Normal gene
Somatic mutation
Somatic mutation
Multiple Tumors
Bilateral
Early-onset
Somatic mutation
Single Tumors
Unilateral
Later-onset
Familial Cancer - Characteristics
Compared to the corresponding sporadic cancers:
1. Age at first presentation is lower
2. Tumors may present at multiple sites in the same
tissue
3. Tumors may occur in different tissues
4. There may be a family history
Familial Melanoma
• ~ 10% of melanoma patients have at least one affected
family member
• Only ~3% of patients have multiple affected relatives
• However, the risk for patients with a predisposition to
melanoma is very high: ~60-80X that of the general
(European) population
Sporadic vs. Familial Melanoma
Sporadic
Familial
Ave. age at diagnosis
54 years
35 years
No. of primaries
Usually one
Often multiple
Presence of dysplastic nevi
(DN)
Some cases
Most cases
Family history
No
2 or more affected
first-degree relatives
Germline mutations in the CDKN2A gene that
predispose to melanoma - Toronto families
24ins
14del
6del
2del
19del
insertion
deletion
I49S
M53I
S56I
V57I
G-34T
R24P
A5T
missense
E2
E1
D85T
T93P
G122V
V126D
5’
E3
3’ UTR
CDKN2A
% Mutations found
CDKN2A mutation detection
rate/number AFM
100
90
80
70
60
50
40
30
20
10
0
5 or more
4
3
2
Number of melanomas in family
multiple
primaries
Problems in Treating Cancer
If a cancer depends on at least 5-7 mutations in
different pathways, and these pathways differ from
cell to cell, then how:
1. Do we identify critical pathways in the cell
2. Determine the critical components of each
pathway?
“The most effective way of destroying a network is
to attack its most connected nodes”
Yuhai Tu, Nature 2000
Tools
1. For testing pathways:
•
Cell lines
•
Tumor biopsies from patients
2. To knock out specific mRNA:
•
siRNA
3. To affect specific proteins:
•
Drugs
4. Delivery/attack: ?viruses
Melanoma treatment with an oncolytic virus, JX-594
(Mastrangelo et al., Cancer Gene Therapy, 6: 409, 1999)