Transcript Urology Cancer Genetics

Cancer Genetics
Diane Stirling
McMillan Nurse Specialist in Genetics
Western General Hospital
Edinburgh
Cancer
•Is common
•Involves genetic change
•Is rarely inherited
Genes
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40,000 pairs
Units of inheritance
Mutations are changes in genes
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No effect
Act with other genetic changes to cause an
effect
Cause genetic disease
Mutations
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Acquired mutations
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Also called somatic mutations
Present only in the descendants of the cell that
they originally occur in
Environmental agents, viruses
Usually repaired by DNA repair mechanisms
Inherited mutations
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Also called germline mutations
Present in every cell in the body
Cancer Development
A single cell
escapes normal cell growth controls
becoming uncontrolled and keeps dividing
Apoptosis
A growth develops which can invade neighbouring
tissues and spread by lymph or blood.
Cell Cycle Control
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GATEKEEPERS
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Oncogenes (proto-oncogenes)
o
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Tumour Suppressors
o
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positive effect on growth and proliferation
negative effect i.e. suppress growth
CARETAKERS
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DNA Repair Mechanisms
Oncogenes (proto-oncogenes)
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Proto-oncogenes have positive effect on
regulation of the cell cycle, cell division and
differentiation
When proto-oncogenes are mutated they are
called oncogenes
Oncogenes can lead to permanently activated
cells
Accelerator
Tumour Suppressors
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Negative effect on regulation of the
cell cycle, cell division and
differentiation
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Induce apoptosis
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Brakes
DNA Repair Genes
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Caretakers
Repair DNA
mutations caused
by replication
errors,
carcinogens etc
Cancer - A multi step process
Tumour Suppressor genes
DNA Repair
Environmental Mutagens
Activated Oncogenes
Loss of Tumour Supressor genes
Loss of DNA Repair
so...
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Cancers (whether sporadic or
hereditary) arise by the activation, in
one cell, of oncogenes and loss of
tumour suppressor function. These
occur by mutations.
Loss of normal DNA repair
mechanisms can aid this process
Inherited Cancers –
tumour suppressor genes
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Tumour suppressor mutations are
responsible for a number of cancer
predisposition syndromes
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Li- Fraumeni syndrome
Von Hippel-Lindau
Tuberous Sclerosis
Retinoblastoma
Familial Breast and Breast /Ovarian Cancer
Inherited Cancers
– mismatch repair genes
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An inherited mutation in a MMR repair gene
results in an increased mutation rate in the
genome
The increased mutation rate leads to
accelerated tumour progression
Known to be involved in hereditary Bowel
Cancer- MLH1, MSH2, MSH6 etc
Inherited cancers - oncogenes
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Not usually inherited (one exception is
RET gene in MEN2)
Act dominantly to induce or maintain cell
transformation – only one copy of the gene
pair needs to be mutated
Each malignant tumour type has it’s own
characteristic spectrum of oncogene
mutations (sporadic)
Knudson’s “Two Hit” Hypothesis
Inherited
Sporadic
Inherited
Change
FIRST HIT
No Change
Acquired
Change
FIRST HIT
Acquired
Change
SECOND HIT
Cancer
CANCER
Acquired
Change
SECOND HIT
Sporadic vs Hereditary Cancer
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Approximately 5% of cancer is due to
an inherited predisposition
When is a cancer hereditary?
Family History
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Dominant pattern of inheritance (with nonpenetrance)
Increased number of individuals affected on
one side of the family
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Younger age of onset
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Multiple primaries e.g. bilateral breast
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Patterns
cancers
(breast/ ovarian, bowel/ endometrial)
or rare
Breast cancer
Ovarian cancer
Hereditary Breast/Ovarian Cancer
48
58
26
35
31
High Risk
- 4 or more individuals affected in 3 generations
Scottish Sub Committee on
Cancer Genetics
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Developed Guidelines for cancer
predisposition risk assessment based on
family history of the following common
cancers
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Breast cancer
Ovarian Cancer
Colon Cancer
Risk categories
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High
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Moderate
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– more than 5 times population risk
–3 to 5 times population risk
Low
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– less than 3 times population risk
Prostate Cancer and genetic factors
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Wide variation in prostate cancer rates in
different ethnic groups
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Highest frequency in African-Americans
Lowest frequency in Asians
Family history is a known risk factor
Monozygotic twins have 4 fold increased
concordance rate compared to dizygotic twins
Prostate Cancer – F/H Risk
Relative Risk increases with number of
affected relatives (1st degree)
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1 affected relative
2 affected relative
3 affected relatives
RR 2
RR 5
RR 11
Prostate Cancer Risk
– Age at diagnosis
The earlier the age at diagnosis the
greater the risk to 1st degree
relatives
before age 50
before age 60
before age 70
RR 1.9
RR 1.4
RR 1.0
Prostate cancer genes
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Various chromosomal loci reported
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Results have been conflicting
High risk gene yet to be cloned
Autosomal dominant, autosomal
recessive and X linked patterns of
inheritance
CRC/BPG UK
Familial Prostate Cancer Study
I.
II.
III.
Multiple-case prostate cancer families
with 3 or more cases at any age
Affected blood-related pairs where one
is <65 years old at diagnosis
Young cases diagnosed <55 years of age
Incidence of prostate cancer in other
cancer predisposition syndromes
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3X increased risk in male BRCA1 carriers
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5X increased risk in male BRCA2 carriers
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However BRCA1 and BRCA2 mutations are
rare in large prostate cancer families
Prostate cancer screening
Should men with a family history of
prostate cancer be offered PSA
(prostate specific antigen) screening?
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PPV of the screening test will increase
with the prevalence of the condition
Narod et al 1995
Men with a normal rectal examination
and a PSA > 3.0μg/l
12% found to have cancer if –ve F/H
27% found to have cancer if +ve F/H
Prostate cancer screening
Many centres offer PSA screening but
there is no consensus on
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Age to start screening
Family history criteria
Testicular Cancer
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Risk of germ-cell tumours varies greatly between
populations
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4 times greater in white population compared to black
population
Brothers of men with testicular cancer had a 2%
risk of developing testicular cancer by age 50
years - 10 fold increase in RR (Formen et al 1992)
Nicholas & Harland 1995
Families with multiple cases of testicular cancer
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Age at presentation slightly younger (mean 29)
compared with non-familial controls (mean 36)
Risk of bilateral disease higher in familial cases
15% vs 5%
Affected sib pairs more commonly reported
that father and son pairs
Renal cell cancer
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2% of all renal cell carcinomas are thought to be
attributable to inherited predisposition
Familial cases are characterised by
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early age of onset
bilaterality
multicentricity
von Hippel-Lindau Disease
What is vHL?
An inherited genetic change which
predisposes the individual to a wide variety
of tumours, both benign and malignant
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Autosomal dominant tumour suppressor gene
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Gene identified in 1993
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Chromosome 3p25-26
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First identified 100 years ago
Incidence (gene frequency) 1 in 100 000
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vHL Natural History
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Mean age of expression 26 years
97% expressing the disease by age 60
years
Studies estimate a life expectancy of
less than 50 years
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(before surveillance programs introduced)
Expression of the disease
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cerebellar haemangioma
retinal angioma
renal cell carcinoma
spinal haemangioma
phaeochromocytoma
Renal, pancreatic and epidydimal cysts
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frequently found but incidence not accurately assessed
Endolymphatic sac tumours
(Mayer et al 1990)
Renal Cell Carcinoma (vHL)
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Occurs in 28% of individuals
2nd most common cause of death in vHL
vHL related RCC occurs at an earlier age
than sporadic RCC
often multiple and bilateral
CT scanning is more sensitive than U/S
Treatment – surgical (with preservation of renal tissue if
possible)
RCC 2 (vHL)
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Diagnosis before symptoms occur
confers a better prognosis
Symptomatic - metastatic disease is
present in 20-30% of presenting
cases
Summary
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Both hereditary and sporadic cancer is a
multi-step process involving oncogenes,
tumour suppressor genes and MMR genes
Inherited mutations are mainly tumour
suppressors or MMR genes
Dominant inheritance
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but TS genes act recessively at cellular level
Knudsons 2 hit hypothesis
Risk assessment based on
Family History
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Dominant pattern of inheritance (with nonpenetrance)
Increased number of individuals affected on
one side of the family

Younger age of onset
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Multiple primaries e.g. bilateral breast
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Patterns
cancers
(breast/ ovarian, bowel/ endometrial)
or rare
Genes and Environment
Inherited
Genetic
Factors
CANCER
Environmental
Factors
Sporadic Cancer
Inherited
Genetic
Factors
CANCER
Environmental
Factors
Hereditary Cancer
Inherited
Genetic
Factors
Cancer
Environmental
Factors