Urology Cancer Genetics
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Transcript of Urology Cancer Genetics
Cancer Genetics
Diane StirlingMcMillan Nurse Specialist in GeneticsWestern General HospitalEdinburgh
Cancer
•Is common
•Involves genetic change
•Is rarely inherited
Genes 40,000 pairs Units of inheritance Mutations are changes in genes
No effect Act with other genetic changes to cause an
effect Cause genetic disease
Mutations
Acquired mutations 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 Also called germline mutations Present in every cell in the body
Cancer Development
escapes normal cell growth controls becoming uncontrolled and keeps dividing
A growth develops which can invade neighbouring tissues and spread by lymph or blood.
Apoptosis
A single cell
Cell Cycle Control
GATEKEEPERS Oncogenes (proto-oncogenes)
o positive effect on growth and proliferation
Tumour Suppressorso negative effect i.e. suppress growth
CARETAKERS DNA Repair Mechanisms
Oncogenes (proto-oncogenes)
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
Negative effect on regulation of the cell cycle, cell division and differentiation
Induce apoptosis
Brakes
DNA Repair Genes
Caretakers
Repair DNA mutations caused by replication errors, carcinogens etc
Tumour Suppressor genesDNA Repair
Environmental MutagensActivated OncogenesLoss of Tumour Supressor genesLoss of DNA Repair
Cancer - A multi step process
so... 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
Tumour suppressor mutations are responsible for a number of cancer predisposition syndromes
o Li- Fraumeni syndromeo Von Hippel-Lindauo Tuberous Sclerosiso Retinoblastomao Familial Breast and Breast /Ovarian Cancer
Inherited Cancers – mismatch repair genes
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
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
Cancer
Inherited Change
FIRST HIT
Acquired Change
SECOND HIT
Acquired Change
SECOND HIT
Acquired Change
FIRST HIT
No Change
CANCER
Inherited Sporadic
Sporadic vs Hereditary Cancer
Approximately 5% of cancer is due to an inherited predisposition
When is a cancer hereditary?
Family History
Dominant pattern of inheritance (with non-penetrance)
Increased number of individuals affected on one side of the family
Younger age of onset
Multiple primaries e.g. bilateral breast
Patterns (breast/ ovarian, bowel/ endometrial) or rare cancers
Breast cancerBreast cancer
Ovarian cancerOvarian cancer
Hereditary Breast/Ovarian Cancer
26
35
31
48
58
High Risk
- 4 or more individuals affected in 3 generations
Scottish Sub Committee on Cancer Genetics
Developed Guidelines for cancer predisposition risk assessment based on family history of the following common cancers Breast cancer Ovarian Cancer Colon Cancer
Risk categories
High – more than 5 times population risk
Moderate –3 to 5 times population risk
Low – less than 3 times population risk
Prostate Cancer and genetic factors
Wide variation in prostate cancer rates in different ethnic groups 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)
1 affected relative RR 2 2 affected relative RR 5 3 affected relatives 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 RR 1.9before age 60 RR 1.4before age 70 RR 1.0
Prostate cancer genes
Various chromosomal loci reported 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. Multiple-case prostate cancer families with 3 or more cases at any age
II. Affected blood-related pairs where one is <65 years old at diagnosis
III. Young cases diagnosed <55 years of age
Incidence of prostate cancer in other cancer predisposition
syndromes
3X increased risk in male BRCA1 carriers
5X increased risk in male BRCA2 carriers
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?
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/H27% found to have cancer if +ve F/H
Prostate cancer screening
Many centres offer PSA screening but there is no consensus on
Age to start screening Family history criteria
Testicular Cancer
Risk of germ-cell tumours varies greatly between populations 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 1995Families with multiple cases of testicular cancer
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
2% of all renal cell carcinomas are thought to be attributable to inherited predisposition
Familial cases are characterised by 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
Autosomal dominant tumour suppressor gene
Gene identified in 1993
Chromosome 3p25-26 First identified 100 years ago Incidence (gene frequency) 1 in 100 000
vHL Natural History
Mean age of expression 26 years 97% expressing the disease by age
60 years Studies estimate a life expectancy
of less than 50 years (before surveillance programs introduced)
Expression of the disease
cerebellar haemangioma retinal angioma renal cell carcinoma spinal haemangioma phaeochromocytoma Renal, pancreatic and epidydimal cysts
frequently found but incidence not accurately assessed
Endolymphatic sac tumours(Mayer et al 1990)
Renal Cell Carcinoma (vHL)
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)
Diagnosis before symptoms occur confers a better prognosis
Symptomatic - metastatic disease is present in 20-30% of presenting cases
Summary
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 but TS genes act recessively at cellular level Knudsons 2 hit hypothesis
Risk assessment based on Family History
Dominant pattern of inheritance (with non-penetrance)
Increased number of individuals affected on one side of the family
Younger age of onset
Multiple primaries e.g. bilateral breast
Patterns (breast/ ovarian, bowel/ endometrial) or rare cancers
Genes and Environment
CANCERInheritedGeneticFactors
EnvironmentalFactors
Sporadic Cancer
CANCEREnvironmental
FactorsInheritedGeneticFactors
Hereditary Cancer
Cancer
InheritedGeneticFactors
EnvironmentalFactors