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Cancer Genetics

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Also called somatic mutations ... Tuberous Sclerosis. Retinoblastoma. Familial Breast and Breast /Ovarian Cancer. Inherited Cancers ... – PowerPoint PPT presentation

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Title: Cancer Genetics


1
Cancer Genetics
  • Diane Stirling
  • McMillan Nurse Specialist in Genetics
  • Western General Hospital
  • Edinburgh

2
Cancer
  • Is common
  • Involves genetic change
  • Is rarely inherited

3
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

4
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

5
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.

6
Cell Cycle Control
  • GATEKEEPERS
  • Oncogenes (proto-oncogenes)
  • positive effect on growth and proliferation
  • Tumour Suppressors
  • negative effect i.e. suppress growth
  • CARETAKERS
  • DNA Repair Mechanisms

7
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

8
Tumour Suppressors
  • Negative effect on regulation of the cell
    cycle, cell division and differentiation
  • Induce apoptosis
  • Brakes

9
DNA Repair Genes
  • Caretakers
  • Repair DNA mutations caused by replication
    errors, carcinogens etc

10
Cancer - A multi step process
Environmental Mutagens Activated Oncogenes Loss
of Tumour Supressor genes Loss of DNA Repair
Tumour Suppressor genes DNA Repair
11
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

12
Inherited Cancers tumour suppressor genes
  • Tumour suppressor mutations are responsible for a
    number of cancer predisposition syndromes
  • Li- Fraumeni syndrome
  • Von Hippel-Lindau
  • Tuberous Sclerosis
  • Retinoblastoma
  • Familial Breast and Breast /Ovarian Cancer

13
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

14
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 its own
    characteristic spectrum of oncogene mutations
    (sporadic)

15
Knudsons 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
16
Sporadic vs Hereditary Cancer
  • Approximately 5 of cancer is due to an inherited
    predisposition
  • When is a cancer hereditary?

17
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

18
Breast cancer
Ovarian cancer
Hereditary Breast/Ovarian Cancer
48
58
35
31
26
High Risk - 4 or more individuals affected in 3
generations
19
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

20
Risk categories
  • High
  • more than 5 times population risk
  • Moderate
  • 3 to 5 times population risk
  • Low
  • less than 3 times population risk

21
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

22
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

23
Prostate Cancer Risk Age at diagnosis
  • The earlier the age at diagnosis the greater the
    risk to 1st degree relatives
  • before age 50 RR 1.9
  • before age 60 RR 1.4
  • before age 70 RR 1.0

24
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

25
CRC/BPG UK Familial Prostate Cancer Study
  • Multiple-case prostate cancer families with 3 or
    more cases at any age
  • Affected blood-related pairs where one is lt65
    years old at diagnosis
  • Young cases diagnosed lt55 years of age

26
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

27
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

28
Narod et al 1995
  • Men with a normal rectal examination and a PSA gt
    3.0µg/l
  • 12 found to have cancer if ve F/H
  • 27 found to have cancer if ve F/H

29
Prostate cancer screening
  • Many centres offer PSA screening but there is no
    consensus on
  • Age to start screening
  • Family history criteria

30
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)

31
Nicholas Harland 1995
  • Families 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

32
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

33
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

34
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)

35
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)

36
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)

37
RCC 2 (vHL)
  • Diagnosis before symptoms occur confers a better
    prognosis
  • Symptomatic - metastatic disease is present in
    20-30 of presenting cases

38
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

39
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

40
Genes and Environment
Inherited Genetic Factors
Environmental Factors
CANCER
41
Sporadic Cancer
Environmental Factors
Inherited Genetic Factors
CANCER
42
Hereditary Cancer
Inherited Genetic Factors
Environmental Factors
Cancer
43
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