Cancer Genetics

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Cancer Genetics

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

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Cancer

• Is common
• Involves genetic change
• Is rarely inherited

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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

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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

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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.

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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

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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

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Tumour Suppressors

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

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DNA Repair Genes

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

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

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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

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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

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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)

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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
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Sporadic vs Hereditary Cancer

• Approximately 5 of cancer is due to an inherited
  predisposition
• When is a cancer hereditary?

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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

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Breast cancer
Ovarian cancer
Hereditary Breast/Ovarian Cancer
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58
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31
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High Risk - 4 or more individuals affected in 3
generations
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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

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Risk categories

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

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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

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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

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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

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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

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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

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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

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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

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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

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Prostate cancer screening

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

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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)

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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

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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

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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

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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)

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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)

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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)

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RCC 2 (vHL)

• Diagnosis before symptoms occur confers a better
  prognosis
• Symptomatic - metastatic disease is present in
  20-30 of presenting cases

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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

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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

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Genes and Environment
Inherited Genetic Factors
Environmental Factors
CANCER
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Sporadic Cancer
Environmental Factors
Inherited Genetic Factors
CANCER
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Hereditary Cancer
Inherited Genetic Factors
Environmental Factors
Cancer
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Thank you