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Cancer Genetics Diane Stirling McMillan Nurse Specialist in Genetics Western General Hospital Edinburgh
Cancer   <ul><li>Is common </li></ul><ul><li>Involves genetic change </li></ul><ul><li>Is rarely inherited </li></ul>
Genes <ul><li>40,000 pairs </li></ul><ul><li>Units of inheritance </li></ul><ul><li>Mutations are changes in genes </li></...
Mutations <ul><li>Acquired mutations </li></ul><ul><ul><li>Also called somatic mutations </li></ul></ul><ul><ul><li>Presen...
Cancer Development  escapes normal cell growth controls  becoming uncontrolled and keeps dividing A growth develops which ...
Cell Cycle Control <ul><li>GATEKEEPERS </li></ul><ul><ul><li>Oncogenes (proto-oncogenes)   </li></ul></ul><ul><ul><ul><li>...
Oncogenes (proto-oncogenes) <ul><li>Proto-oncogenes have positive effect on  regulation of the cell cycle, cell division a...
Tumour Suppressors <ul><li>Negative effect  on  regulation of the cell cycle, cell division and differentiation </li></ul>...
DNA Repair Genes <ul><li>Caretakers </li></ul><ul><li>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 Tumo...
so... <ul><li>Cancers (whether sporadic or hereditary) arise by the activation, in one cell, of oncogenes  and  loss of tu...
Inherited Cancers –  tumour suppressor genes <ul><li>Tumour suppressor mutations are responsible for a number of cancer pr...
Inherited Cancers  – mismatch repair genes <ul><li>An inherited mutation in a MMR repair gene results in an increased muta...
Inherited cancers - oncogenes <ul><li>Not usually inherited  (one exception is RET gene in MEN2) </li></ul><ul><li>Act dom...
Knudson’s “Two Hit” Hypothesis Cancer Inherited  Change FIRST HIT Acquired  Change SECOND HIT Acquired  Change SECOND HIT ...
Sporadic vs Hereditary Cancer <ul><li>Approximately 5% of cancer is due to an inherited predisposition </li></ul><ul><li>W...
Family History <ul><li>Dominant pattern of inheritance (with non-penetrance) </li></ul><ul><li>Increased number of individ...
Breast cancer Ovarian cancer Hereditary Breast/Ovarian Cancer 26 35 31 48 58 High Risk - 4 or more individuals affected in...
Scottish Sub Committee on  Cancer Genetics <ul><li>Developed Guidelines for cancer predisposition risk assessment based on...
Risk categories <ul><li>High  </li></ul><ul><ul><li>– more than 5 times population risk </li></ul></ul><ul><li>Moderate  <...
Prostate Cancer and genetic factors <ul><li>Wide variation in prostate cancer rates in different ethnic groups </li></ul><...
Prostate Cancer – F/H Risk <ul><li>Relative Risk increases with number of affected relatives (1 st  degree) </li></ul><ul>...
Prostate Cancer Risk  – Age at diagnosis <ul><li>The earlier the age at diagnosis the greater the risk to 1 st  degree rel...
Prostate cancer genes <ul><li>Various chromosomal loci reported </li></ul><ul><ul><li>Results have been conflicting </li><...
CRC/BPG UK  Familial Prostate Cancer Study <ul><li>Multiple-case prostate cancer families with 3 or more cases at any age ...
Incidence of prostate cancer in other cancer predisposition syndromes <ul><li>3X increased risk in male BRCA1 carriers </l...
Prostate cancer screening <ul><li>Should men with a family history of prostate cancer be offered PSA (prostate specific an...
Narod et al 1995 <ul><li>Men with a normal rectal examination and a PSA >  3.0μg/l  </li></ul><ul><li>12% found to have ca...
Prostate cancer screening <ul><li>Many centres offer PSA screening but there is no consensus on </li></ul><ul><ul><li>Age ...
Testicular Cancer <ul><li>Risk of germ-cell tumours varies greatly between populations </li></ul><ul><ul><li>4 times great...
Nicholas & Harland 1995 <ul><li>Families with multiple cases of testicular cancer </li></ul><ul><li>Age at presentation sl...
Renal cell cancer <ul><li>2% of all renal cell carcinomas are thought to be attributable to inherited predisposition </li>...
What is vHL? <ul><li>An inherited genetic change which predisposes the individual to a wide variety of tumours, both benig...
vHL Natural History <ul><li>Mean age of expression 26 years </li></ul><ul><li>97% expressing the disease by age 60 years <...
Expression of the disease <ul><li>cerebellar haemangioma  </li></ul><ul><li>retinal angioma  </li></ul><ul><li>renal cell ...
Renal Cell Carcinoma (vHL) <ul><li>Occurs in 28% of individuals </li></ul><ul><li>2 nd  most common cause of death in vHL ...
RCC 2 (vHL) <ul><li>Diagnosis before symptoms occur confers a better prognosis </li></ul><ul><li>Symptomatic - metastatic ...
Summary <ul><li>Both hereditary and sporadic cancer is a multi-step process involving oncogenes, tumour suppressor genes a...
Risk assessment based on Family History <ul><li>Dominant pattern of inheritance (with non-penetrance) </li></ul><ul><li>In...
Genes and Environment CANCER Inherited Genetic Factors Environmental Factors
Sporadic Cancer CANCER Environmental Factors Inherited Genetic Factors
Hereditary Cancer Cancer Inherited Genetic Factors Environmental Factors
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Urology Cancer Genetics

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Transcript of "Urology Cancer Genetics"

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