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Cancer Genetics Diane Stirling McMillan Nurse Specialist in Genetics Western General Hospital Edinburgh 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 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 GATEKEEPERS Oncogenes (proto-oncogenes) o Tumour Suppressors o positive effect on growth and proliferation 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 Cancer - A multi step process Tumour Suppressor genes DNA Repair Environmental Mutagens Activated Oncogenes Loss of Tumour Supressor genes Loss of DNA Repair 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 o o o o Li- Fraumeni syndrome Von Hippel-Lindau Tuberous Sclerosis Retinoblastoma 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 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 Approximately 5% of cancer is due to an inherited predisposition When is a cancer hereditary? Family History Dominant pattern of inheritance (with nonpenetrance) Increased number of individuals affected on one side of the family Younger age of onset Multiple primaries e.g. bilateral breast 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 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 Moderate – more than 5 times population risk –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 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 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. 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 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/H 27% 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 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 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 nonpenetrance) Increased number of individuals affected on one side of the family Younger age of onset Multiple primaries e.g. bilateral breast 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