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 Inherited 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 Genetic mutations can be aqcuired or inheritied Acquired mutations are mutations that develop often during the process of DNA replication and cell division. They are also referred to as somatic mutations and they are only present in the descendents of they cell that they originate in. Inherited mutations, also called germline mutations, are present from the very first cell, and are 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 CARETAKERS Oncogenes (proto-oncogenes) positive effect on growth and proliferation Tumour Suppressors negative effect i.e. suppress growth CARETAKERS DNA Repair Mechanisms In 1997 Kinzler and Vogelstein coined the terms Gatekeeper and caretaker to distinguish between the cancer susceptibility genes that act directly to control cellular proliferation and differentiation (gatekeepers) and those genes that maintain the integrity of the genome (caretakers) Gatekeepers May be divided into 2 classes – Oncogenes that produce a positive effect on cell growth and proliferation and tumour suppressor genes that have a negative effect. Caretaker genes are those genes that are responsible for the repair of replication error that occur during the cell cycle.

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 Oncogenes have a positive effect on the regulation of the cell cycle, cell division and differentiation. So if oncogenes are mutated this can lead to permanently activated cells. One way to think about oncogenes is to liken them to an accelerator in a car. If the accelerator is stuck on the car will go faster and faster and the driver loses control of the car. If an oncogene is permanently switched on the control of the cell proliferation is lost and mutated cells are produced at a faster and faster rate. Although mutations in the oncogenes are important in production of a malignant tumour – inherited mutations in these genes that cause genetic predisposition to cancer are rare. Mutations in these genes are usually acquired mutations. One exception is RET gene activation in MEN2.

Tumour Suppressors Negative effect on regulation of the cell cycle, cell division and differentiation Induce apoptosis Brakes Tumour suppressor genes have a negative effect on cell growth and proliferation. Their function is to induce apoptosis and they act in a recessive manner by the loss of their function. Again if we use the car sinario and liken the tumour suppressor to the brake on a car. A normally functioning brake will be abe to slow the car down and gives the driver contorl over the speed of the car. If however the brake does not work then the driver loses control of the car’s speed. If tumour suppressor genes do not work properly then cells that should die off do not and they are allowed to continue to replicate increasing the chances of further mutations being acquired.

DNA Repair Genes Caretakers Repair DNA mutations caused by replication errors, carcinogens etc Sugar phosphate

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

Hereditary Breast/Ovarian Cancer Breast cancer Ovarian cancer Hereditary Breast/Ovarian Cancer 48 58 35 31 26 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 Low – 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   Caused by a combination of genetic and environmental factors. It is known that genetic factors are important because of the wide variation in prostate cancer rates between different ethnic groups and because a family history of prostate cancer is a risk factor for the development of this cancer. Difficulties with studying the genetic bases of PC – typically occurs at a late age and it is rare to have DNA from living affected men in more than one generation. Difficult to define age-of-onset of PC as the diagnosis is only rarely made on men with symptoms due to cancer. More commonly the diagnosis is made when a man undergoes surgery for symptoms of benign hyperplasia and malignant cells are found in the pathology specimen. Or a raised PSA is found on a screening test. Twin studies provide strong evidence for a genetic component to prostate cancer. From a registry of 4840 males twin pairs in Sweden, 458 cases of prostate cancer were identified. There were 16 concordant pairs among 1649 monozygotic twins but only 6 concordant pairs among 2938 dizygotic twin pairs (Grönberg et al 1994). Twin studies cannot be used to infer the genetic mode of transmission Steinberg et al 1990 – Large case control study (691) RR for brothers 3 RR for fathers 2 RR for grandfathers 1.9 RR for uncles 1.7 Carter et al 1992 - concluded that PC inheritance best fits an autosomal dominant model, where a rare susceptibility gene with a high lifetime penetrance was transmitted. Weakness of above study is that history of prostate cancer is based on the recollection of the index patient and not confirmed by pathology reports. Reported history of PC in 2nd degree relatives tends to be inaccurate. PC patients may be may be more likely to be aware of the diagnosis of PC in relatives, may be more diligent in their search for additional cases, or may be more likely to misinterpret benign disease as cancer, than healthy controls. NOT all studies of PC have concluded that the data best fits a dominant model. In several studies the risk for brothers was found to be significantly greater than the risk for sons or fathers of cases. This is consistent with recessive or X linked inheritance. Relative risk increases with number of affected relatives (1st degree) affected 1 2 2 5 3 11 RR Li-Fraumeni – Incidence of prostate cancer increased but not testicular cancer IN SUMMARY There is likely to be a great deal of genetic heterogeneity in familial prostate cancer. Smith study confirms one highly penetrant dominant susceptibility gene but there are likely to be others. Recessive and X linked genes are also probable. There is no benign precursor for hereditary prostate cancer and familial cancers do not appear to be systematically different form sporadic ones. BRCA1 & BRCA2 risk of prostate cancer. SCREENING Little is known about the environmental causes of PC, current preventative strategies focus on early detection through screening. FH is probably the most important known factor that can be used to identify men at high risk. The serum test for PSA is proposed to be a sensitive and specific means of detecting asymptomatic prostate cancer prior to metastatic spread. It is hoped that population-based screening programs using PSA will be successful in reducing mortality from the disease. The positive predictive value of the screening test will increase with the prevalence of the condition in the screened population. Narod et al 1995 found that the PPV of a PSA test above 3.0μg/l was higher for men with a positive family history of PC – Men with a normal rectal examination and a PSA > than 3.0, 12% were found to have cancer in the FH was negative but 27% were found to have cancer if there was an affected 1st degree relative. It is currently recommended in many centres that PSA screening be offered to men with a family history of PC but as yet there is no consensus yet to what age the screening should begin.

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 1.9 before age 60 RR 1.4 before 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 Genetic variation may influence the rate at which prostate cancer develops pr the rate at which the cancer progresses or is metastasised. The family history is also important for interpreting a screening test of an increased level of prostate specific antigen is more likely to lead to a diagnosis of prostate cancer if there is a known family history.

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 <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 Narod et al 1995 found that the PPV of a PSA test above 3.0μg/l was higher for men with a positive family history of PC – Men with a normal rectal examination and a PSA > than 3.0, 12% were found to have cancer in the FH was negative but 27% were found to have cancer if there was an affected 1st degree relative. It is currently recommended in many centres that PSA screening be offered to men with a family history of PC but as yet there is no consensus yet to what age the screening should begin.

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 Specific genes and environmental factors involved have yet to be identified.

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 Inherited Genetic Factors CANCER Environmental

Sporadic Cancer Environmental Factors Inherited Genetic Factors CANCER

Hereditary Cancer Inherited Genetic Factors Cancer Environmental

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