Cancer Genetics

Diane StirlingMcMillan Nurse Specialist in GeneticsWestern General HospitalEdinburgh

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

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

Cell Cycle Control

GATEKEEPERS Oncogenes (proto-oncogenes)

o positive effect on growth and proliferation

Tumour Suppressorso 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

Tumour Suppressor genesDNA Repair

Environmental MutagensActivated OncogenesLoss of Tumour Supressor genesLoss of DNA Repair

Cancer - A multi step process

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 Li- Fraumeni syndromeo Von Hippel-Lindauo Tuberous Sclerosiso Retinoblastomao 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

Cancer

Inherited Change

FIRST HIT

Acquired Change

SECOND HIT

Acquired Change

SECOND HIT

Acquired Change

FIRST HIT

No Change

CANCER

Inherited Sporadic

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

Breast cancerBreast cancer

Ovarian cancerOvarian cancer

Hereditary Breast/Ovarian Cancer

26

35

31

48

58

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 – more than 5 times population risk

Moderate –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 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 1.9before age 60 RR 1.4before 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

CRC/BPG UK Familial Prostate Cancer Study

I. Multiple-case prostate cancer families with 3 or more cases at any age

II. Affected blood-related pairs where one is <65 years old at diagnosis

III. 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/H27% 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 1995Families 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 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

CANCERInheritedGeneticFactors

EnvironmentalFactors

Sporadic Cancer

CANCEREnvironmental

FactorsInheritedGeneticFactors

Hereditary Cancer

Cancer

InheritedGeneticFactors

EnvironmentalFactors