Supporting Genetics Education for Health Genetics – What do Cancer Nurses need to know? On-Line...

Supporting Genetics Education for Healthwww.geneticseducation.nhs.uk

Genetics – What do Cancer Nurses need to know?

On-Line lecture Feb 2009


• Cancer develops because of a complex mix of environmental and genetic factors.

• For some:-– Environmental factors

pose the greatest risk

• For others:-– It is inherited

susceptibility

• For most:-– Combination of all the

above.

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Enhancing patient care by integrating genetics in clinical practiceThe UK Workforce Competences for Genetics in Clinical Practice

for Non-Genetics Healthcare Staff

• Not all of the competences will be applicable to every role

• May be useful in:• developing services• provision/guidance of

training and education


The Genetic Competences

1. Identify where genetics is relevant in your area of practice

2. Identify individuals with or at risk of genetic conditions

3. Gather multi-generational family history information

4. Use multi-generational family history information to draw a pedigree

5. Recognise a mode of inheritance in a family

6. Assess genetic risk

7. Refer individuals to specialist sources of assistance

8. Order a genetic laboratory test

9.Communicate genetic information to individuals, families and healthcare staff


Half of the population have had a 1st or 2nd degree relative diagnosed with cancer


1st degree

(parents, siblings,

children)



2nd degree

(grandparents,

aunts, uncles,

nieces, nephews)



2nd degree

(grandparents,

aunts, uncles,

nieces, nephews)

Only 5% - 10% will have an inherited genetic factor



Cancers Arise From Gene Mutations

in genes protecting against cancer

tumour


All cancer is genetic

BUT

not all cancer is inherited!


• Somatic mutation– Localised to a specific tissue

– Not in germline tissues– Not inherited

Most Cancers Arise From Somatic Mutations

breast

or

bowel


Knudson’s ‘Two-Hit Hypothesis’

(Somatic Mutation)

Second hit

First hit

tumour


• Germline mutation– In egg or sperm– May be passed on

(inherited)– All cells in offspring carry

the mutation

5-10% of Cancers Arise From Germline Mutations

Parent

Child


Knudson’s ‘Two-Hit Hypothesis’

(Germline Mutation)

Second hit is

somatic

tumour

First hit is in germline


What is a gene?

• A sequence of DNA

• An instruction to build a protein

for a specific purpose - structural or functional


DNA

T A

C G


DNA Proteins Bodycodes for

that make

up the


ATAAATGTATGAATACTCCATTTTTCTATTATCCTATATGGCCCCAGGTGTAATTGTATAGTATCTCTTTTTACTGTTAAATGCTGCAATAAGACTCACATGCAAAAAGCTGTATCTCTAAGCACTTAATAATTTGTTTCCCCAGGAGAGTGATTCGATGATGGTGGATCCAACCAATGACATCCGGATTATAGGCTCCATCACAGTGGTGATTCTTCTAGGAATTTCAGTAGCTGGAATGGAATGGGAGGCAAAGGTAAATTTCTCAAAAATGATATTATCAACAGTGGCTGGTCAGGTCCTGAACAAATTGCAGGAGTAGAGGGAACTCCATATTCAAAAGGAATTGCTGTTATTACCTGCTATGGTGAAATGAGCAGGCAAGTGCTAGGTGGAACACCAAGCCTGCAAAGCACGAAGCCCAGGCAGTCATGATTCAGGGCTCACGAGTCACATGACTGCCGTATTTTGTCTCTCTGTGCTGTCACCAAGGCGGCTGCCTTATGCACAGACCCCTTATGATCATAGCAGTGGTGCACGCTGGAAGCCTGGGTCTCTCAATCACAAACCCTGGTTCCTCTTTCAAGCTGCCTGTGGGTGCAAAAGCCCAAGAGAAATGGCAAGTGTGTTGAGAACATAAGAGAGGCAAAAACTATCATTCTCATCTGAAAGCCAGTACTTCACCAGCAAATTTAGGCACATCATAGGCTTTAGAACCAGAAAATCTCTGAGTTTAACTAGTGATAAAATGGATAGTAAATTTCCGAATGATGGGAAACATGTCTTTTGCCTCCTTTGTAATTCCCTCAAGTGACTGGTGCAATTGAAAATATTCCTACGAGCCTGTGGATGAAGTAACTAGATCTCAAGCAGTCATGAGATGTGGAAAGACAGCCAAAGCCTCCCACCTATAAGTCAATAGAAAACATTCCTACATGGCATTTATTTGTAGATTATGCATTCACACATTCAACAAAAATTAAGTTAGTGCCTACCACATGTTGAGCATTCTTCTAGGCACTGATATTCACCTGTGACCAAAACAGGCCTAATCCCTATATATGGTCTATGAAGAGATCAATAATAAGCAAGCAAATAAAGAAATAAATATAAAAAGAGAATTTGTGAAAATTAGTATCAACAGGACACTGTGATGAAAAAACACAGAACCCTACTTTAGATAACTTTATTCCCTGAGTGAGGCAATGAAGTTTAGTTAGCAGTAGAGGGTAGCATTTAAAGCTCCAGCTCTGTAGTTAGAGTGCCTGAATTTGAATCCAGCTTATATCTCTGCAGCCTTTAGTAAATTATTTAACCTCTCGGTGCTTCAGTGTCTTTACCTTTAAAATGAGGATAATAATATTGCCTACTCCATAAGGTTGTCAGTTTGTTGGTGGTATTATTTACCTAAAAGAATGCAGGGAAAGTAAATCTGCAACTGCTCTATTGTAAGCCCTCAGTGAACAGATAGCTGTTATTATTTAAATGGGCCAGGCACGGTGGCACATACCTGTAATCCCAGCACTTTGGGAGGCTGAGGCGGGCAGATCACGAGGTCAGGAGTTCGAGGCCAGCCTGGCCAACATGGTCAAACCCTGTCTCTATTAAAAATATAAAATTAGCCAGGGTGGCGTATGCCTGTAATCCCAGCTACTCAGGAGGCTGAGGCAGGAGAATTGCTTGAACCCAGGAGGTGGAGGTTGCAGTGAGCCGAGATCGTGCCATTGCATTCCAGCCTGGGCGACAGAGTGAGACTCCATCTTGGGAAAACAAAATAAAATAAAAAAACATAAAAGATTAAATTTTCAAGAAAGGCCCTCTGAGGAGGTAACTAAGACTTAAAGGATGAAAAGAAGGAAATAGCTATGCAAGAAGTAGAGTGAAGTGCTTTCCAGGTAAAGGAAACAGCATATGGCAACACCAAGCCATAAACACCTTGCAGCATTGGAGGGGCTGAAGGAAGACCATCTGACCAGTCAACTTTGCAGACTGCTTGTGCTGAGCACACAGCGGCAGCCTGACGTCAAGTGCACTGGGAATCACAGGAATTGTATTCATCATTCTGCATTCTCGAACTGCTGCAGTTAGCACTGGGAACAGAAACAACCCATAAGTGCTCTGCTGAAAACAAACAAACAAAACCCCCCTCAAGTTTATCAGTGTTAAAACTTTTGGCTTCCTTTACATTCCTGGGACAATGGTGGAAGTTACCCATCTGCTACTTAGAATGTTACAGAAAT


Did you know?

The vast majority of DNA in the human genome - 97% - has no known function

There are 3 billion (3,000,000,000) letters in the DNA code in every cell in your body

Our DNA is 98% identical to chimpanzees!


Did you know?




And many other animals and insects!


I suppose you realise that if my DNA had been in a different order,

I could have been a brain surgeon!!


Did you know?

Between humans, our DNA differs by only 0.2%.





DNA Proteins Body

Gene = sequence of DNA

one gene one proteincodes for

Thus, as there are ~30,000 genes our body must consist

of around 30,000 proteins


• Proteins are a string of amino acids

• Can be of any length and combination

• This will differ according to their structure and function

Genetic Code


The Genetic Code

(NB – U is substituted for T)


What might go wrong with a gene?

What goes ‘right’ with a gene?!


ATAAATGTATGAATACTCCATTTTTCTATTATCCTATATGGCCCCAGGTGTAATTGTATAGTATCTCTTTTTACTGTTAAATGCTGCAATAAGACTCACATGCAAAAAGCTGTATCTCTAAGCACTTAATAATTTGTTTCCCCAGGAGAGTGATTCGATGATGGTGGATCCAACCAATGACATCCGGATTATAGGCTCCATCACAGTGGTGATTCTTCTAGGAATTTCAGTAGCTGGAATGGAATGGGAGGCAAAGGTAAATTTCTCAAAAATGATATTATCAACAGTGGCTGGTCAGGTCCTGAACAAATTGCAGGAGTAGAGGGAACTCCATATTCAAAAGGAATTGCTGTTATTACCTGCTATGGTGAAATGAGCAGGCAAGTGCTAGGTGGAACACCAAGCCTGCAAAGCACGAAGCCCAGGCAGTCATGATTCAGGGCTCACGAGTCACATGACTGCCGTATTTTGTCTCTCTGTGCTGTCACCAAGGCGGCTGCCTTATGCACAGACCCCTTATGATCATAGCAGTGGTGCACGCTGGAAGCCTGGGTCTCTCAATCACAAACCCTGGTTCCTCTTTCAAGCTGCCTGTGGGTGCAAAAGCCCAAGAGAAATGGCAAGTGTGTTGAGAACATAAGAGAGGCAAAAACTATCATTCTCATCTGAAAGCCAGTACTTCACCAGCAAATTTAGGCACATCATAGGCTTTAGAACCAGAAAATCTCTGAGTTTAACTAGTGATAAAATGGATAGTAAATTTCCGAATGATGGGAAACATGTCTTTTGCCTCCTTTGTAATTCCCTCAAGTGACTGGTGCAATTGAAAATATTCCTACGAGCCTGTGGATGAAGTAACTAGATCTCAAGCAGTCATGAGATGTGGAAAGACAGCCAAAGCCTCCCACCTATAAGTCAATAGAAAACATTCCTACATGGCATTTATTTGTAGATTATGCATTCACACATTCAACAAAAATTAAGTTAGTGCCTACCACATGTTGAGCATTCTTCTCGGCACTGATATGGACCTGTGACCAAAACAGGCCTAATCCCTATATATGGTCTATGAAGAGATCAATAATAAGCAAGCAAATAAAGAAATAAATATAAAAAGAGAATTTGTGAAAATTAGTATCAACAGGACACTGTGATGAAAAAACACAGAACCCTACTTTAGATAACTTTATTCCCTGAGTGAGGCAATGAAGTTTAGTTAGCAGTAGAGGGTAGCATTTAAAGCTCCAGCTCTGTAGTTAGAGTGCCTGAATTTGAATCCAGCTTATATCTCTGCAGCCTTTAGTAAATTATTTAACCTCTCGGTGCTTCAGTGTCTTTACCTTTAAAATGAGGATAATAATATTGCCTACTCCATAAGGTTGTCAGTTTGTTGGTGGTATTATTTACCTAAAAGAATGCAGGGAAAGTAAATCTGCAACTGCTCTATTGTAAGCCCTCAGTGAACAGATAGCTGTTATTATTTAAATGGGCCAGGCACGGTGGCACATACCTGTAATCCCAGCACTTTGGGAGGCTGAGGCGGGCAGATCACGAGGTCAGGAGTTCGAGGCCAGCCTGGCCAACATGGTCAAACCCTGTCTCTATTAAAAATATAAAATTAGCCAGGGTGGCGTATGCCTGTAATCCCAGCTACTCAGGAGGCTGAGGCAGGAGAATTGCTTGAACCCAGGAGGTGGAGGTTGCAGTGAGCCGAGATCGTGCCATTGCATTCCAGCCTGGGCGACAGAGTGAGACTCCATCTTGGGAAAACAAAATAAAATAAAAAAACATAAAAGATTAAATTTTCAAGAAAGGCCCTCTGAGGAGGTAACTAAGACTTAAAGGATGAAAAGAAGGAAATAGCTATGCAAGAAGTAGAGTGAAGTGCTTTCCAGGTAAAGGAAACAGCATATGGCAACACCAAGCCATAAACACCTTGCAGCATTGGAGGGGCTGAAGGAAGACCATCTGACCAGTCAACTTTGCAGACTGCTTGTGCTGAGCACACAGCGGCAGCCTGACGTCAAGTGCACTGGGAATCACAGGAATTGTATTCATCATTCTGCATTCTCGAACTGCTGCAGTTAGCACTGGGAACAGAAACAACCCATAAGTGCTCTGCTGAAAACAAACAAACAAAACCCCCCTCAAGTTTATCAGTGTTAAAACTTTTGGCTTCCTTTACATTCCTGGGACAATGGTGGAAGTTACCCATCTGCTACTTAGAATGTTACAGAAAT

TTCTCGGCACTGATATGGACC


The genetic code is ‘read’ in 3-letter words…



TTC TCG GCA CTG ATA TGG ACC

Phe - Ser - Ala - Leu - Iso - Trp - Thr


How are genes copied?

now have two strands from one


Replication Fork

CTG CAC GTC TAC GAC GTG CAG ATG

ACT TGG

TGA ACC

T


Replication Fork


ACT TGG

TGA ACC

TG


Replication Fork


ACT TGG

TGA ACC

TGA


Replication Fork


ACT TGG

TGA ACC

TGA ACC

ACT TGG


However:

sometimes a natural variation in DNA sequence occurs due to mistakes made in copying the DNA…




Phe - Ser - Ala - Leu - Iso - Trp - Thr


TTCTCGGCGCTGATATGGACC

TTC TCG GCG CTG ATA TGG ACC

Phe – Ser – Ala – Leu – Iso – Trp - Thr

‘Silent’ mutation


TTCTCGGAGCTGATATGGACC

TTC TCG GAG CTG ATA TGG ACC

Phe – Ser – Glu – Leu – Iso – Trp - Thr

‘Missense’ mutation


TTCTCGGAGCTGATATGAACC

TTC TCG GAG CTG ATA TGA ACC

Phe – Ser – Glu – Leu – Iso – Stop

‘Nonsense’ mutation




Phe - Arg - His - Stop

TTC CGG CAC TGA TAT CGA CCT

‘Frameshift’ mutation


Gene Mutations

• Only significant if they occur in ‘important’ part of gene

• Disrupt or remove function of protein thereby leading to disorder

• Nonsense and frameshift mutations likely to be most ‘severe’ though not necessarily


Gene mutations and inherited cancer


Examples of hereditary cancer genes

1p35 SDHA/B/C Phaechromocytoma/Paraganglioma2p16 MSH2 HNPCC2p16 MSH6 HNPCC 3p21 MLH1 HNPCC3p25 VHL von Hippel-Lindau5q21 APC Colon polyposis7p22 PMS2 HNPCC9p21 P16 (CDKN2) Melanoma/pancreatic 10q22 PTEN Cowdens syndrome10q11 RET MEN211q13 MEN1 MEN113q12 BRCA2 HBOC 13q14 RB1 Retinoblastoma16q22.1 CDH1 Gastric cancer17p13 TP53 Li-Fraumeni17q21 BRCA1 HBOC


The Cell Cycle

M M (mitosis)(mitosis)

GG11

(cell (cell growth)growth)

REPAIRS AHEAD

S (synthesis)S (synthesis)

G0 (resting)

Oncogenes

Tumor suppressor genes

GG22

DNA repairgenes


Multi-Step Carcinogenesis (eg, Colon Cancer)

Normal epithelium

Hyper-proliferativeepithelium

Earlyadenoma

Lateadenoma

Carcinoma Metastasis

Loss ofLoss ofAPCAPC

ActivationActivationof of K-rasK-ras

Loss ofLoss of18q18q

Loss ofLoss ofTP53TP53

Other Other alterationsalterations

Adapted from Fearon ER. Adapted from Fearon ER. CellCell 61:759, 1990 61:759, 1990

Inter-mediate

adenoma

ASCO


Genes Associated With Cancer

1. Tumor suppressor genes: the cell’s brakes for tumor growth

Normal genes (prevent cancer)


Tumor Suppressor Genes

1st mutation(susceptible carrier)

2nd mutation or loss (leads to cancer)



2. Oncogenes: accelerate cell division

Normal genes (regulate cell growth)


Oncogenes

1 mutation sufficient for role in cancer development

1st mutation(leads to accelerated

cell division)



3. DNA damage-response genes: the repair mechanics for DNA

A G C T GA G C T G

TT CCTT AA CCT C G A CT C G A C

A G C T GA G C T G

Base pair mismatch

Normal DNA repair


DNA damage-response genes:

A G C T GA G C T G

TT CCTT AA CC Base pair mismatch

Mutation introduced by

unrepaired DNA

T C T C TT A C A C

A G A G AA T GT G


How are cancer predispositions inherited?


Etiology of Breast Cancer

Sporadic75%

Familial20%

Hereditary5%


Hereditary Breast Cancer (high risk)

• ~5% of all Breast Cancers• Monogenetic disorder• Autosomal dominant inheritance• High penetrance• Early onset• Cancer syndrome (other cancers also)• BRCA1+2 only known genes of major

importance


Parents

Gametes

AUTOSOMAL DOMINANT INHERITANCE

egg/sperm


Parents

Gametes

Offspring



Parents

Gametes

Offspring


Affected Unaffected


Autosomal Dominant Inheritance

Each child has 50% chance of inheriting the mutation

Equally likely to affect males and females

No “skipped generations”

Equally transmitted by men and women Affected

Normal


Penetrance

• The proportion of individuals with the gene fault that show signs of the condition

• Most cancer susceptibility genes are dominant with ‘incomplete penetrance’


Penetrance


80% Penetrance (approx BRCA1 female breast cancer risk)


6% Penetrance (approx BRCA2 male breast cancer risk)


May appear to “skip” generations Individuals inherit altered cancer susceptibility gene -

not cancer

Normal

Carrier, affected with cancer

Susceptible Carrier

Penetrance


Factors Affecting Penetrance

Modifier genes Carcinogens

Not everyone with an altered gene develops cancer

Response to DNA damage

Hormonal/ reproductive

factors


Age-Specific Penetrance

HNPCC mutation carriers

General population

Modified from Aarnio M et al. Modified from Aarnio M et al. Int J CancerInt J Cancer 64:430, 1995 64:430, 1995

00 2020 4040 6060 808000

2020

4040

6060

8080

100100

Affected with colorectal

cancer (%)

Age in years


High Risk Indicators

• Multiple family members with tumours at same site

• Early age of onset• History of individuals with multiple

primary tumours• Recognised associations:

– Breast/ovary– Bowel/Endometrium– etc.


Breast Cancer

36

45

30 31

34


NICE - familial breast cancerMammographic surveillance

High risk:

30-40 individualised strategies– Mammography or MRI?

40-50 annual

50+ individualised strategies


FAP

d 34

d 40


Genetics of FAP

• Caused by mutations in APC gene (found on chromosome 5)

• ~30% occur as the result of new mutations

• Correlation between position of mutation &:– Severity of effect– Presence of CHRPEs and desmoids


FAP: Key Points

• CRC risk is 100% in untreated FAP patients

• Genetic testing identifies most APC mutation carriers

• Endoscopic surveillance and prophylactic colectomy can improve survival in at-risk patients

• Non-carriers can be spared anxiety and the need for increased surveillance


Family History is the key to diagnosing HNPCC

CRCdx 50s

CRCdx 45

CRCdx 61

CRCdx 75

OvarianCa, dx

64

CRCdx 48

CRCdx 52

EndometrialCa, dx 59

CRCdx 42

45


Genetic Features of HNPCC

• Autosomal dominant inheritance• Penetrance ~80%• Genes belong to DNA mismatch repair

family • A number of genes involved (MLH1, MSH2, MSH6, PMS1, PMS2)


Amsterdam Criteria 3 or more relatives with CRC One case a 1o degree relative of the

others Two or more generations One CRC by age 50 FAP excluded

Modified Amsterdam criteria: An endometrial cancer can be substituted for one of the CRC


Taking a Pedigree


Drawing up the family tree gives information about the relatives and also:

• helps establish the family agenda and dynamics

• may reveal individuals interpretation and beliefs about what is happening in the family

•Has the potential to raise issues of paternity


Peter Jones28.4.1884d 23.09.1974

Edith 17.10.1887 3.7.1965

Herbert Jones 29.9.14 d. 8.6.03

Gertrude 24.11.20

88

68

Joyce Jones 22.9.46

Stephen Jones 12.10.42 30.4.86

Catherine 12.2.46

Paul Jones 7.4.70

Sarah Barclay 5.5.73

Ann Brown 29.9.48

Thomas Phillips 10.9.07

Mary 3.1.10

17.6.63

42

Emma 30.9.73

Kieran 11.4.95

Katie 7.2.70

Bob Peters 27.7.45

Sally 28.4.47

Key:

Ca lung

Ca colon


Start with the couple being seen

Use clear symbols: circles for females, squares for males

Add in their children

Record names, dates of birth

Emma 30.9.73

Paul Jones 7.4.70

The horizontal line denotes a relationship (males usually on the left, females on right)

Kieran 11.4.95

The vertical line denotes offspring of the relationship

“Have you had any children with other partners?”


Paul Jones 7.4.70

Emma 30.9.73

Kieran 11.4.95

Choose one parent and ask about: brothers and sister and their children

parents and grandparents

Make sure you ask about ethnicity


Colour in the symbol if the

personis affected

Joyce Jones 22.9.46

Paul Jones 7.4.70


Catherine 12.2.46


Ann Brown 29.9.48

42

Emma 30.9.73

Kieran 11.4.95

Put a sloping line through the symbol(from the bottom left hand corner) if the person has died

Add the age at which diagnosis was made


Joyce Jones 22.9.46

Paul Jones 7.4.70


Catherine 12.2.46


Ann Brown 29.9.48


Mary 3.1.10

17.6.63

42

Emma 30.9.73

Kieran 11.4.95


Peter Jones28.4.1884d 23.09.1974

Edith 17.10.1887 3.7.1965


Gertrude 24.11.20

68

Joyce Jones 22.9.46

Paul Jones 7.4.70


Catherine 12.2.46


Ann Brown 29.9.48


Mary 3.1.10

17.6.63

42

Emma 30.9.73

Kieran 11.4.95

Key:

Ca lung

Ca colon

Use a key if more than one form of cancer

88


Peter Jones28.4.1884d 23.09.1974

Edith 17.10.1887 3.7.1965


Gertrude 24.11.20

88

68

Joyce Jones 22.9.46


Catherine 12.2.46

Paul Jones 7.4.70


Ann Brown 29.9.48


Mary 3.1.10

17.6.63

42

Emma 30.9.73

Kieran 11.4.95

Add information on the

other side of the family


Peter Jones28.4.1884d 23.09.1974

Edith 17.10.1887 3.7.1965


Gertrude 24.11.20

88

68

Joyce Jones 22.9.46


Catherine 12.2.46

Paul Jones 7.4.70


Ann Brown 29.9.48


Mary 3.1.10

17.6.63

42

Emma 30.9.73

Kieran 11.4.95

Katie 7.2.70

Bob Peters 27.7.45

Sally 28.4.47


Other pedigree symbols

4 unaffectedpersons whosesex is unknown

consanguineous

Double line joinsunion of

couple 4

no offspring

P

identical;non-identicalTwins:

pregnantdouble line indicates that relationship has ended


Drawing a pedigree

Pedigree Template-One of the resources available from the NHS National Genetics Education and Development Centre


In summary…

00 2020 4040 6060 8080002020404060608080

100100


www.geneticseducation.nhs.uk

- Existing resources

- Resources developed by the Centre

Resource database

Searchable- Search all

- Linked to educational outcomes

Evaluated

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