Clinical Cancer Genetics

Question 1

1. What can we do to reduce cancer risk in people at increased genetic risk?

Answer 1

Screening, Prevention, Early Detection

Question 2

2. Define DNA?

Answer 2

A molecule which contains the human genetic code

Question 3

3. What is the function of genes?

How many are in the human body?

Answer 3

o The instructions to tell the body how to grow, develop and function – translated into proteins.
o ~ 20,000 genes in the human genome with 2 copies of most genes – one on each chromosome

Question 4

4. How many bases in the entire human genome

Where is the entire length of DNA contained in?

Answer 4

•The human genome (3 billion bases)

The entire length of DNA contained in human cells.

Question 5

5. Approx how many genetic changes are there between two unrelated people?

Answer 5

•We have around 5 million different genetic changes compared to another unrelated person –> Genetic Variation

Question 6

6. List some cancer statistics:
   - Lifetime risk
   - % that is sporadic, familial and high risk genes

Answer 6

• Cancer is a common disease in humans: There is a 1 in 2 lifetime risk of developing cancer.
• 65% sporadic, 25% familial and 10% high risk genes.

Question 7

7. Most cancers are sporadic , what does this mean?

Answer 7

• Most cancers are “sporadic” – due to acquired (somatic) mutations within a cell giving it a growth advantage
• Acquired mutations in cancer genes “drive” the cell to become cancerous.
• Repair mechanisms, carcinogens etc.

Question 8

8. What is an inherited cancer risk?

Answer 8

•Some genetic changes we are born with may influence our lifetime cancer risk
o	High (cancer predisposition genes), moderate and low risk changes. 
o	E.g. multifactorial breast cancer (common).

Question 9

9. What is more common :
   - High risk cancer predisposition genes
   - Low risk cancer predisposition genes?

Answer 9

• High risk cancer predisposition genes are rare.

* Low risk genetic changes are more common but only increase cancer risk by a little.

Question 10

10. How can we use GWAS to see a patients risk of developing cancer?

Answer 10

•Compare single nucleotide polymorphisms (SNPS) in cases and controls to see the likelihood of developing cancer.

Question 11

11. What is a polygenic disease?

Answer 11

A genetic disorder that is caused by the combined action of more than one gene.

Question 12

12. How does having a polygenic disease affect your risk of developing cancer?

Answer 12

•Presence of common variants shifts the normal distribution of developing cancer to the right (higher risk).

Question 13

13. For the following cancers list the associated high risk cancer predisposing gene that goes with it and the % of 
•	Breast cancer		
•	Ovarian 			
•	Colon 			
•	Melanoma			
•	Medullary thyroid		
•	Retinoblastoma		
•	Prostate			
•	Pancreatic

Answer 13

Breast cancer 5-10% BRCA

Ovarian 10% BRCA

Colon 5-10% Lynch

Melanoma 10% CDKN2A

Medullary thyroid 25% RET

Retinoblastoma 40% RB1

Prostate 5-10% BRCA2

Pancreatic 10% BRCA2

Question 14

14. What different approaches are there for assessing inherited cancer risk?

Answer 14

-> 3 generations of family history assessment
and look out for :
• Bilateral (pair of organs) cancer or multiple cancers in the same individual.
• Young age of onset e.g. breast cancer under the age of 40.
• Multiple cancer diagnoses of same type in closely related individuals (number, type and how closely related)
• Multiple cancer diagnoses of cancers related to specific CPG in closely related individuals

Question 15

15. What are certain pathological subtypes of cancers most likely to be due to?
    - Give some examples?

Answer 15

High risk CPG (cancer predisposing genes)
o High grade serous ovarian cancer: BRCA1/2
o Medullary thyroid cancer: RET
o Triple negative breast cancer: BRCA1/2
o Type 2 papillary kidney cancer: FH

Question 16

16. What kind of molecular tests would we do on a tumour?

Answer 16

sequencing shows genetic changes which could indicate inherited risk – need to check with a blood test e.g.
o Immunohistochemistry of mismatch repair genes in Lynch Syndrome.
o BRCA gene sequencing in ovarian cancer

Question 17

17. What are two syndromic features of cancer and what cancers can they be a sign on?

Answer 17

o	Trichilemmoma (skin legions – increased risk of thyroid, breast and womb cancer).
o	Musculocutaneous pigmentation (increased risk of cancer and bowel polyps).

Question 18

18. What kinds of decisions need to be made on assessment of cancer?

Answer 18

• Is there an increased inherited risk of cancer and how high is it?
• Does the patient need genetic testing to look for high risk cancer predisposition genes?
o Usually around a 1 in 10 chance of finding a mutation in a high risk cancer predisposition gene.
• Does the patient and/or their relatives need extra screening or other measures to reduce cancer risk?

Question 19

19. Where would you find the criteria that needs to be met to decide whose offered genetic testing?

Answer 19

National Genomic Test Directory

Question 20

20. What type are most cancers
    - Sporadic
    - Inherited genetic changes

Answer 20

• Most cancers are sporadic due to acquired (somatic) mutations which occur only in the cancer cell
• A smaller proportion of cancers occur due to inherited genetic changes

Question 21

21. What two types of inherited genetic changes are there?

Answer 21

o These can be multiple lower risk genetic variants – this is known as multifactorial or polygenic risk
o Or a single high risk genetic variant in a cancer predisposition gene

Question 22

22. Summarise how you would asses for an inherited cancer risk?

Answer 22

o Take a 3 generational family history:
– Ages, types of cancer and number of affected relatives.
– Ethnic origin – higher rate of CPG in some populations.
o Consider the types of cancer in detail to see if they increase the chance of a high risk cancer predisposition gene (CPG).
o Look for any rare syndromic features which could indicate a high risk cancer predisposition gene.
o Use the National Genomic Test Directory Eligibility Criteria to decide if genetic testing is indicated.

Question 23

23. In multifactorial or polygenic cancers, what % chance is there of CPG or gene testing being negative?

Answer 23

<10% chance of CPG or gene testing is negative

Question 24

24. How can we manage inherited cancer risk?

Answer 24

•Offer screening, prevention and early detection advice (SPED) – use algorithms to work out who has moderate risk (mammograms every 3 years) and who has high risk (annual mammograms) to decide how they are screened.

Question 25

25. How does chemoprevention work? | - What is an disadvantage

Answer 25

o Taking a medication to reduce cancer risk e.g. tamoxifen/SERM for breast cancer or aspirin for colorectal cancer. Disad = May have side effects on quality of life

Question 26

26. What are some considerations that need to thought about when doing a genetic test for High risk CPGs?

Answer 26

Implications for individual: Recurrence risks or Risks of other cancers o Implications for relatives – How to share information – Concerns about children – Family planning options (e.g. prenatal, PGD)

Question 27

27. What is the difference between diagnostic AND predictive testing?

Answer 27

* Diagnostic testing: To confirm whether a CPG has caused the cancer. * Predictive testing: To identify if an unaffected person carries a CPG

Question 28

28. Does healthcare insurance cover predictive testing?

Answer 28

Current moratorium (ban) for predictive testing

Question 29

29. What is the next steps if no genetic variants are identified in tests (most likely outcome, 90% of cases)?

Answer 29

o Screening and management on personal and family history o Referral for screening/further management only if indicated on above assessment o Reassuring for patient but reiterate participation in population screening programmes

Question 30

30. What is the next steps if a disease causing variant in a CPG is found (rare-10% of cases)

Answer 30

o Screening and management tailored to specific CPG | o Should be reviewed by NHS clinical genetics service

Question 31

31. What should be the next steps if the outcome of genetic testing is that a variant of uncertain significance (VUS) is found?

Answer 31

o Benign until proven guilty o Referral for screening/further management only if indicated on above assessment o May be anxiety provoking for patient - Need to understand how common genetic variation is

Question 32

32. For both SPORADIC and HEREDITARY cancers, what is the likelihood of getting other cancers or recurrence of that cancer?

Answer 32

Hereditary : -High risks of recurrence/other associated cancers Sporadic: -No increased risk of other cancers

Question 33

33. For both SPORADIC and HEREDITARY cancer what is the risk of cancers in relative?

Answer 33

Hereditary : -High cancer risks in relatives Sporadic: -Usually small increased risk of cancer in relatives

Question 34

34 . For both SPORADIC and HEREDITARY cancer, what type (if any) genetic testing takes place

Answer 34

Hereditary: Offer testing to at risk individuals and screening/preventative management to gene carriers. Sporadic: No genetic testing indicated.

Question 35

35. For both SPORADIC and HEREDITARY what differences would there be in treatment / clinical management is there?

Answer 35

Hereditary: •May have alter treatment of affected individuals. Sporadic: •Normal clinical management for affected individuals.

Question 36

36. Compare somatic and germline mutations?

Answer 36

Somatic : - occur in nongermline tissue - Cannot be inherited - Mutation in tumour (eg breast ) Germline: - Present in egg and sperm - Can be inherited - Cause cancer family syndrome - Mutation in egg or sperm --> All cells affected in the offspring

Question 37

37. What type of cancer is breast cancer associated with?

Answer 37

Ovarian cancer

Question 38

38. When there is a mutation in the BRCA1 gene, what risks are there in UNAFFECTED carriers? Give the chance % of getting that cancer

Answer 38

1. Breast Cancer (lifetime risk to 80yrs) 60-90% chance 2. Ovarian Cancer (lifetime risk: mainly after 40) 40-60% 3. Male Breast Cancer (lifetime risk) 0.1-1.% 4.Prostate Cancer (Lifetime risk similar to population risk) 8%

Question 39

39. When there is a mutation in the BRCA1 gene, what risks are there in AFFECTED carriers? Give the chance % of getting that cancer

Answer 39

1. Women with unilateral breast cancer (lifetime risk of contralateral breast cancer) -50% Overall 5 year risk - 10%

Question 40

40. When there is a mutation in the BRCA2 gene, what risks are there in UNAFFECTED carriers? Give the chance % of getting that cancer

Answer 40

1. Breast Cancer (lifetime risk to 80yrs) 45-85% chance 2. Ovarian Cancer (lifetime risk, mainly after 50) 10-30% 3. Male Breast Cancer (lifetime risk) 5-10% 4.Prostate Cancer (Lifetime risk ) 25%

Question 41

41. When there is a mutation in the BRCA2 gene, what risks are there in AFFECTED carriers? Give the chance % of getting that cancer

Answer 41

1. Women with unilateral breast cancer (lifetime risk of contralateral breast cancer) -50% Overall 5 year risk - 5-10%

Question 42

42. What kind of surveillance is needed for - Breast Cancer - Ovarian Cancer - Other Cancers

Answer 42

Breast: - Advise on breast awareness - Annual mammography from 40-70 - Annual MRI from 30-50 - No breast surveillance for male carriers Ovary: -Ovarian Surveillance is not recommended Other Cancers: - No surveillance is recommended for other cancers - Carrier might be used for research

Question 43

43. Is Chemoprevention suitable for BRAC1 or BRAC2 mutation carriers?

Answer 43

BRAC1 carriers: -Not suitable BRACA2: - Discuss benefits and side effects - Can be offered if no contra-indications

Question 44

44. What risk reducing surgery can be done to reduce breast cancer?

Answer 44

- Bilateral risk-reducing mastectomy | - Breast cancer risk reduction 90-95%

Question 45

44. What risk reducing surgery can be done to reduce ovarian cancer as well as breast cancer what are some side effects what is a medicine alternative?

Answer 45

- Bilateral salpingo-oophorectomy (remove ovary and fallopian tubes) once childbearing is complete - Reduces risk of ovarian cancer by 95% - Reduces risk of breast cancer by 50% - Side effect : premature menopause - HRT should be offered to women until 50 in women who have not had ER positive breast cancer

Question 46

46. The management of cancer depends on the risk level : | - What kind of management would you need for moderate - high risk?

Answer 46

– Screening and early detection mainstay of management and chemoprevention as risk increases

Question 47

47. The management of cancer depends on the risk level : | - What kind of management would you need for high risk cancer predisposition genes?

Answer 47

– Gene specific guidelines: Screening, Chemoprevention and Surgical management