Clinical Cancer Genetics

Question 1

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

Answer 1

Putting people in screening programmes to:

• prevent the cancer
• detect it early

Question 2

What makes individuals different from one another?

Answer 2

Genetic variation

-may influence our chance of developing disease

Question 3

Prevalence of cancer

Answer 3

Common disease:

-1 in 2 lifetime risk of developing cancer

Question 4

Genetic Predisposition to Cancer

Answer 4

2/3rds of cancers are “sporadic”

1/3rd of cancers are genetic (inherited)

• a small proportion (~5-10%) are due to a single high risk genetic change in a cancer predisposition gene
• larger proportion due to the inheritance of multiple lower risk factors (familial)

Question 5

Sporadic cancer arises from

Answer 5

acquired somatic mutations in cancer genes which “drive” the cell to become cancer
-NOT inherited changes

Question 6

Inherited cancer arises from

Answer 6

genetic changes we are born with which increase the risk of developing cancer:

High Risk Changes
-cancer predisposition genes (very rare)

Moderate Risk Changes

Low Risk Changes

• more common
• e.g. SNPs/common variants

Question 7

High Risk Genetic Changes: cancer predisposition genes

Answer 7

very rare in the population, but if you have one, you have a really high chance of developing cancer in your lifetime

Question 8

Low Risk Genetic Changes

Answer 8

More common in the population. Having one low risk genetic change only increases risk of cancer by a small amount, but if you have many of them, they all add up and the risk increases (multifactorial/polygenic)
-e.g. SNPs/common variants

Question 9

What does clustering of the same types of cancer in a family indicate?

Answer 9

Increased multifactorial risk of cancer (polygenic):

• SNPs more common in cases than in controls
• With these common variants your risk of developing cancer is pushed from the normal distribution
• Cases are on average at a higher prior risk of developing cancer than the normal population

Question 10

What affects the likelihood of the cancer being due to a high risk cancer predisposition gene?

Answer 10

How likely you are to have a high-risk cancer predisposition gene depends on the type of cancer

Question 11

Why identify patients with increased genetic predisposition to cancer?

Answer 11

• provides reason for why developed cancer
• Informs medical management and surgical options
• Informs patient about future cancer risks
• Informs relatives about cancer risk - access to screening/ risk reducing surgery

Question 12

How do we assess inherited cancer risk?

Answer 12

• Take 3 generational family history
• Consider types of cancer to see if they increase chance of a high risk CPG
• Assess pathology
• Molecular testing
• Look for rare syndromic features which could indicate high risk CPG
• Use National Genomic Test Directory Eligibility Criteria to decide if genetic testing is indicated

Question 13

Assessing inherited cancer risk: Family history assessment

Answer 13

Take 3 generation family history

• number of affected relatives
• age at which they got cancer (e.g. breast cancer rare under 40)
• types of cancer (e.g. whether there has been multiple cancer diagnoses of the same type in closely related individuals)
• ethnic origin- higher rate of CPG in some populations
• look at certain patterns for high risk CPG (e.g. breast and ovarian usually together in families)

Question 14

Assessing inherited cancer risk: Pathology

Answer 14

Certain pathological subtypes of cancer are more likely to be due to high risk CPGs e.g.:

• High grade serous ovarian cancer (BRCA1/2)
• Medullary thyroid cancer (RET)
• Triple negative breast cancer (BRCA1/2)
• Type 2 papillary kidney cancer (FH)

Question 15

Assessing inherited cancer risk: Molecular Testing

Answer 15

Tumour testing may identify genetic changes which could indicate inherited risk.

Need to check with a blood test:

• immunohistochemistry of mismatch repair genes in Lynch syndrome
• BRCA gene sequencing in ovarian cancer

Question 16

Assessing inherited cancer risk: Syndromic Features

Answer 16

Trichilemmoma:
-specific skin lesion strongly associated with mutations in PTEN gene, which causes Cowden syndrome, which increases risk of thyroid, breast and womb cancer

Mucocutaenous Pigmentation :

• mutation in STK11 gene causing Peutz-Jeghers syndrome, which is associated with increased risk of breast cancer and bowel polyps
• indicates an inherited cause for a person’s cancer

Question 17

Assessing inherited cancer risk: National Genomic Test Directory

Answer 17

The national genomic test directory tells you who you are allowed to offer a gene test to. This gives you a list of criteria of the number of people in a family or the type of cancer you would need to have to be offered genetic testing to look for a high-risk cancer gene.

Question 18

Decisions to make on assessment of inherited cancer

Answer 18

· Is there an increased inherited risk of cancer?

· How high is the risk?

· Does the patient need genetic testing to look for high risk cancer predisposition genes?
-usually around a 1 in 10 chance of finding a mutation in a high risk CPG

· Does the patient and/or their relatives need extra screening or other measures to reduce cancer risk?

Question 19

Management of inherited cancer risk

Answer 19

SPED:

• offer screening, prevention and early detection advice

Question 20

Prevalence of breast cancer

Answer 20

Because breast cancer is very common (1 in 8 women), it is not unusual to see multiple cases of breast cancer at older ages (after 40) within a family. This would be a classic multifactorial/polygenic risk pattern. Not indicative of high risk gene predisposition because the people are a bit older and there are no other associated cancer types.

However, an unaffected person should be offered extra screening because they’ve got multiple other relatives who have had breast cancer.

Question 21

How do we work out what screening women should get for breast cancer?

Answer 21

An algorithm is used to work out exactly what screening people should get:

Green Category (17-30% lifetime risk of breast)

• start annual mammograms at age of 40 until they are 49
• then a mammogram every 3 years

Yellow Category (>30% and deemed high risk of developing cancer)

• annual mammograms between 40 and 59
• then a mammogram every 3 years

Question 22

Prevention of breast cancer in higher risk women

Answer 22

Chemoprevention

Question 23

What is chemoprevention?

Answer 23

Chemoprevention:

• Taking a medication to reduce breast cancer risk
• Breast cancer: tamoxifen/SERM (selective oestrogen reuptake modulator)
• Colorectal cancer: aspirin

Question 24

Analysing family tree including multiple breast cancers

Answer 24

This family tree calls for more worrying because of the amount of breast cancer, the ages and the fact that it is linked with ovarian cancer.

This all points to high risk cancer predisposition genes (CPGs), and therefore genetic testing is done (e.g. BRCA testing).

Implications for individual if high risk CPG found:

• Recurrence risks
• Risks of other cancers

Implications for relatives if high risk CPG found:

• How to share information
• Concerns about children
• Family planning options (E.g. prenatal, PGD)

Question 25

Implications for individual if a high risk CPG was found

Answer 25

- Recurrence risks | - Risks of other cancers

Question 26

Implications for relatives if a high risk CPG was found

Answer 26

- How to share information - Concerns about children - Family planning options (E.g. prenatal, PGD)

Question 27

Testing for high risk CPGs

Answer 27

Diagnostic Testing - to confirm whether a CPG has caused the cancer - patient already has the cancer Predictive Testing - to identify if an unaffected person carries a CPG - insurance implications (current moratorium for predictive testing)

Question 28

Testing for high risk CPGs

Answer 28

Diagnostic Testing - to confirm whether a CPG has caused the cancer - patient already has the cancer Predictive Testing - to identify if an unaffected person carries a CPG - insurance implications (current moratorium for predictive testing)

Question 29

Outcomes of Testing for CPG

Answer 29

1) No genetic variant identified (most likely) - screening and management on personal and family history - referral for screening/further management only if indicated on above assessment - reassuring for patient but reiterate participation in population screening programmes 2) Disease causing variant in CPG identified - screening and management tailored to specific CPG - should be reviewed by NHS clinical genetics service 3) Variant of Uncertain Significance (VUS) Identified - benign until proven guilty - referral for screening/further management only if indicated on above assessment - may be anxiety provoking for patient. Need to understand how common genetic variation is and that most VUS are benign

Question 30

Hereditary Cancer vs Sporadic Cancer

Answer 30

Hereditary Cancers - High risks of recurrence/other associated cancers - High cancer risks in relatives - We can offer testing to at risk individuals - We can offer screening and preventative management to gene carriers - May alter treatment of affected individuals Sporadic Cancers - No increased risk of other cancers - Usually small increased risk to relatives - No genetic testing indicated - Normal clinical management for affected individuals

Question 31

Cause of sporadic cancer

Answer 31

Sporadic Cancer→somatic mutations · Occurs after division of the fertilised egg · Only present in a subset of cells · Not inherited from a parent

Question 32

Cause of Hereditary Cancer

Answer 32

``` Hereditary Cancer→germline mutations +/- somatic mutations · Present in the fertilised egg · Present in every cell in the body · Can be inherited from a parent · Can be passed to offspring ```

Question 33

Breast and Ovarian Cancer

Answer 33

- BRCA1 and BRCA2 genes - monogenic causes - Involved in DNA repair and regulation of transcription - Disease-causing variants result in an increased risk to develop certain cancers - Common in specific populations e.g. Polish, Jewish

Question 34

Compare BRCA1 vs BRCA2

Answer 34

Question 35

Case of breast cancer (pic)

Answer 35

Suspicions: - Age of breast cancer (in 30s) which is unusual - Pattern of breast cancer and ovarian cancer which fits with known breast and ovarian predisposition gene BRCA - Also, tree shows many relatives with cancer In this case, we would want to do a genetic test. We would do it in an affected person, preferably the person with breast cancer at the younger age. Result showed there was a BRCA2 mutation. This allows to offer her treatment. · Risk reducing bilateral mastectomy offered when being treated for cancer · Allows us to test her sister

Question 36

Management of those with a BRCA2 mutation (and hence CPG)

Answer 36

Screening: -All women with a BRCA2 mutation should be having annual breast MRI for any breast tissue from the ages of 30-40. At the age of 40, we do a mammogram as well as the MRI until the age of 50. After 50, the women have annual mammograms. Surgical Management: - There is no good screening for ovarian cancer, and so recommendation for BRCA2 mutation carriers is that they have risk-reducing surgery of the fallopian tubes and ovaries. But because the risk is not increased until after 50 years of age, we recommend that about the age of 45. - Risk reducing breast surgery can also be done (bilateral risk reducing mastectomy). Chemoprevention: -Chemoprevention for BRCA2 mutation carriers can also be undergone to reduce breast cancer risk if they are still having breast tissue.

Question 37

Lynch syndrome

Answer 37

- Mismatch repair - mutations in any gene: MLH1, MSH2, MSH6 and PMS2 - Disease-causing variants result in an increased risk to develop certain cancers > colorectal, endometrial and ovariann

Question 38

Test for Lynch syndrome

Answer 38

Tumour sample: loss of protein expression via IHC

Question 39

Carrier management for Lynch syndrome

Answer 39

Screening - colorectal, gastric and symptom awareness Risk-reducing surgery - Hysterectomy Chemoprevention - low dose aspirin Research Cancer management Family matters