Clinical Cancer Genetics

Question 1

Where do mutations occur?

Answer 1

germline or somatic

Question 2

How is knowing germline mutations useful?

Answer 2

informs future cancer risk
Informs treatment decisions
provides info for other family members

Question 3

Compare common to rare variants and the effects size

Answer 3

Most common variants have smallest effect size - implicated with common disease
rare variants cause mendelian disease

Question 4

How many high risk predisposition are usually in familial risk?

Answer 4

Multifactorial/polygenic risk - no single high risk gene detected, usually multiple lower risk genetic factors and environmental factors

high risk cancer predisposition genes are rare

Question 5

Which cancer types have some chance of high risk cancer predisposition genes (familial risk from single gene depending on cancer)?

Answer 5

Breast, colon, prostate, ovarian, melanoma

Question 6

Why do we need to identify patients with increased genetic predisposition to cancer?

Answer 6

Informs medical management and surgical options
Provides reasons why cancer developed
Informs patient about future cancer risk
Informs relatives about cancer risk - access to screening , early detection and risk reducing surgery

Question 7

How do we identify patients with increased genetic predisposition to cancer once they have developed the cancer?

Answer 7

Family history (multifactorial or polygenic risk)
Syndromic features (type of cancer)
Tumour testing
Pathology of cancer and molecular features
Cancer history
Personal history
Polygenic risk scores

Question 8

What factors do we look for in a family history in pedigree chart showing those that have canceR?

Answer 8

Multiple cancers in same individual
Young age on onset
Multiple cancer diagnosis os same type in closely related individuals
Multiple cancer

Question 9

What are polygenic risk scores?

Answer 9

Genetic testing of multiple low risk factors to indicate increased genetic susceptibility to cancer

Question 10

How are polygenic risk scores found?

Answer 10

Look for cancer associated SNPs from GWAS (genome wide association studies)

test to see if cancer patients have more of a specific mutation compared to controls

Question 11

What are constitutional mutations?

Answer 11

same thing as germline mutations - just another way to say it

Question 12

What can inherited susceptibility to cancer be caused by?

Answer 12

Multifactorial/polygenic risk

HIgh risk cancer predisposition gene

Question 13

How do you know if cause if multifactorial or high risk gene?

Answer 13

More people in family tree all closely linked have = high risk gene
Spread out and not many people = multifactorial

Question 14

What is stratified prevention?

Answer 14

categorising everyone into risk groups, and those at higher risk are screened for often to prevent (e.g. mammogram for above 47 yrs old) or have intervention + family history taken

Question 15

What is the guidlines for offering scrrening for cancer?

Answer 15

Identify people with high polygenic multifactorial risk and use family history
- can not due SNP testing, (GWAS only does that for research purposes)

Question 16

Which type of inherited cancer is most common?

Answer 16

Familial cancer is higher than high risk cancer predisposition genes (CPGs)

Question 17

Give examples of screening, prevention and early detection

Answer 17

Mammograms
Colonscopies
Chemoprevention

Question 18

When is high risk CPG (high risk genes) tested for?

Answer 18

If likelihood of finding pathogenic variant is higher then 10%

Question 19

Is recessive or dominant autosomal inheritance of high risk genes (CPGs) higher risk?

Answer 19

Autosomal dominant inheritance (50% chance of passing on). one gene enough for predisposition

Question 20

When does autosomal recessive inheritance cause predisposition to cancer?

Answer 20

If healthy carriers passes on 2 pathogenic variants (one from each parent), child with both variants has the predisposition to certain cancers not the parents with one gene each

Question 21

Give an example of a recessive high risk gene

Answer 21

MUTYH gene gives predisposition to colon polyps and cancer

Question 22

Which autosomal dominant cancer predispositions are linked to autosomal recessive conditions?

Answer 22

BRCA2 in fanconi anaemia gene

ATM gene causing ataxia telangiectasia

Question 23

What different diagnostic genetic testing can be done once cancer is discovered?

Answer 23

Single gene - test for known gene for specific cancer
NGS panel (more than 1 gene for specific cancer) - most common test
WES , WGS - too much infor

Question 24

What happens in diagnostic genetic testing if no. disease causing variant is found as the cause of cancer

Answer 24

Manage based on family history and personal diagnosis

Question 25

What happens in diagnostic genetic testing if variant of uncertain significance if found as the cause of cancer

Answer 25

Analyse variant

Manage based on family history and personal history

Question 26

What happens in diagnostic genetic testing if disease causing variant (known pathogenic variant) is found as the cause of cancer

Answer 26

Manage as per gene specific protocol

Can offer cascade screening to relatives

Question 27

If pathogenic variant is found with diagnostic genetic testing, what cascade screening is offered to relatives?

Answer 27

SPED (screening, prevention and early detectio)

• non invasive imagine
• invasive
• chemoprevention
• risk reducing surgeries e.g. remove ovaries for ovarian cancer

Question 28

What is predictive testing?

Answer 28

A test in a WELL person to predict future risk aka siblings have cancer with BRCA2 gene, unaffected and well sibling is tested

• if predictive variant not present, manage as if were rest of population
• if predicted pathogenic variant found, manage as per specific protocol

Question 29

What are the monogenic causes for hereditary breast cancers?

Answer 29

BRCA1 and BRCA2 genes

• genes involved in DNA repair and regulation of transcription
• presence only increases RISK of developing compared to rest of population

Question 30

What is the management for BRCA1/2 carriers?

Answer 30

Screening
Risk reducing surgery
Chemoprevention for BRCA2 carriers
Male BRCA2 carriers recommedned to have PSA (prostate specific antigen) test

Question 31

What is lynch syndrome?

Answer 31

Hereditary colorectal , womb and ovarian cancer (inherited)

Question 32

What mutations are there in Lynch syndrome?

Answer 32

MLH1, MSH2, MSH6 and PMS2

- disease causing variants increase risk of developing certain cancers

Question 33

What is carrier management for Lynch syndrome?

Answer 33

Screen - colorectal and gastric
Symptoms awareness
Risk reducing surgery
Chemoprevention - low dose aspirin
Cancer managment
Family

Question 34

Just know management plans for high risk gene carrier e for hereditary breast and ovarian caner syndrome as well as for lynch syndrome