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Prostate Cancer Genetics
Justin Lorentz, MSc, CGC
Genetic Counsellor
Male Oncology Research and Education (MORE) Lead
Sunnybrook Odette Cancer Centre
Medcan
Goals
SECTION 1 - GENETICS
• Genetic Counsellors
• Cancer
• Genetics
SECTION 2 – GENETIC TESTING
• Genetic Testing (tissue vs germline)
• How To Access Genetic Testing
SECTION 3 – PROSTATE CANCER GENETICS
• Genes Connected to Prostate Cancer
• How Genetic Testing Impacts Prostate Cancer Risk, Aggressiveness, Treatment
SECTION 4 – OTHER PROSTATE CANCER RISK FACTORS
• Family History
• Ancestry
SECTION 1
Genetics
Pedigree = Family Tree
Genes
mutation = pathogenic variant
mutation
http://www.encognitive.com/node/10741
Inheriting a Pathogenic Variant
Germline
What is cancer?
http://www.encognitive.com/node/10741
SECTION 2
Genetic Testing
Germline Testing Tissue Testing
Cancer Genetic Testing
• Saliva sample
• Blood sample
• Mutation present or
absent (generally)
• Tumour sample
• Liquid biopsy
• Mutation always
present
https://www.precisionmed.ch/en/what-is-cancer/
Germline Genetic Test Results
https://sanogenetics.com/blog/what-is-a-genetic-variant-of-uncertain-significance/
common uncommon rare
Mutation = likely pathogenic / pathogenic variant
Why Should Prostate Cancer Patients Get Genetic Testing?
– Understand prostate cancer risk?
– Potential risk for other cancers? (eg. colon cancer, breast cancer)
– Cascade testing for family members? (eg. siblings, children)
– Prostate cancer aggressiveness
– Recommendations for clinical treatment of localized disease
– Active Surveillance
– Surgery
– Radiation
– Eligibility for PARPi Clinical Trials
Emily Thain, MSc, CGC
Genetic Counsellor,
Princess Margaret
Cancer Centre
Traditional Model
Mainstream Model
Genetic Testing Process
https://www.womensacademics.ca/active-studies/the-screen-project-study/
Genetic Non-Discrimination Act (GNA)
GNA is a law that protects you from use of genetic test results in certain
settings.
GNA prevents the following from using genetic test results against you:
• Insurance companies
• Life insurance, Critical illness insurance
• Federal government-regulated employers
GNA does NOT prevent insurers/employers from using…
• information about your personal history of cancer
• information about your family history cancer
SECTION 3
Prostate Cancer
Genetics
PMID: 2743384
11.8% 82/692 people with
metastatic prostate cancer
inherited a germline mutation
BRCA2 37 5.35%
ATM 11 1.59%
CHEK2 10 1.87%
BRCA1 6 0.87%
Prostate Cancer Risk
HOXB13 +++
BRCA1
BRCA2
MLH1
MSH2
MSH6
PMS2
ATM
CHEK2
PALB2
Prostate Cancer Risk
HOXB13 +++
BRCA1 +
BRCA2 ++
MLH1
MSH2
MSH6
PMS2
ATM
CHEK2
PALB2
Hereditary Breast/Ovarian Cancer
Site BRCA1 BRCA2 ATM CHEK2 PALB2
General
Population
Breast
(female)
60%-72% 55%-69% 20%-40% 23%-27% 32%-53% 11-12%
Ovarian 39%–58% 13%–29% 2%–3% N/A 3%-5% 1.3%
Prostate 7%–26% 19%–61% increased
risk
increased
risk
increased
risk
11.6%
Pancreas ≤5% 5%–10% ~5%–10% N/A 2%-5%
no data on
SEER
Breast (male) 0.2%-1.2% 1.8%-7.1% N/A N/A 0.9% ≤1%
Colorectal N/A N/A N/A N/A
N/A
4.2%
Gastric? ?? ?? N/A N/A N/A 0.9%
Prostate Cancer Risk
HOXB13 +++
BRCA1 +
BRCA2 ++
MLH1 ?
MSH2 +
MSH6 +
PMS2 -
ATM
CHEK2
PALB2
Prostate Cancer Risk
HOXB13 +++
BRCA1 +
BRCA2 ++
MLH1 ?
MSH2 +
MSH6 +
PMS2 -
ATM +
CHEK2
PALB2
Prostate Cancer Risk
HOXB13 +++
BRCA1 +
BRCA2 ++
MLH1 ?
MSH2 +
MSH6 +
PMS2 -
ATM +
CHEK2 +
PALB2
Prostate Cancer Risk
HOXB13 +++
BRCA1 +
BRCA2 ++
MLH1 ?
MSH2 +
MSH6 +
PMS2 -
ATM +
CHEK2 +
PALB2 -
🤠
Prostate Cancer Risk Aggressive?
HOXB13 +++ ?
BRCA1 +
BRCA2 ++
MLH1 ?
MSH2 +
MSH6 +
PMS2 -
ATM +
CHEK2 +
PALB2 ?
Prostate Cancer Risk Aggressive?
HOXB13 +++ ?
BRCA1 + ?
BRCA2 ++ Y
MLH1 ?
MSH2 +
MSH6 +
PMS2 -
ATM +
CHEK2 +
PALB2 ?
Prostate Cancer Risk Aggressive?
HOXB13 +++ ?
BRCA1 + ?
BRCA2 ++ Y
MLH1 ? N
MSH2 + ?
MSH6 + ?
PMS2 - -
ATM +
CHEK2 +
PALB2 ?
Prostate Cancer Risk Aggressive?
HOXB13 +++ ?
BRCA1 + ?
BRCA2 ++ Y
MLH1 ? N
MSH2 + ?
MSH6 + ?
PMS2 - -
ATM + ?
CHEK2 +
PALB2 ?
Prostate Cancer Risk Agressive?
HOXB13 +++ ?
BRCA1 + ?
BRCA2 ++ Y
MLH1 ? N
MSH2 + ?
MSH6 + N
PMS2 - -
ATM + ?
CHEK2 + N
PALB2 ?
Prostate Cancer Risk Agressive?
HOXB13 +++ ?
BRCA1 + ?
BRCA2 ++ Y
MLH1 ? N
MSH2 + ?
MSH6 + N
PMS2 - -
ATM + ?
CHEK2 + N
PALB2 ? Y?
Prostate Cancer Risk Treatment
(AS/Sx/XRT)
HOXB13 +++ -
BRCA1 + ?
BRCA2 ++ Y
MLH1 ? -
MSH2 + -
MSH6 + -
PMS2 - -
ATM + ?
CHEK2 + -
PALB2 ? ?
Prostate Cancer Risk mPC
HOXB13 +++ -
BRCA1 + Y
BRCA2 ++ Y
MLH1 +/-
MSH2 ++
MSH6 ++
PMS2 -
ATM + Y
CHEK2 + -
Prostate Cancer Risk mPC
HOXB13 +++ -
BRCA1 + Y
BRCA2 ++ Y
MLH1 ? Y
MSH2 + Y
MSH6 + Y
PMS2 - Y
ATM + -
CHEK2 + -
PALB2 ? -
SECTION 4
Other Prostate
Cancer Risk
Factors
Hereditary Cancer vs Not Hereditary Cancer
Heritability = proportion of variance in cancer risk due to genetic differences between people
• Prospective study of 80,309 MZ
and 123,382 same-sex DZ twins
followed for a median of 32 years
PMID: 26746459
Risk Group RR
Brother with prostate cancer diagnosed at any age 2.84
Father with prostate cancer diagnosed at any age 2.12
One affected FDR diagnosed at any age 2.22
One affected SDR diagnosed at any age 1.88
West Africa
• Sierra Leone
• Liberia
• Ivory Coast
• Ghana
Caribbean
• Trinidad & Tobago
• Jamaica
• Turks and Caicos
• The Bahamas
• Saint Vincent
• Honduras
• Haiti
• Grenada
• Barbados
PMID: 3966810
3
PMID: 3966810
3
Questions?