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Inherited Risk for Breast
and Ovarian Cancer: 2016
Update
2016-07-19
Mark Robson, MD
Attending, Clinical Genetics and Brea...
Reasons for familial aggregations
• Chance
• Shared environmental factors
• Shared socio-cultural risk factors
• Shared ge...
• Early onset
• Bilateral disease
• Male = female transmission
• Incomplete penetrance
• Gender-variable expression
Autoso...
• Most common cause of autosomal dominant
predisposition to breast (and ovarian) cancer
• How common are BRCA1/2 mutations...
Cancers and Interventions for BRCA
Cancer Risk (to age 80) Intervention
Breast 50-80%
Breast MRI
Preventive mastectomy
Ova...
Risk modifiers for BRCA1/2 risk?
• Impact of traditional RF on risk unclear
– Age at start/stop periods, age of first chil...
Non-surgical interventions for BRCA
risks
• Oral contraceptives decrease OC risk
– Effect on BC risk unclear but likely li...
Breast Cancer Linkage Consortium
(Breast only)
BRCA1
28%
BRCA2
37%
BRCAx
35%
Ford et al, Am J Hum Genet 1998
Cowden Syndrome
PTEN
Peutz-Jegher’s Syndrome
STK11/LKB1
Yoo et al, BMC Genetics 2008
Li-Fraumeni Syndrome
TP53
Bilateral breast, 40
Leukemia,
33
Brain tumor, 32
Breast, 40
Osteosarcoma, 42
Breast,
35
Soft ti...
Hereditary Diffuse Gastric Cancer
CDH1
High-penetrance
P53, PTEN, CDH1, STK11
• Rare, recognizable syndromes
• Multi-site cancer predispositions
• “True negative...
Genetic architecture of breast cancer riskAlleleFrequency
Relative Risk
Common variants
(GWAS)
1 2 5 ≥10
Rare variants
(mo...
”Moderate penetrance” genes
• ATM
• BRIP1
• BARD1
• BLM
• CHEK2
• MRE11
• NBN
• PALB2
• RAD50
• RAD51C
• RAD51D
• XRCC2
• ...
Results of Multigene Testing
0.00%
0.10%
0.20%
0.30%
0.40%
0.50%
0.60%
0.70%
0.80%
0.90%
1.00%
CHEK2 ATM PALB2 BRIP1 NBN B...
Results of Multigene Testing
CHEK2
29%
ATM
22%
PALB2
19%
BRIP1
10%
NBN
6%
BARD1
5%
RAD51C
5%
RAD51D
2%
RAD50
1%MRE11
1%
Average Risks of Moderate
Penetrance Genes
Gene Breast Cancer (by 80) Ovarian Cancer (by 80) Other cancers
CHEK2 25-30% No...
Complexities in working with
moderate penetrance mutations
• These are NOT BRCA1/2
– Risks are lower (in general)
– Breast...
Summary suggestions
Gene
Mammogram
CBE
Breast MRI RRSO Colonoscopy
Pancreas
Screening
ATM Annual starting at 40* No FH Cli...
Beyond BRCA Mutations: What's New in the World of Genetic Testing?
Beyond BRCA Mutations: What's New in the World of Genetic Testing?
Beyond BRCA Mutations: What's New in the World of Genetic Testing?
Beyond BRCA Mutations: What's New in the World of Genetic Testing?
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Beyond BRCA Mutations: What's New in the World of Genetic Testing?

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Dr. Mark Robson, Clinic Director of the Clinical Genetics Service at Memorial Sloan Kettering Cancer Center, presents a medical update regarding the latest developments in genetic testing as it relates to breast and ovarian cancer. Topics include non-BRCA mutations, including both high-penetrance and so-called moderate penetrance mutations, and a framework for management of these.

Presented in collaboration with FORCE.

Veröffentlicht in: Gesundheit & Medizin
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Beyond BRCA Mutations: What's New in the World of Genetic Testing?

  1. 1. Inherited Risk for Breast and Ovarian Cancer: 2016 Update 2016-07-19 Mark Robson, MD Attending, Clinical Genetics and Breast Medicine Services @MarkRobsonMD
  2. 2. Reasons for familial aggregations • Chance • Shared environmental factors • Shared socio-cultural risk factors • Shared genetic factors
  3. 3. • Early onset • Bilateral disease • Male = female transmission • Incomplete penetrance • Gender-variable expression Autosomal Dominant Predisposition
  4. 4. • Most common cause of autosomal dominant predisposition to breast (and ovarian) cancer • How common are BRCA1/2 mutations? – About 1 in 200 individuals of European ancestry • About 1 in 300 (Finns) to 1 in 600 (African-American) non-AJ • About 1 in 40 Ashkenazi Jewish ancestry
  5. 5. Cancers and Interventions for BRCA Cancer Risk (to age 80) Intervention Breast 50-80% Breast MRI Preventive mastectomy Ovarian 15-60% RRSO +/- hysterectomy ? Salpingectomy Prostate 25-30% DRE/PSA Male breast 3-8% Awareness ?Mammogram Pancreas 3-5% (mainly B2) Investigational screening ?Colon Uncertain Early colonoscopy
  6. 6. Risk modifiers for BRCA1/2 risk? • Impact of traditional RF on risk unclear – Age at start/stop periods, age of first childbirth, number of children, etc • No clear environmental modifiers • Genetic background factors are influential
  7. 7. Non-surgical interventions for BRCA risks • Oral contraceptives decrease OC risk – Effect on BC risk unclear but likely limited • Early menopause may decrease BC risk – B2> B1, new data suggests more limited benefit • Impact of tamoxifen, raloxifene,AIs unclear
  8. 8. Breast Cancer Linkage Consortium (Breast only) BRCA1 28% BRCA2 37% BRCAx 35% Ford et al, Am J Hum Genet 1998
  9. 9. Cowden Syndrome PTEN
  10. 10. Peutz-Jegher’s Syndrome STK11/LKB1 Yoo et al, BMC Genetics 2008
  11. 11. Li-Fraumeni Syndrome TP53 Bilateral breast, 40 Leukemia, 33 Brain tumor, 32 Breast, 40 Osteosarcoma, 42 Breast, 35 Soft tissue sarcoma, 7 Leukemia, 6 50
  12. 12. Hereditary Diffuse Gastric Cancer CDH1
  13. 13. High-penetrance P53, PTEN, CDH1, STK11 • Rare, recognizable syndromes • Multi-site cancer predispositions • “True negative” results meaningful
  14. 14. Genetic architecture of breast cancer riskAlleleFrequency Relative Risk Common variants (GWAS) 1 2 5 ≥10 Rare variants (moderate) Rare variants (high penetrance)
  15. 15. ”Moderate penetrance” genes • ATM • BRIP1 • BARD1 • BLM • CHEK2 • MRE11 • NBN • PALB2 • RAD50 • RAD51C • RAD51D • XRCC2 • SLX4 Found in ~3% of BRCA-negative families undergoing testing
  16. 16. Results of Multigene Testing 0.00% 0.10% 0.20% 0.30% 0.40% 0.50% 0.60% 0.70% 0.80% 0.90% 1.00% CHEK2 ATM PALB2 BRIP1 NBN BARD1 RAD51C RAD51D Percentage of cases with mutations (n=91,216)
  17. 17. Results of Multigene Testing CHEK2 29% ATM 22% PALB2 19% BRIP1 10% NBN 6% BARD1 5% RAD51C 5% RAD51D 2% RAD50 1%MRE11 1%
  18. 18. Average Risks of Moderate Penetrance Genes Gene Breast Cancer (by 80) Ovarian Cancer (by 80) Other cancers CHEK2 25-30% Not increased ?Colon ATM ~30% Not increased ?Pancreas PALB2 ~44% Not clearly increased ?Pancreas BRIP1 Not clearly increased 10-15% NBN ~30% Not clearly increased BARD1 Undefined Undefined RAD51C Not clearly increased 5-10% RAD51D Not clearly increased 10-15% Risks may be different for different mutations (e.g. CHEK2, ATM) Risks are not currently well-defined for some genes Risks are likely to be significantly modified by other factors Some families appear to be at much higher than average risk, others lower
  19. 19. Complexities in working with moderate penetrance mutations • These are NOT BRCA1/2 – Risks are lower (in general) – Breast cancer genes not clearly linked to OC – OC genes not clearly linked to BC • Risks in younger women generally less than BRCA1/2 (but modified by family history) • Individuals testing negative for family mutations may remain at significant risk
  20. 20. Summary suggestions Gene Mammogram CBE Breast MRI RRSO Colonoscopy Pancreas Screening ATM Annual starting at 40* No FH Clinical trial CHEK2 (truncating) Annual starting at 40* No ?Discuss at 40 NBN Annual starting at 40* No FH PALB2 Annual starting at 30 No (for now) FH Clinical trial BRIP1/RAD51C/RAD51D FH Around 50 yrs FH Individuals with mutations of uncertain clinical validity (presently including BARD1, CHEK2 p.I157T and possibly p.S428F, MRE11A, RAD50/51B, SLX4, and XRCC2) should be managed as indicated by family history. *Start surveillance at 35 if significant FH of breast cancer (FDR with early onset) or if targeting lower threshold (e.g. population 40 year-old risk) Breast MRI for BRIP1/RAD51C/D only if FH model CLTR>20% RRSO for ATM, CHEK2, NBN, PALB2 only if indicated by family history, not mutation alone Consider RRSO for BRIP1/RAD51C/D earlier than 50 if close relatives with OC

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