beyond brca mutations: what's new in the world of genetic testing?
TRANSCRIPT
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Inherited Risk for Breast and Ovarian Cancer: 2016 Update
2016-07-19Mark Robson, MDAttending, Clinical Genetics and Breast Medicine Services@MarkRobsonMD
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Reasons for familial aggregations• Chance• Shared environmental factors• Shared socio-cultural risk factors• Shared genetic factors
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• Early onset
• Bilateral disease
• Male = female transmission
• Incomplete penetrance
• Gender-variable expression
Autosomal Dominant Predisposition
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• 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
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Cancers and Interventions for BRCACancer Risk (to age
80) Intervention
Breast 50-80%Breast MRIPreventive 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
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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
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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
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Breast Cancer Linkage Consortium (Breast only)
BRCA128%
BRCA237%
BRCAx35%
Ford et al, Am J Hum Genet 1998
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Cowden SyndromePTEN
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Peutz-Jegher’s SyndromeSTK11/LKB1
Yoo et al, BMC Genetics 2008
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Li-Fraumeni Syndrome TP53
Bilateral breast, 40
Leukemia, 33
Brain tumor, 32
Breast, 40Osteosarcoma, 42
Breast, 35
Soft tissue sarcoma, 7
Leukemia, 6
50
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Hereditary Diffuse Gastric CancerCDH1
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High-penetranceP53, PTEN, CDH1, STK11
• Rare, recognizable syndromes
• Multi-site cancer predispositions
• “True negative” results meaningful
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Genetic architecture of breast cancer risk
Alle
le F
requ
ency
Relative Risk
Common variants (GWAS)
1 2 5 ≥10
Rare variants (moderate)
Rare variants (high penetrance)
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”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
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Results of Multigene Testing
CHEK2 ATM PALB2 BRIP1 NBN BARD1 RAD51C RAD51D0.00%
0.10%
0.20%
0.30%
0.40%
0.50%
0.60%
0.70%
0.80%
0.90%
1.00%
Percentage of cases with mutations (n=91,216)
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Results of Multigene Testing
CHEK229%
ATM22%
PALB219%
BRIP110%
NBN6%
BARD15%
RAD51C5%
RAD51D2%
RAD501%
MRE111%
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Average Risks of Moderate Penetrance GenesGene 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 genesRisks are likely to be significantly modified by other factorsSome families appear to be at much higher than average risk, others lower
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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
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Summary suggestions
Gene
MammogramCBE
Breast MRI RRSO ColonoscopyPancreas 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 aloneConsider RRSO for BRIP1/RAD51C/D earlier than 50 if close relatives with OC