Beyond BRCA Mutations: What's New in the World of Genetic Testing?
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Transcript of Beyond BRCA Mutations: What's New in the World of Genetic Testing?
Inherited Risk for Breast and Ovarian Cancer: 2016 Update
2016-07-19Mark Robson, MDAttending, Clinical Genetics and Breast Medicine Services@MarkRobsonMD
Reasons for familial aggregations• Chance• Shared environmental factors• Shared socio-cultural risk factors• Shared genetic factors
• Early onset
• Bilateral disease
• Male = female transmission
• Incomplete penetrance
• Gender-variable expression
Autosomal Dominant Predisposition
• 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
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
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
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
Breast Cancer Linkage Consortium (Breast only)
BRCA128%
BRCA237%
BRCAx35%
Ford et al, Am J Hum Genet 1998
Cowden SyndromePTEN
Peutz-Jegher’s SyndromeSTK11/LKB1
Yoo et al, BMC Genetics 2008
Li-Fraumeni Syndrome TP53
Bilateral breast, 40
Leukemia, 33
Brain tumor, 32
Breast, 40Osteosarcoma, 42
Breast, 35
Soft tissue sarcoma, 7
Leukemia, 6
50
Hereditary Diffuse Gastric CancerCDH1
High-penetranceP53, PTEN, CDH1, STK11
• Rare, recognizable syndromes
• Multi-site cancer predispositions
• “True negative” results meaningful
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)
”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
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)
Results of Multigene Testing
CHEK229%
ATM22%
PALB219%
BRIP110%
NBN6%
BARD15%
RAD51C5%
RAD51D2%
RAD501%
MRE111%
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
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
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