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Karin Dahan
Hérédité et
cancer du sein
d.43y dx.
58y
dx.
35y
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Considerations in risk assessment and in indentifying
a family history of gynecologic cancer risk
High-penetrance gynecologic cancer susceptibility
genes
Low- and Moderate-penetrance genes associated with
gynecologic cancer
Objectives
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http://www.acog.org/-/media/Committee-Opinions/Committee-on-Genetics/co634.pdf?
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Dominant with incomplete penetrance
• May appear to « skip » generations
• Individuals inherit altered cancer susceptibility gene, not cancer
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Pitfall
Small family sizes and premature deaths or adoption may limit the information
Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than seen on the maternal side
A reported family history may be
erroneous, or a person may be unaware of relatives affected with cancer
http://www.cancer.gov/types/breast/hp/breast-ovarian-genetics-pdq
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d.43y
dx.32y
1. Family size and premature death
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Early onset
Walsh T et al , JAMA 2006. 295:1379-1388 Antoniou et al, Am J Hum Genet 2003.72(5): 1117–1130
TP53
IPGIPGIPGIPGCopyright ©2003 American Association for Cancer Research
Olivier, M. et al. Cancer Res 2003;63:6643-6650
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DelE13_15DelE13_15
d.43y
dx.32y
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2. Accuracy of family
cancer histories
≥3 relatives with BC
2 relatives with BC, one of whom was diagnosed ≤ age 50 yrs
First degree relative with bilateral BC
A history of BC in a male relative
Combination of both breast and ovarian or fallopian tube or primary peritoneal cancer among first and second degree relatives
Combination of 2 relatives with ovarian or fallopian tube or primary peritoneal cancer
2013 NCCN criteria for HBOC
JAMA 292:1480-85, 2004
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Ovarian, fallopian tube and peritoneal carcinoma
Walsh et al, PNAS. 2011;108:18032-18037
N: 85 /360 (24%)
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Cumulative risk of Breast and Ovarian Cancer
Antoniou et al, Am J Hum Genet, 2003, 72(5): 1117–1130
BRCA1 BRCA2
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Lynch syndrome pedigree
Colon dx35y Colon dx57y
Breast dx45y
Ovary dx46y Colon dx81y
Bonadona et al, JAMA. 2011;305(22):2304-2310
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Conclusion: The risk of colorectal cancer is increased in female carriers of BRCA1 mutations below the age of 50 years but not in women with BRCA2 mutations or in older women. Based on the results reported here, we recommend screening for colorectal cancer for women with a BRCA1 mutation be initiated at an age of 40 years.
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Harkness EF, et al. J Med Genet 2015;52:553–556
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Early onset BC ( ≤ age 35)
Two BC with the first ≤ age 50
High grade serous or papillary epithelial
ovarian/fallopian tube/primary peritoneal
cancer at any age
Both BC and either ovarian cancer,
fallopian tube cancer, or primary
peritoneal cancer
Triple negative breast cancer <age 50
Men with BC at any age
27 may 2015
3. Identification of high-risk individuals
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Triple negative breast cancer
Breast Cancer Res Treat 2013, 137 (1): 119-25 J Clin Oncol 2015,33 (4): 304-11
The prevalence of germline BRCA mutations : 9-35%
In women (241) between ages 50 to 59 with no known family history
18 (7.5%) had detectable mutations in BRCA1/2
The most relevant gene apart BRCA1/2 is PALB2 : 1.2% of patients
Carriers Median age at diagnosis
Triple negative
BRCA1 (3797 patients) 40 yrs 69%
BRCA2 (2392 patients) 43 yrs 16%
Cancer Epidemiol Biomarkers Prev 2012, 21(1):134-47
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High-penetrance gynecologic cancer
susceptibility genes
PTEN
BRCA1
BRCA2 PALB2
CDH1
MLH1
MSH2 MSH6
MUTyH
BRCA1
BRCA1
BRCA2 TP53
STK11
Endometrium
Ovary
Breast
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Bilateral breast cancer
dx 45 and 55 years
Breast cancer
dx 44 years
Multiple hamartomatous polyps
small bowel
stomach
colon
Mucocutaneous hyperpigmentation
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Peutz-Jeghers Syndrome
Incidence 1-9 in 100,000
Polyps in the intestine
Pigmentation (brown or bluish spots)
Lifetime risk of BC : 40 - 50%
Other cancers ; colon, pancreas, stomach,
ovary, small intestine, lung, cervix, testes,
uterus, and esophagus Boardman et al, Ann Intern Med. 1 June 1998;128(11):896-899
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Summary
http://www.acog.org/-/media/Committee-Opinions/Committee-on-Genetics/co634.pdf?
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Low penetrance cancer susceptibility gene
Prevalence of PALB2 mutations : 0.8% overall in a series of 1479
patients
Increasing to 1.05% in those with a strong family history
Cumulative risk of BC among 154 families
14% by 50 years of age
and 35% by 70 years of age
Breast cancer risks were higher in those with a significant family history
Cancer 2014, 120:963–967 N Engl J Med 2014, 371:497–506
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Depuis le 1/1/2015
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Notre expérience
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Futur
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Lancet Oncol 2011 , 12(5):477-88
Intermediate and low risk
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For many of the genes in categories 1 and 2,
risks of breast/ovarian cancer are not well defined
it is unclear if women who test negative for a mutation that
was found in an affected relative are really at general population
risk
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Summary
Genetic counseling and high penetrance genes
o Well-defined guidelines
o At-risk family members by predictive testing
o Screening and prevention programs
New developments and their challenges
o high-speed sequencing technologies and moderate penetrance genes
o analyses of somatic and germline data
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