Genetic Cancer Syndromes-Scientific
Background & Clinical Implications
Asher Salmon M.D, Ph.DHadassah University Hospital Ein Kerem
• The risk for breast cancer 11 %
• The risk for ovarian cancer 1.4 %
• Only 5-10% are due to genetic predisposition
Family 1
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Family 2: Familial Breast Ovarian Cancer
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Clinical Characteristics
• Multiple family relatives diagnosed with breast cancer
• Early age of onset• Higher prevalence of bilateral cancer • Presence of associated tumors (ovary,
colon, prostate).
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Familial Breast Cancer
Syndrome Characteristics GeneBRCA1 Breast / Ovary 17qBRCA2 Breast, male/female 13BRCA3 ? ?Lynch II Colon, endometrium 2p;3p; ovary, stomach, brainLi-Fraumeni Sarcoma, brain 17p
adrenocorticalCowdan’s dis Multiple hamartomas PTENChk2 breast-colon (x2BC)ATM
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BRCA1 gene:
• chromosome 17q21• Predisposing genetic factors is 5-10%• Female mutation carriers have a 60-80%
life time risk for developing breast cancer• 20-40% life time risk for developing
ovarian cancer.
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BRCA2 gene
• Chromosome 13q 12-13• The life-time breast cancer risk – 60-85%• The life-time ovarian cancer risk – 10-20%• Male – 6% lifetime breast risk. • Association with – colon, prostate,
pancreas, gallbladder, bile duct stomach cancer and malignant melanoma.
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The Road To Malignancy
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Normal
Invasion
MetastasisInherited gene
Somatic mutations)5-6(
Sporadic tumors arise after somatic inactivation of both copies of a tumor suppressor gene
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Normal Normal Transformation
Somatic Mutation I Somatic Mutation II
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Normal Transformation
Tumor development in BRCA1/2 carriers
Germline mutation Somatic mutation-LOH (Knudson)
Function of BRCA1 and 2 proteins
• Tumor suppressor gene• Transcription pathway • Cell cycle control pathway• DNA damage repair pathway
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BRCA gene functionGatekeepers of genomic stability:
BRCA1&2 are in complex with Rad51; Rad51 participate in cellular response to DNA damage (ds breaks)
BRCA1 is phosphorilated by by ATM kinase in response to DNA damage
BRCA1 interacts with p53 induction of p21 cell cycle inhibition
BRCA gene functionControl of sex steroid regulated pathways:
BRCA proteins elevates in puberty and in response to estrogen stimuli
BRCA1 suppress the ER signaling in mammary epithelialcells
BRCA1 mice conditional knockout regulation of mammary ducts morphology
185delAG mutation in exon 2 of BRCA1
• WT: 5’---AAT CTT AGA GTG TCC CA---3’
• Mutant: 5’---AAT CTT AG- T GTC CCA---3’
185delAG: Two bp deletion at codon23, creates a stop codon at codon 39
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Ashkenazi Founder Mutations in BRCA1
185delAG Prevalence - 1%
5382insC Prevalence - 0.4%
Ashkenazi Jews (10% and more)20% of Jewish women who developed breast cancer before the age of 40y carry – 185delAG mutation.
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• Ashkenazi Jews – 6174delT• Prevalence of 1.2%
• Yemanite Jews - 8752delAG• Prevalence of 1.0%
• Iceland - 999del5
Founder Mutation of BRCA2
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Frequency of recurrent BRCA1 and BRCA2 mutations in Healthy Ashkenazi Jewish population
Gene Mutation Exon Frequency
BRCA1 185delAG 2 1.05%5382insC 20 0.11%
BRCA2 6174delT 11 1.36%BRCA1+2 2.5%
Compared to 1:800 in other populations!!!
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Frequency of BRCA carriers in the Ashkenazi population in Israel
• Carrier frequency 1 in 40
• Number of Ashkenazi females in Israel 1,000,000
Female Carriers n=25,000
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BRCA1 BRCA2BC 56-85 37-85
OC 15-45 10-27 male BC 0? 6
Prostate 6 6-14
Colon 0? 5(not confirmed by population based studies)
•
Lifetime (by age 80 years) Cancer Risks (%) in BRCA1/2 Carriers
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BRCA1 breast/ovarian cancer risks
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Eles & Poules 2000
BRCA2 breast/ovarian cancer risks
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Eles & Poules 2000
Tumor characteristics and prognosis
Ovarian cancer
Serous papillary
not borderline or muscinus
High grade, high p53
Better prognosis: better response to chemo? DDP?
Tumor characteristics and prognosis
Breast cancer
High grade
BRCA1: Higher T
ER-, PR- Her 2- (triple negative)
G3, high pleomorphism, high mitotic count
less DCIS, medullary, distinct gene expression
= Basal like carcinoma
prognosis: worse(?), partially corrected by chemo
Hormonal Risk Factors
• Prolonged exposure to estrogen (increase numbers of menstrual cycle)
• Long-term use of HRT• Long-term use of OC • Age at first live birth • Obesity (in postmenopausal androsteron to
estrone by adipose tissue).
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Non-hormonal Risk Factors
• Exposure to ionizing radiation• Alcohol consumption (alcohol exposure to
estrogen).• Smoking• Dietary factors (?) (high diet in fat “well
done” meat).
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Oral Contraceptives and Ovarian ca• Modan et al, N Eng J Med, 2001
751 controls, without ovarian cancer, 1.5% BRCA1/2 +840 women with ovarian cancer, 29% BRCA1/2+Oral contraceptive use reduced the risk only in noncarriers.
McLauglin et al, Lancet Oncol 2007800 cases Vs 2400 controls. Reduction in OC risk
50-60% in BRCA1 & 2
Oral Contraceptives and breast ca
• Narod et al, JNCI, 2002.• Matched case-control, 1311 pairs• In BRCA1: OR 1.2.
More than 5y use - OR 1.33 use before age 30 - OR 1.29 diagnosis before age 40 – OR 1.38 use before 1975 – OR 1.42
• No association in BRCA2 (small numbers?)
Risk modifiers *Pregnancies in non-carriers reduction in risk by 5%
with reduction of first birth year by 5y. In carriers-risk opposite.
*Smoking - 1000 case-control carriers, no association with smoking, age start ect.
*physical activity
*low weight at puberty
*Modifiers genes
Prevention
• Surveillance• Prophylactic mastectomy• Prophylactic oophorectomy• Chemoprevention
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Early Detection - mammography
Brekelmans et al: 1,200, of them 118 carriers diagnosed by screening: carriers 5/9 (56%)
non-carr 26/35 (74%)Schuer et al: 165 carriers
diagnosed by screening: 6/12 (50%)
More aggressive-Interval cancersBreast density, young age, less spiculated
tumor .
Early detection - mammography
• Kauff et al, 1648 ASCO 2001
215 women in MSKCC
102/215 – BRCA1/2 mutation carriers.
Carriers were less likely to be diagnosed by screening – 20% vs. 39%.
Mutation carriers were more likely to present with palpable mass 67% vs. 47%.
Early detection-mammographyMammograpgy – possible increased sensitivity to XRT due to BRCA mutation
detectibility: lower than in non-carriers
Early detection - MRI
Warner et al: 196 (96 carriers) screened by mammo, US, MRI, BCE
6 tumors detected, all less than 1cm
6 by MRI, 2/6 by mammo, 3/6 by US, 2/6 by BCE
Kohl et al: 192 high risk (35 carriers)
9 tumors detected, all less than 1cm (6-brca1, 1-brca2)
MRI mammo us mammo+us
Sensitivity: 100% 30% 30% 44%
Specificity: 95% 93% 80%
Early detection
Frequency? Interval cancer?
Sensitivity of MRI to high, specificity ?? - many biopsies (cost-13,930 euro per BC by MRI vs 4,930)
No data regarding impact on mortality
In studies some of pt diagnostics, different risk populations
• 639 women Moderate-high risk (according to family history)
• In 214 high risk : expected - 53 • incidence - 3 • Reduction in risk : >90% (p<0.001)• (of them 26 carriers, no BC case)• Reduction in death : 100%
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Prophylactic Mastectomy
Hartman L.C.1999 639. HR 214-425
Satisfaction with prophylactic mastectomy (N=562)
Frost M (JAMA) 2000
Choice to have prophylactic mastectomy again (N=567)
Frost M (JAMA) 2000
Prophylactic Mx in carriers
Meijers-Heijboer (NEJM) 139 carriers, 2.9y follow up, oophorectomy
79 :mx - 0 BC63 follow-up - 8 BC (6.7 expected)
HR – 0, p=0.003Rebbeck et alCase-control (adj-mut,age) multicenter, 6y follow up
2/105 mastectomized Vs 184/384 followedHR-0.05, when corrected to oophorectomy 0.09
Prophylactic Mx in carriers
No randomization, no data of impact on survival
More family history-more operated
Those with occult ca. out of analysis
Oophorectomy done in many – also protective
Prophylactic Mastectomy
• Bilateral Mastectomy – lowers the incidence of breast cancer by 90%-100%
• Prophylactic Mastectomy an option – 57% of women at high risk.
• Subcutaneous and nipple sparing; risk?, better body image
• Actually performed the surgery – 25%
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Frost M (JAMA) 2000
• The role of the health care professional is to provide data about all optopns in a balanced mannaer
• The primary motivation for the procedure must derive from the patient herself
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Prophylactic Mastectomy
Prophylactic Oophorectomy
Kauff et al (NEJM): no. 170, 140 prior BC, age>35, 20 months follow upProspective non-randomized
98 operated - 3 BC72 controls - 8 BC HR-0.32
*self selection bias*reduction of BC in BRCA1 carriers although usually ER-
Prophylactic Oophorectomy
• Rebbeck T., NEJM, 2002, retrospective• OC risk: Cases: 259 carriers, oophorectomy.
control: 292 – follow up Hazard ratio of OC – 0.04 (2.3%-st I, 0.8%
peritoneal) BC risk: Cases – 99 oohporectomy. 21 BC Control: 142 - no surgery 60 BC Hazard ratio of BC reduced to 0.47
Use of HRT did not negate the reduction in BC risk. (50% of cases vs 19% in controls)
Prophylactic oophorectomy
•Domchek et al, Lancet Oncol, 2006•Retrospective
•188 cases Vs 478 controled•Med follow-up 2-3 years
•Reduction in mortality 70-80%
Option of Chemoprevention
• Oophorectomy / LhRh agonist
» Aromatase inhibitors ?
• Tamoxifen.
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Tamoxifen – Prevention TrailsThe NSABP-P1
Risk reduction by 49% Reduction of ER+, but not ER- (Study population: old woman, lobular carcinoma in
situ, atypical ductal hyperplasia)
Of BC patients, 19 carriers. 8-BRCA1 of them 5 treated---RR-1.67 (NS)11-BRCA2 of them 3 treated---RR-0.38 (NS)
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Tamoxifen in BRCA1/2 carriers • Narod et al, Lancet 2000. Retrospective
comparisson of tamoxifen use in 209-BB and 384-unilateral BC.
• Tamoxifen reduced the risk of contralateral breast cancer by 50% in carrier of BRCA1/2 Mutations
• BRCA1 – OR- 0.38 (sig, n=476) • BRCA2 – OR- 0.63 (sig, n=117)• In users of >2-4years• When combined with oophorectomy: OR-0.16
Survival bias!!!
Chemoprevention in BRCA1&2 Carriers
• The penetrance curves for breast cancer starts to increase at 35 years.
• The steepest part – 40-50 years.• Chemoprevention 10 years before the
increase in incidence – 35 year at least.
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Adverse Effects of Tamoxifen Chemoprevention
Endometrial cancer
Thromboembolic complication
Quality of life – hot flushes, vaginal discharge
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Future?
Raloxifen Vs. Tamoxifen
LhRh analogs
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Predictive Models• Grann et al JCO, 2002• Simulated cohort of 30-y.o. women. BC & OC
expected incidence from literature. Mortality from SEER.
quality adjusted• Survival : Tamoxifen – 1.8y 2.8y oophorectomy – 2.6y 4.4y tam+oophorec. – 4.6y 6.3y mastectomy - 3.5y 2.6y max &ooph - 4.9y 2.6y
Recommendations to Carriers• Careful follow up of the breast & ovaries
every 6 months• Oophorectomy at 40y or earlier.• Chemoprevention- No!• Risk reduction mastectomy• Colonoscopy age 40?• HRT• Oral contraceptives???
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BRCA Mutation Analysis:Benefits
• In healthy carriers: recommendations and guidance of possible prevention and follow up
• In healthy individuals, non-carriers (relatives of carriers) reduces anxiety markedly
• Recommendation to high risk families with no mutation detected; rare variants ???
Should be performed only in the frame of onco-genetic clinic and with psychological and medical support
Should be performed only in the frame of onco-genetic clinic with psychological and medical support
Familial Colorectal Cancer
incidance* CRC risk FAP 1% 100%
HNPCC 1-5% 70-90%
CRC family history 10-15% 15%
Hamartomatous polyposis rare- Peutz Jeghers
- Juvenile polyposis
*among CRC patients
Familial CRC: genes Gene
Non polyposis Syndromes
HNPCC (Lynch, Muir, Turcot) msh2, mlh1, msh6, pms1, pms2 Familial clustering of late onset I1307KAPC, TGFbetaRII
CRC
Polyposis Syndromes FAP APC
Peutz-Jeghers STK11 Juvenile Polyposis SMAD4, PTEN
Characteristics of Hereditary CRC
Early age at onset
Multiple CRC in an individual
Other tumors in family: endometrial, breast, sabecous cyst.
Hamartomatous polyps
HNPCC Incidance: 1/1000
CRC risk: 70-85%
Endometrium: 50%
Synchronous & metachronous CRC: 35%
Other tumours 15%)renal pelvis, ureter, stomach, small bowel, OC, BC, brain(
HNPCC-clinical features
Proximal colon
Better prognosis
Benign adenomas at early age - villous
- more dysplastic
Pathology: TIL (tumor infiltrating lymphocytes Crohn’s like lymphocytic reaction (
HNPCC – Amsterdam criteria
At least 3 cases of HNPCC related tumors
One is first degree relative of the others
2 successive genrations
At least one diagnosed under 50y
FAP excluded
HNPCC – gene function
Correction of mismatch during DNA replication
MSHs complex recognise mismatch
MLH, PMS complex recruited later to accomplish mismatch repair
Also recognises lesions caused by exogenous mutagenes
HNPCC – gene function
Mismtch repair deficiency microsatellite instability
Microsatellite – repetative noncoding DNA sequences - susceptible to mismatch replication errores
Mismatch in MS (MSI) frameshift mutations in genes involved in tumor intiation
and progression: APC, kras , p53, TGFbetaRII
HNPCC – gene function
TGF beta receptor II – tumor supressor gene
- mutated in 90% of MSI colon cancer
TGF beta family: growth regulation of epithel especialy colon. induces apoptosis
bindes to receptor with 2 subunits RI, RII
RII – includes 10bp polyadenin repeat vulnerable to mutation in MSI tumors
In MSI - low tumors also mutations (other) in TGFbetaRII or downstream genes (SMAD2, SMAD4)
HNPCC – mulecular genetic tests
MSI – 70% of HNPCC tumors 15% of sporadics
50-60% in pt diagnosed under 30y
Half of MSI germline mutation is found
Immunohistochemistry: MLH1, MSH2, MSH6 loss of expression
Mutation detection done after combining MSI +IHC + clinics
In 60% mutation in MLH1, MSH2
HNPCC - treatment interval
20 - 25y colonoscopy 2y
30 – 35y gynecologic examination, vaginal US 1-2y
30 – 35y gastrodoudenoscopy 1-2y
30 – 35y Abdominal US, cytology urine 5y
Total colectomy + ileorectal anastomosis in CRC pt)risk for syn or metachronous – 25 – 40%(
FAP Autosomal dominant
1/8000
Clinical features: hundreds to thousends of polyps ( decades 2 – 3)
100% cancer by age 45
UGI polyps–doudenal: 50-90%, potentially malig) in less then 5%(
gastric : 10%, non malignant
FAP – extracolonic manifestation
Desmoid tumors OsteomasCongenital retinal pigmented epithelium (CRPE, in 75%)
Other tumors: thyroid, hepatoblastoma, brain
Genotype/phenotype correlation
FAP – gene function
Cell adhesion
Differentiation
Apoptosis
Cell cycle regulation
Transmition of signals to the nucleus
FAP - recommendationSurvaillance
intervalGenetic testing 12ySigmoidoscopy 12y 2yColonoscopy, endoscopy 18-20y 1yDuodenoscopy 30y 2y
Prophylactic surgery :proctocolectomy & ileal poutch anastomosis (age; polyps no.
&desmoid tu(.Colectomy & ileorectal anastomosis (rectal ca. mortality-12%)
Breast Cancer Susceptibility :Genes
BRCA1BRCA2
A Frameshift Mutation
A1 A2 A3 A4 A5 A6 A7
- - - - - - - - - - - - - - - - - - - - -
del
A1 A2 A3 A A stop codon
- - - - - - - - - - - - - - - - - -
Protein truncation
A Frameshift Mutation
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Ashkenazi Mutations in Breast and Ovarian CA Patients
Distribution by age
0
10
20
30
40
50
60
70
80
90
<30 30-39 40-49 50-65 >65
OvaryBreast
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Cases with bilateral Controls P
disease (n=209) (n=384)
Radiotherapy 101(48%) 212(55%) 0.110
Chemotherapy 88(42%) 234(61%) 0.0001
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III2
Narod, 2000
Frequency of Psychological and Social outcomes of prophylactic mastectomy
Frost M (JAMA) 2000
Prophylactic Mastectomy
• Reasons for having had prophylactic mastectomy
• Long-term psychological and social function
• What factors are associated with prophylactic mastectomy satisfaction or dissatisfaction for women at high risk?
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Frost M (JAMA) 2000
The contribution of the BRCA mutation to breast and ovarian cancer morbidity in
Ashkenazi patients
0
10
20
30
40
50
60
70
80
90
BC&OC OC BBC BC<40y BC healthy
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