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Clinical genetics
of cancer family syndromes
– Polish experience
J. Lubiński
INTERNATIONAL HEREDITARY CANCER CENTER
POMERANIAN MEDICAL UNIVERSITY, SZCZECIN, POLAND
READ-GENE SA
Sankt Petersburg 4.10.2014
Hereditary Cancer Center Szczecin
Pomeranian Medical University:
 Cancer Genetics Outpatient Clinics
 Dept Genetics Pathology
 Internetional Hereditary Cancer Center
(journal – Hereditary Cancer in Clinical Practice: IF 2.1)
 Oncology clinics:
 Chemotherapy
 Surgery
 Gynecology
 Urology
 Others
Read-Gene Spin-off Company
Acknowledgment
 Cybulski Cezary1, Byrski Tomasz1, Jakubowska Anna1, Gronwald Jacek1, Huzarski Tomasz1,
Wokołorczyk Dominika1, Masojć Bartłomiej1, Dębniak Tadeusz1, Górski Bohdan1, Narod Steven
A.2, Marczyk Elżbieta3, Blecharz Paweł3, Ashuryk Oleg1, Zuziak Dorota4, Wiśniowski Rafał4,
Godlewski Dariusz5, Jaworska Katarzyna1*, Durda Katarzyna1, Gupta Satish1*, Muszyńska
Magdalena1, Sukiennicki Grzegorz1, Grodzki Tomasz6, Waloszczyk Piotr6, Jaworowska Ewa7,
Lubiński Jakub7, Kładny Józef8, Wilk Grażyna9, Górecka Barbara9, Sikorski Andrzej10, Gołąb
Adam10, Tołoczko-Grabarek Aleksandra1, Lubiński Jan1:
 1Department of Genetics and Pathomorphology, International Hereditary Cancer Center,
Pomeranian Medical University, Szczecin;
2Women’s College Research Institute, Toronto, Ontario, Canada;
3Regional Oncology Center, Bielsko-Biała;
4Oncology Institute, Kraków;
5Center for Epidemiology and Prevention, Poznań;
6Lung Diseases Hospital, Szczecin;
7Department of Otolaryngology and Laryngological Oncology, Pomeranian Medical University,
Szczecin;
8Clinics of Surgey, Pomeranian Medical University, Szczecin;
9Department of Radiology, Pomeranian Medical University, Szczecin;
10Clinics of Urology, Pomeranian Medical University, Szczecin;
*Postgraduate School of Molecular Medicine, Warsaw Medical University.
Family history of cancer
– strong indication
of high genetic risk of malignancies
West Pomerania 2000-2001
 1.7 mln of inhabitants
 1.28 mln (75%) of cancer family
histories collected via family
doctors
West Pomerania 2000-2001
 BRCA1 testing – all of females
with at least one breast / ovarian
cancer among relatives
West Pomerania 2000-2001
 Other DNA tests – MSH2 / MLH1; VHL;
RB1; APC etc.
 Limited to persons pre-selected
depending on pedigrees and other
clinical data
West Pomerania 2000-2001
 HNPCC
1 CRC
≥ 1 cancer from the spectrum
(CRC, END, SB, urinary t.)
≥ 1 cancer dgn <50 yrs
 Familial aggregation of the cancers of one-two
sites i.e. colon, stomach, pancreas, breast –
ovaries, etc.
 Other strong cancer familial aggregations
Luck!!!
Poland
 If genetic events present
they are expressed strongly
Górski B. et al. AJHG, June 2000
POLISH PANEL
OF BRCA1 MUTATIONS
 BRCA 1
 BRCA2
~65%
~4%
Górski B. et al. Int. J. Can, 2004
POLISH FAMILIES WITH STRONG AGGREGATION
OF BREAST/OVARIAN CANCERS (n=200)
 5382 ins C
 C 61 G
 4153 del A
90% of mutations
Górski B. et al. Int. J. Can, 2004
BRCA1 FOUNDER MUTATIONS
IN POLAND
 GÓRSKI B. ET AL.
- PATENT NO P335917
- MULTIPLEX PCR - 50€
POPULATION SCREENINGS
IN POLAND
 4% (~200) of BRCA1
carriers among 5000
relatives of women with
breast cancer dgn < 50
yrs or ovarian cancer dgn
at any age
 Thanks to geneticists
- oncologists from 20
Polish centers!
BRCA1 – REGISTRY
– SZCZECIN – POLAND
> 5000 CARRIERS
THE LARGEST REGISTRY
IN THE WORLD
CHEK2 mutations
- Poland - epidemiology
a) Protein truncating mutations
1100 delC
IS2 + 1 G  A
1,5%
del5000
b) Missense mutation
I157T
5%
CHEK2 mutations
- high risk of breast cancer OR > 5
a) PTM + family history
C. Cybulski et al. 2011 JCO
b) PTM + I157T
C. Cybulski et al. 2009 JMG
c) PTM + CYP1 B1
T. Huzarski et al. 2012 in prep.
d) I157T + BRCA2 5972 C/T
P. Serrano-Fernández Br Can Res Treat 2009
Sequencing in diagnostics
of high genetic risk of breast cancer
Cybulski C., Scott R. Lubiński J., 2014
„Exom sequencing”
 144 women with breast cancer from
families with ≥ 3 BC cases
 11 BRCA1/2 founder mutations (−)
 4 CHEK2 founder mutations (−)
Cybulski C. 2014
Results
 12 BRCA2 mutations
 5 BRCA1 mutations





3 PALB2
2 ATM
1 BARD1
1 CHEK2
1 XRCC2
 + candidate genes
single mutations
17/144 11,8%
9/144 6,3%
5/144 3,5%
Mutations detected using
„Exom sequencing”
Gen
Exon 1
HGVS Protein 1
ATM
49
p.Glu2366*
ATM
40
p.Glu1991*
ATM
8
p.Glu564*
BRIP1
19
p.Ser895_IIe896delins*
CHEK2
8
p.Leu301fs
PALB2
12
p.Tyr1108*
PALB2
4
p.Arg170fs
PALB2
3
p.Gln60fs
XRCC2
2
p.Phe32fs
Conclusions
 Costs of sequencing
 BRCA1/2
 Gene panel
~500 €
~1500 €
 It is important to develop an algorithm for
selection of families with breast cancers for
diagnostic sequencing
 BRCA1/2 mutation frequency in
triple negative breast cancers
Scott R. 2014
BRCA1/2 mutations – breast cancers
No — triple negative
<51 r.ż.
51–60 r.ż.
> 60 r.ż.
8/469 (1,7%)
10/1115 (0,9%)
5/1093 (0,5%)
<51 r.ż.
51–60 r.ż.
> 60 r.ż.
Test
Standard - 3 mutations
Triple negative
Test
Standard - 3 mutations
35/90 (38,9%) 22/170 (12,9%)
7/1242 (4,7%)
Extended - 8 mutations
3/90 (3,3%)
0/170 (0%)
0/1242 (0%)
„NGS”
8/90 (8.8%)
9/170 (5,3%)
6/1242 (4%)
11/55 = 20%
Scott R. 2014
Conclusions
 Assuming an acceptable cost of 10 000 zł of
detection of one BRCA1/2 mutation carrier,
sequencing costs of 2 000 zł is economically
justified for patients with breast cancers: triple
negative and early onset (<51 years of age)
Purpose
 To estimate the influence of the oral contraceptive
use by BRCA1 carriers on risk of breast cancer with
respect:
- age of beginning
- duration
Patients and Methods
 72 participating centers (13 countries)
 CASE-CONTROL STUDY: BRCA1 carriers - 2492
women affected with breast cancer vs. 2492 matched
healthy controls
 Data were collected from the questonnaires
 Varibles between cases and controls were compared using Student’s t-test
and chi-square test; conditional logistic regression was used to estimate
OR and 95% CI
Relationship between oral contraceptive use and breast cancer risk
among BRCA1 mutation carriers
Variable
Controls (n)
Cases (n)
OR
(95 % CI)a
P
1,048
1,00
(1,03–1,36)
0,02
Oral contraceptive use
Never
1,084
Ever
1,408
1,474
1,18
Trend per year
1,01
(1,00–1,03)
0,05
Never
1,084
1,018
1,00
0–<5
629
630
1,14
(0,97–1,35)
0,11
5–<10
431
455
1,19
(0,99–1,43)
0,07
10–<15
225
258
1,27
(1,02–1,60)
0,04
15–<30
123
131
1,23
(0,92–1,65)
0,16
Trend
0,02
1,084
1,018
1,00
<20
526
619
1,45
(1,20–1,75)
0,0001
20–<25
235
534
1,19
(0,99–1,42)
0,06
25–<30
205
191
1,06
(0,84–1,33)
0,62
30–>60
142
130
0,98
(0,76–1,27)
0,88
Trendb
0,0003
1,302
1,302
1,40
(1,14–1,70)
0,001
40–50 years
980
980
0,95
(0,76–1,20)
0,68
>50 years
210
210
1,08
(0,66–1,77)
0,75
Duration of use (years)
Age at first use (years)
Never
Age of diagnosis, ever/never use
<40 years
Relationship between duration of oral contraceptive use prior to age 20
and breast cancer risk among BRCA1 mutation carriers
Relationship between oral contraceptive use and risk of breast cancer
diagnosed prior to age 40 among BRCA1 mutation carriers
Conclusion
 Effect of oral contraceptive is harmful for early-onset
breast cancer if use is initiated prior to age 25
 Women with BRCA1 mutation should be advised to
avoid oral contraceptive use before age of 25
Purpose
 To estimate the reduction in risk of ovarian, fallopian tube, or
peritoneal cancer in BRCA1/2 carriers after oophorectomy;
 To estimate the impact of prophylactic oophorectomy on allcause mortality;
 To estimate 5-year survival associated with clinically detected
ovarian, occult, and peritoneal cancers diagnosed in the
cohort.
Patients and Methods
 5,783 BRCA1/2 carriers
 An average follow-up period - 5.6 years
 Hazard ratios (HRs) for cancer incidence and allcause mortality associated with oophorectomy were
evaluated
91.6%
54.4%
38.4%
Conclusion
 Preventive oophorectomy was associated with an 80%
reduction in the risk of ovarian, fallopian tube, or peritoneal
cancer in BRCA1 or BRCA2 carriers and a 77% reduction in
all-cause mortality.
Studies on micro- and
macro- elements – summarization
Retrospective studies
 Selection of individuals with a few times
of increased chance of cancer detection
– CT of the lung, coloscopy, PSA and
prostate biopsies
Lubiński J. 2014
Prospective observational
studies
 Micro- macro- elements levels
as cancer risk factor
Lubiński J. 2014
Mortality – all causes
Risk of death (95% CI)
n=13887 adults, 18 yrs follow-up, USA
60
70
Poland
140
USA
Serum selenium concentration (µg/l)
M. Rayman, Lancet 2012
Se; independantly on genotypes
BRCA(−)
Quartiles
Cancers
Control
Se
n=45
n=221
48.2–69.4
11
54
69.5–75.9
8
58
75.9–84.1
10
55
84.4–128.1
16
50
16 & 50 vs 8 & 58
p=0,11; OR=2.3; CI=0.9–5.8
BRCA(−)
Ranges
Se
<70
70–85
85–100
>100
Cancers
Control
11
57
18
116
7
35
9
9
9 & 9 vs 36 & 212
p=0,0004; OR=5.89; CI=2.19–15.84
BRCA(+)
Quartiles
Cancers
Control
Se
n=45
n=90
49.9–67.0
12
22
67.1–72.9
14
20
73.1–80.1
9
25
80.2–131.1
11
23
14 & 20 vs 9 & 25
p=0,3; OR=1.94; CI=0.7–5.4
BRCA(+)
Ranges
Cancers
Control
Se
n=45
n=90
<70
23
31
70–85
17
44
85–100
3
10
>100
2
3
23 & 31 vs 17 & 44
p=0,14;OR=1.9; CI=0.8–4.2
Fe/Zn; „S” nAA
BRCA(−)
Quartiles
Cancers
Controls
Fe/Zn
n=32
(n=173)
<0.88
10
41
0.88–1.10
8
43
1.10–1.30
0
51
>1.30
51
38
14 & 38 vs 0 & 51
p=0.0002; OR=38.8; CI=2.24–671
BRCA(+)
Quartiles
Cancers
Controls
Fe/Zn
n=35
n=68
<0.78
13
12
0.80–1.13
5
21
1.13–1.46
4
22
1.51–4.22
13
13
26 & 25 vs 9 & 43
p=0,0007; OR=4.97; CI=2.01–12.28
BRCA(−)
Ranges
Fe/Zn
Cancers
Controls
>1.10–1.40
0
65
≤1.10–>1.40
32
108
p<0,0001; OR=39.24; CI=2.36–652
BRCA(+)
Ranges
Fe/Zn
Cancers
Controls
0.80–1.50
9
43
<0.8 & >1.5
26
25
p=0,0007; OR=4.97; CI=2.01–12.28
Cancer risk can be decreased
by supplementation?
Clinical trials
American study
— NPC (Nutritional Prevention of Cancer)
 n=1312;
 mean age 63 yrs (18–80)
 randomised study;
 Se 200 μg/day or placebo;
 observation length 6–8 yrs;
 initial level of Se concentration
114 μg/l plasma
American study — NPC
Independantly on tumor site
Mortality
Se
Placebo
40
Morbidity
Se
105
Risk
p
66
0,59
0,008
Placebo
Risk
p
137
0,75
0,03
American study — NPC
Total morbidity depending on initial concentration of Se
Se level
Se
Placebo Risk
p
≤ 105,2 μg/l
27
54
0,51
0,005
105,3–121,6 μg/l
34
46
0,70
0,11
> 121,6 μg/l
44
37
1,20
0,43
American study — NPC
Morbidity on cancer
Site
Se
Placebo
Risk
p
Prostate
22
42
0,48
0,005
Lung
25
35
0,74
0,26
Colon
9
19
0,46
0,057
Breast
11
6
1,89
0,21
Meta-analysis of Randomized Controlled Trials
of Selenium Supplements in Cancer Prevention
Lee et al. Nutrition & Cancer, 2011; 63:1185-95
9 RCTs were included; 8 involved high-risk populations
Main analysis
Se supplementation alone was found to have an overall
preventive effect on cancer incidence
RR = 0.76; 95% CI = 0.58 to 0.99; n = 9
Subgroup analyses
The preventive effect was observed in
populations with low baseline serum Se (<125.6 g/L)
RR = 0.64; 95% CI = 0.53 to 0.78; n = 7
populations at high risk for cancer
RR = 0.68; 95% CI = 0.58 to 0.80; n = 8.
Rayman M. Szczecin 30.08.2012
Clinical trial
 Prevention of hereditary breast cancer by
personalized optimization of body Se, Zn, Fe
levels using diet supplements
 N=12000 females HBC, HBO
 N=2000 females BRCA1 carriers
 7000 supplementation with measurement of
microelements levels
 7000 controls
 5 years follow up (2014-2019)
Cisplatinum
in preoperative treatment
Authors
 T. Byrski, T. Huzarski, R. Dent, E. Marczyk, J. Gronwald, J. Jakubowicz,
C. Cybulski, R. Wiśniowski, D. Godlewski, J. Lubiński, S. Narod
Acknowledgments
 M. Siołek, M. Szwiec, H. Symonowicz, D. Surdyka, O. Ashuryk,
A. Jakubowska, B. Górski, T. Dębniak, D. Zuziak, D. Sawka
Thanks to Estēe Lauder
Patients
 107 BRCA1 carriers with breast cancers
in clinical stage I-III treated with cisplatinum
(4 cycles every 3 weeks 75 mg/m2)
December 2006 – June 2014
Response for treatment
Cisplatinum subgroup of advanced cancers




N3
N2
T4
T3+N
2
7
4
10
Pathological complete response – results




N3
1/2
N2
3/7
T4
2/4
T3+N 5/10
Cisplatinum
in preoperative treatment – control group
 4 314 breast cancer patients
 113 BRCA1 carriers
 29 standard preoperative treatment
(AT, TAC, FAC, FEC, AC)
Results
Groups
Effects
Cisplatinum
Controls
Pathological complete remission
48% (11/23)
10% (3/29)
Partial remission
52% (12/23)
69% (20/29)
0% (0/23)
21% (6/29)
No response
BRCA1 – dependant breast cancers
Treatment 2006-2014
(4,5 yrs „follow up”)
 Cisplatinum + adnexectomy, n=48
Deaths 1 (2%)
 Controls n=70
standard treatment
Death 9 (12,9%)
Conclusion
 Cisplatinum is extremaly effective
in preoperative treatment of breast cancers
in BRCA1 mutation carriers A1
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