BRCA2 - Tumori Ereditari

EFFETTO FONDATORE DELLE
MUTAZIONI BRCA1 E BRCA2
RICORRENTI NELL’AREA DEL
TRIVENETO
Elisa Pin, Elisa Cupelli, Lara della Puppa, Angela
Valentina D’Elia, Giuseppe Damante, Laura Papi,
Gianmaria Miolo, Riccardo Dolcetti, Clelia de
Giacomi, Andrea Piga, Carla Dellach,
Alessandra Viel
Modena 18-19 novembre 2010
BRCA RECURRENT MUTATIONS
BRCA1
BRCA2
MUTATION
CRO
BIC
MUTATION
CRO
BIC
C39Y
7x
4x (1)
IVS16-2A>G
10x
5x (1)
795delT
7x
12x
5910C>G (Y1894X)
5x
61x
1806C>T(Q536X)
7x
88x (1)
9106C>T (Q2858X)
5x
10x (1)
5385insC
7x
1063x (1)
C61G
7x
222x
235 G>A 300T>G
(C39Y)
(C61G)
1806C>T
795delT (Q536X)
5385insC
BRCA1
1
2
3
5 6
7 8 9 10
11
5910C>G
(Y1894X)
12 131415 16 17 18 19 20 21 22 23
24
9106C>T
(Q2858X)
IVS16-2A>G
BRCA2
1 2 3 4 5 6
7 8 9
10
11
12 13 14 15 16 17 18 19
20
21 22 23 24 25 26 27
BIC
BRCA1
BRCA2
AUSTRIA
FRIULI
VENEZIA
GIULIA IVS16-2A>G
UDINE
795delT
VENETO
GORIZIA
PORDENONE 5910C>G (Y1894X)
9106C>T (Q2960X)
TREVISO
1806C>T (Q536X)
VENEZIA
SLOVENIA
235G>A (C39Y)
300T>G (C61G)
1806C>T (Q536X)
5385insC
TRIESTE
KOPER
The 8 recurrent mutations represent 38% (55/145) of
the identified BRCA mutations in our total series of
screened cases, but more than 50%, if we focus on the
families with probable North-East Italian origin.
The comparison of haplotypes among families with the same mutation
can distinguish whether high frequency BRCA alleles derive from a
single mutation event (old or recent) or whether they are arisen
independently more than once.
Cases and Controls
BRCA1 (5 mutations):
- 33 carrier probands
- 48 relatives (21 carrier, 27
non-carrier)
- 91 healthy controls from the
same geographic area.
BRCA2 (3 mutations):
- 19 carrier probands
- 44 relatives (21 carrier, 23
non-carrier)
- 91 healthy controls from the
same geographic area.
Haplotype analysis of 7 polymorphic markers flanking the BRCA1 locus (chr.17q21)
Haplotype analysis of 7 polymorphic markers flanking the BRCA2 locus (chr.13q12)
Seq. Pos. chr.17
HuRef
Celera
Prim Ass
Marshfield (cM)
D17S806
41180919-41181089
42264655-42264825
45811845-45812021
66.85
D17S902
37412061-37412214
38356859-38357011
41647204-41647339
64.16
D17S1325
37300854-37301077
38245247-38245460
41535531-41535746
D17S855 (BRCA1)
36971090-36971236
37861601-37861747
41204744-41204894
D17S1328
36925543-36925738
37816051-37816246
41159779-41159976
D17S800
34850782-34850955
35717993-35718164
39056423-39056594
62.01
D17S250
32947505-32947658
33812922-33813073
37152092-37152243
62.01
8233 kb
4.84 cM
T
C
Seq. Pos. chr.13
HuRef
Celera
Prim Ass
Marshfield (cM)
D13S267
15075879 - 15076032
15330793 - 15330946
34264233 - 34264380
26.87
D13S171
14064951 - 14065177
14320748 - 14320974
33253937 - 33254167
25.08
D13S1701
13955677 - 13955966
14211351 - 14211640
33144530 - 33144819
D13S1698
13516128 - 13516286
13771290 - 13771448
32704522 - 32704676
D13S260
13247998 - 13248162
13503800 - 13503964
32436833 - 32436997
23.65
D13S290
12240204 - 12240379
12495878 - 12496055
31429323 - 31429512
21.51
D13S1246
11923172 - 11923372
12174871 - 12175071
31105534 - 31105738
20.44 ?
BRCA2
3155 kb
6.43cM
T
C
BRCA2 CASE-CONTROL CARRIER FREQUENCIES
D13S171
D13S267
IVS16 - 2A>Gprobands
(9)
CONTROLS
(85 - 91)
144
9
0
100
%
0%
44
41
52
%
48%
Fisher p
5910C<G probands
(5)
CONTROLS
(85 - 91)
others
3
2
60
%
40%
34
51
40
%
60%
(5)
CONTROLS
(85 - 91)
Fisher p
others
155
others
158
others
174
others
9
0
9
0
8
1
8
1
9
0
100%
0%
100%
0%
89%
11%
89%
11%
100%
0%
67%
33%
61
29
26
62
40
51
26
64
74
13
48
42
68%
32%
30%
70%
44%
56%
29%
71%
85%
15%
53%
47%
4
1
80
%
20%
44
41
52
%
48%
0.366
0.000049
0.013131
0.000712
205
others
6
3
0.504
0.604
226
others
299
others
155
others
162
others
174
others
201
others
5
0
5
0
5
0
5
0
5
0
4
1
100%
0%
100%
0%
100%
0%
100%
0%
100%
0%
80%
20%
40
50
26
62
40
51
17
73
74
13
24
66
44%
56%
30%
70%
44%
56%
19%
84%
85%
15%
27%
73%
0.021086
others
D13S1246
299
0.398
144
D13S290
D13S260
others
0.054
156
D13S1698
230
0.0045
Fisher p
9106C>T probands
others
D13S1701
0.003269
0.019988
0.000454
0.025
1
240
others
287
others
173
others
168
others
174
others
199
others
5
0
5
0
4
1
4
1
5
0
4
1
100%
0%
100%
0%
80%
20%
80%
20%
100%
0%
80%
20%
50
40
21
67
3
88
26
64
74
13
29
61
56%
40%
24%
76%
3%
97%
29%
71%
85%
15%
32%
68%
0.071
0.001265
0.000051
BRCA2
0.033
1
0.047
BRCA2 CASE-CONTROL ALLELE FREQUENCIES
D13S171
D13S267
IVS16 - 2A>Gprobands
(18 alleles)
CONTROLS
(170 - 182 alleles)
(10 alleles)
CONTROLS
(170 - 182 alleles)
(10 alleles)
CONTROLS
(170 - 182 alleles)
Fisher p
D13S260
230
others
299
others
155
others
158
others
174
others
14
4
13
5
10
8
11
7
9
9
14
4
78%
22%
72%
28%
56%
44%
61%
39%
50%
50%
78%
22%
68
102
73
107
51
125
46
136
28
152
105
69
40%
60%
41%
59%
29%
71%
25%
75%
16%
84%
60%
40%
0.044
0.0025
0.031
0.004264
D13S1246
D13S290
others
0.001530
205
others
7
39%
11
61%
60
33%
120
67%
0.203
0.612
156
others
226
others
299
others
155
others
162
others
174
others
201
others
3
7
5
5
6
4
6
4
5
5
7
3
4
6
30%
70%
50%
50%
60%
40%
50%
50%
50%
50%
57%
43%
40%
60%
38
132
40
140
51
125
46
136
19
161
105
69
26
154
22%
78%
22%
78%
29%
71%
25%
75%
11%
89%
60%
40%
14%
86%
Fisher p
9106C>T probands
D13S1698
144
Fisher p
5910C<G probands
D13S1701
0.058
0.697
0.070
0.025
0.003493
0.742
0.053
144
others
240
others
287
others
173
others
168
others
174
others
199
others
5
5
7
3
5
5
5
5
4
6
8
2
4
6
50%
50%
70%
30%
50%
50%
50%
50%
40%
60%
80%
20%
40%
60%
68
102
61
119
22
154
4
178
28
152
105
69
32
148
40%
60%
34%
66%
12%
88%
2%
98%
16%
84%
60%
40%
18%
82%
0.529
0.036
0.006161
0.000014
BRCA2
0.066709
0.320
0.097
BRCA1 HAPLOTYPE SPAN
Shared by all carriers
MUT
D17S806
D17S902
D17S855
D17S1328
D17S800
D17S250
C39Y
170
149
149
247
170
149
795delT
170
149
149
247
174
1806C>T
170
145
145
247
5385insC
170
141
151
C61G
172
141
153
Proband
Yes/No
Control
Yes/no
P
7/0
83/7
1
149
7/0
10/80
170
153
5/0
83/7
247
170
153
7/0
33/56
247
166
147
7/0
3/87
1.5x 10-6
1
1.5x10-3
1x10-8
Shared by at least 50% carriers
MUT
D17S806
D17S902
D17S855
D17S1328
D17S800
D17S250
Proband
Yes/No
Control
Yes/no
P
C39Y
170
149
149
247
170
149
5/2
7/82
2.3x10-4
795delT
170
149
149
247
174
149
4/3
2/84
1.7x10-4
1806C>T
170
145
145
247
170
153
4/1
1/85
0.9x10-5
5385insC
170
141
151
247
170
153
4/3
4/85
6.6x10-4
C61G
172
141
153
247
166
147
5/2
1/87
0.2x10-5
BRCA2 HAPLOTYPE SPAN
Shared by all carriers
D13S267
D13S171
D13S1701
D13S1698
D13S260
D13S290
D13S1246
IVS16-2
144
230
299
155
160
174
205
5910C>G
156
226
299
155
162
174
9106C>T
144
240
287
173
168
174
MUT
Proband
Yes/No
Control
Yes/no
P
9/0
22/67
1.2x10 -
201
5/0
0/91
1x10 - 8
199
5/0
15/74
2.8x10 -
5
4
Shared by at least 50% carriers
MUT
D13S267
D13S171
D13S1701
D13S1698
D13S260
D13S290
D13S1246
Proband
Yes/No
Control
Yes/no
P
IVS16-2
144
230
299
155
160
174
205
6/3
2/89
1.8x10 -6
5910C>G
156
226
299
155
162
174
201
3/2
0/91
6.9x10 - 5
9106C>T
144
240
287
173
168
174
199
3/2
0/91
6.9x10 - 5
BRCA1 3228-3329delAG
Manual haplotype
reconstruction, assuming
the least number of possible
recombinations
Mutation age estimate with
the DMLE+2.2 software:
129 generations= 3225years
for example….
BRCA1 795delT
BR704
D17S250
D17S800
155
BR328, BR384
BR573, BR613
149
170/176
247
D17S855
149
D17S902
149
162
BR573
159
BR392
145/155
174
D17S1328
D17S806
BR128
170
BR128, BR328,
BR384, BR392,
BR613, BR704
•
•
•
•
•
PROVISIONAL CONCLUSIONS
The haplotypes significantly associated to the single mutations have
been identified by combining the analyses of
• allele frequency in probands and controls
• allelotype segregation in the families
These haplotypes are frequents in probands but absent or rare in
controls, and cosegregate with BRCA mutation in the family.
This preliminary analysis supports the “common ancestor”
hypothesis for all the investigated mutations.
In some cases this analysis will allow to establish the n° of
generations (and approximate age) of the recurrent mutations.
A specific test for this panel of recurrent mutations (5 BRCA1, 3
BRCA2) could represent a rapid and less expensive strategy for
mutation screening in the FVG/Veneto population.
Ringraziamenti: Associazioni UNICREDIT FVG e ANDOS

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