DATA ANALYSIS OF 179 BRCA1 OR
BRCA2 MUTATED FAMILIES.
THE ITALIAN CONSORTIUM FOR
HEREDITARY BREAST AND OVARIAN
CANCER.
DATABASES
Italian Consortium for Hereditary
breast and ovarian cancer
Aviano
Milano
Chieti-Aquila
Padova
Modena
Pisa
179 families BRCA mutated
104 families BRCA1 mutated
75 families BRCA2 mutated
Other Tumors
Breast
1:1
1:2
1:3
2:1
Colonrectum 50
~60
2:2
CNS 50
51
3:1
BRCA2 Q2960X
Breast sx 40
67
4:1
WT
38
3:2
Breast 31
34
4:2
WT
34
3:3
Breast 48
52
4:3
BRCA2
Breast 37
48
5:1
22
4:4
50
5:2
17
3:4
Breast 44
47
4:5
47
1:4
2:3
~60
3:5
BRCA2
Breast 30
75
4:6
WT
44
5:3
18
3:6
BRCA2
Breast 65
73
4:7
47
3:7
68
4:8
42
4:9
39
4:10
40
BRCA1 AND BRCA2 RECURRENT MUTATIONS
N° of families
per mutation
11
N° of mutations N° of mutations
BRCA1
BRCA2
1
(C61G)
10
1
(5382insC)
9
1
(6696delTC)
6
1
(1499insA)
5
2
(5083del19,
C64R)
4
3
1
(1207delA,
(IVS16-2A>G)
4035delTT)
3
3
3
(1207delA,
(432delA,
4035delTT,
9326insA,
Q563X)
Q2960X)
2
4
6
(1100delAT,
(5950delCT,
2846del4,
6132del4,
962del4,
6431insA,
delEx17)
9481insA,
9629delG,
Y1844X)
1
48
39
No. of different
63
50
mutations
BRCA mutated family profile
HBC 83 (46 %)
HBOC 69 (39 %)
HOC
11 ( 6 %)
MBC
16 (9 %)
Total 179 Families
Hereditary Breast Cancer (HBC, with cases of female breast
cancer only) , Hereditary Breast and Ovarian Cancer (HBOC, with
cases of both breast and ovarian cancer), Hereditary Ovarian
Cancer (HOC, with cases of ovarian cancer only) and Male Breast
Cancer (MBC, with at least 1 case of male breast cancer).
BRCA1
HBC
HBOC
HOC
MBC
TOT
41
52
10
1
104
BRCA2
TOT
42
17
1
15
75
83
69
11
13
179
P
0.04
0.0004
0.03
0.00003
Statistically significant differences were observed
between two genes within family groups
ANALYSIS OF AGE AT ONSET OF BREAST AND
OVARIAN CANCER IN MUTATION CARRIERS
Average age of BrCa onset
on mutation carriers
Average age of OvCa onset
on mutation carriers
BRCA1
BRCA2
40.4±10.6
45.5±10.9
48.3±8.9
57.8±7.2
P<0.005 (Kruskal-Wallys Test)
KAPLAN-MEIER ESTIMATE OF PROPORTION OF
DISEASE-FREE MUTATION CARRIERS
BRCA2
N=89
(12 censored)
BRCA1
N=133
(17 censored)
Age
P < 0.005, Cox-Mantel log-rank test
HETEROGENEITY BETWEEN LOCI FOR CANCERS
OTHER THAN BREAST OR OVARIAN
BRCA1 BRCA2
Cancer
families families
Lung
15
16
Gastric
11
15
Uterus
11
10
Prostate
4
14
Colonrectum
8
6
Hepatobiliary
9
5
CNS
8
5
Gastrointestinal
10
2
Leukemya
7
5
Pancreas
2
10
Others
35
26
Total
120
114
Chi
Total
square
31
0.104
26
0.838
19
0.222
18
6.084
14
0.192
14
0.948
13
0.547
12
4.934
12
0.239
12
5.755
63
0.942
234 20.806
P = 0.022
We summarized all our results about heterogeneity
between loci by fitting a logistic regression model to
the following variables:
1)the age of cancer onset in the proband
2)presence of ovarian cancer in the family (either in
the proband or in a relative)
3)presence of male breast cancer in the family (either
in the proband or in a relative)
4)presence of either prostate or pancreas cancer in
the family.
All four variables were statistically associated with the
mutated locus at the 0.001 significance level, and
were weakly correlated one to the other
FREQUENCY OF OBSERVED BRCA MUTATIONS AS A
FUNCTION OF P (THE PROBABILITY OF FINDING A
BRCA2 MUTATION)
BRCA1
BRCA2
0.8-0.9
CONCLUSIONS
•A relevant proportion of mutations occur in multiple
independent families across Italy
•A substantial level of phenotypic heterogeneity exists
between BRCA1- and BRCA2-mutated families
•A regressive model based on this heterogeneity is highly
efficient in directing the mutational screening
These are a critical step in the
development of simple and less
expensive diagnostic approaches to
DNA analysis and facilitate carriers
detection and genetic counseling
*Partecipant Units:
Co-ordinating unit: Generoso Bevilacqua, M. Adelaide Caligo, Giovanna Cipollini, Paolo
Aretini, Elisa Sensi, Chiara Ghimenti, Mariella Tancredi. Dipartimento di Oncologia, dei
Trapianti e delle NuoveTecnologie in Medicina. Divisione di Anatomia Patologica e di
Diagnostica Molecolare ed Ultrastrutturale, Università di Pisa. Silvano Presciuttini
Dipartimento di Biomedicina Sperimentale Infettiva e Pubblica, Università di Pisa.
Alessandra Viel, Manuela Santarosa, Dolcetti Riccardo, Centro Riferimento Oncologico,
IRCCS, Aviano, Maria Grazia Tibiletti, Universita' dell'Insubria, Varese.
Unit1: Renato Mariani-Costantini, Alessandro Cama, Mario Falchetti: Dipartimento di
Oncologia e Neuroscienze, Università "G. D'Annunzio", Chieti ;Cristina D'Amico, Laura
Ottini: Dipartimento di Medicina Sperimentale, Università "La Sapienza", Roma. Paolo
Marchetti, Enrico Ricevuto, Z. Cristiana di Rocco, Roberta Bisegna, Corrado Ficorella.
Dipartimento di Medicina Sperimentale, Università dell'Aquila.
Unit2: Luigi Chieco-Bianchi, Emma D’Andrea, Arcangela De Nicolo, Simona Agata,
Dipartimento di Sc. Oncologiche e Chirurgiche, Sezione di Oncologia, Università di
Padova. Chiara Menin, Marco Montagna, IST - Sezione Biotecnologie, Università di Padova.
Unit3: Paolo Radice, Barbara Pasini, Valeria Pensotti, Rosella Crucianelli, Alberto Conti,
Giovanbattista Spatti, Giuseppe De Palo, Marco Pierotti. Istituto Nazionale Tumori, Milano.
Unit4: Sergio Ferrari, Laura Cortesi, Daniela Turchetti, Chiara Bertoni, Dipartimento di
Scienze Biomediche, Sezione di Chimica Biologica, Università di Modena.