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 179 families BRCA mutated Milano Pisa Padova ModenaChieti-Aquila Aviano 104 families BRCA1 mutated75 families BRCA2 mutated

1:1 1:2 2:1 Colonrectum 50 ~60 2:2 CNS :3 ~60 1:3 1:4 3:1 BRCA2 Q2960X Breast sx :2 Breast :3 Breast :5 BRCA2 Breast :6 BRCA2 Breast :4 Breast :7 68 4:1 WT 38 4:2 WT 34 4:3 BRCA2 Breast :4 50 4:5 47 4:6 WT 44 4:7 47 4:8 42 5:1 22 5:2 17 5:3 18 4:9 39 4:10 40 Other TumorsBreast

BRCA1 AND BRCA2 RECURRENT MUTATIONS

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). BRCA mutated family profile

BRCA1 BRCA2 TOT P HBC HBOC HOC MBC TOT Statistically significant differences were observed between two genes within family groups

BRCA1BRCA2 Average age of BrCa onset 40.4± ±10.9 on mutation carriers Average age of OvCa onset 48.3± ±7.2 on mutation carriers P<0.005 (Kruskal-Wallys Test) ANALYSIS OF AGE AT ONSET OF BREAST AND OVARIAN CANCER IN MUTATION CARRIERS

KAPLAN-MEIER ESTIMATE OF PROPORTION OF DISEASE-FREE MUTATION CARRIERS Age BRCA1 BRCA2 N=133 (17 censored) N=89 (12 censored) P < 0.005, Cox-Mantel log-rank test

HETEROGENEITY BETWEEN LOCI FOR CANCERS OTHER THAN BREAST OR OVARIAN

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 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

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 CONCLUSIONS

*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 DAndrea, 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.