EPIDEMIOLOGY Novel BRCA1 and BRCA2 germline mutations and assessment of mutation spectrum and prevalence in Italian breast and/or ovarian cancer families Giuseppe Giannini Æ Carlo Capalbo Æ Elisabetta Ristori Æ Enrico Ricevuto Æ Tina Sidoni Æ Amelia Buffone Æ Enrico Cortesi Æ Paolo Marchetti Æ Giovanni Scambia Æ Silverio Tomao Æ Christian Rinaldi Æ Massimo Zani Æ Sergio Ferraro Æ Luigi Frati Æ Isabella Screpanti Æ Alberto Gulino Received: 12 December 2005 / Accepted: 11 March 2006 / Published online: 9 May 2006 Ó Springer Science+Business Media B.V. 2006 Abstract Familial aggregations of breast/ovarian cancer cases frequently depend on BRCA1/2 pathogenic muta- tions. Here we counselled 120 Italian breast/ovarian cancer families and selected 73 probands for BRCA1/2 mutation screening. Through this analysis we defined the prevalence of BRCA1/2 pathogenic mutations occurring in Italian breast/ovarian cancer families, enlarged the spectrum of Italian BRCA1/2 mutations by 15% and report on the identification of 13 novel variants, including two deleteri- ous truncating mutations and two potentially pathogenic missense mutations, on the BRCA1 and BRCA2 genes. Finally in hereditary breast cancer families with three or more female breast cancer cases we observed a low mutation prevalence and a significant association with BRCA2 mutations. Keywords BRCA1 Æ BRCA2 Æ Breast cancer Æ Familial cancer Æ Ovarian cancer Introduction Breast cancer concerns approximately 30% of all cancers in women. It is an extremely complex, heterogeneous and multifactorial disease characterised by a progressive mul- tistep process caused by interactions of both genetic and non-genetic factors. About 70% of all breast cancers are sporadic forms, 20% are familial and about 10% are hereditary [1]. Several genes confer susceptibility to breast and/or ovarian cancer. However, BRCA1 (OMIM #113705) and BRCA2 (OMIM #600185) are the most important genes in the context of the inherited syndromes. BRCA1 maps on chromosome 17p21 and encodes a protein of ~ 220 kDa [2]. BRCA2 is a large gene, localised on the long arm of chromosome 13 and encodes a protein of 380 kDa [3]. Both proteins are involved in a multitude of cellular processes, including but not limited to, DNA damage repair [4]. It was recently estimated that a com- bination of BRCA1 and BRCA2 gene mutation is respon- sible for about 20–30% of the cases with breast cancer familial history [5, 6] and genetic testing for mutations in these genes is pivotal for the evaluation of breast/ovarian cancer risk in familial aggregations. Pathogenic mutations in BRCA1 and BRCA2 strongly increase the risk of developing breast and/or ovarian cancer. Initial data from the Linkage Consortium Study indicated an 85% probability G. Giannini (&) Æ C. Capalbo Æ E. Ristori Æ A. Buffone Æ E. Cortesi Æ M. Zani Æ S. Ferraro Æ L. Frati Æ I. Screpanti Æ A. Gulino Department of Experimental Medicine and Pathology, University La Sapienza, Policlinico Umberto I Viale Regina Elena, 324, 00161 Rome, Italy e-mail: giuseppe.giannini@uniroma1.it Tel.: +39-06-4958637 Fax: +39-06-4461974 P. Marchetti Medical Oncology, IDI-IRCCS, 00167 Rome, Italy E. Ricevuto Æ T. Sidoni Æ P. Marchetti Department of Experimental Medicine, University of L’Aquila, 67010 L’Aquila, Italy G. Scambia Department of Oncology, Catholic University of the Sacred Heart, Campobasso, Italy S. Tomao Department of Medical Oncology, Regina Elena Cancer Institute, Rome, Italy C. Rinaldi Æ L. Frati Æ A. Gulino Neuromed Institute, Pozzilli, Italy Breast Cancer Res Treat (2006) 100:83–91 DOI 10.1007/s10549-006-9225-9 123