This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ottini, L. Articles by Palli, D. Search for Related Content PubMed PubMed Citation Articles by Ottini, L. Articles by Palli, D.

BRCA1 and BRCA2 Mutation Status and Tumor Characteristics in Male Breast Cancer

A Population-based Study in Italy¹

Department of Experimental Medicine and Pathology, University La Sapienza, 00161 Roma [L. O., M. F., M. D. M.]; Department of Oncology and Neurosciences, University Gabriele D’Annunzio, 66013 Chieti [C. D., B. M., G. A., M. F., A. C., R. M-C.]; Molecular and Nutritional Epidemiology Unit, Centro per lo Studio e la Prevenzione Oncologica (CSPO), Scientific Institute of Tuscany, 50135 Florence [G. M., C. S., D. G., D. P.]; and Department of Pathology, University of Florence, 50139 Florence [V. V., S. B.], Italy

To investigate at the population level the impact of BRCA1/BRCA2 gene alterations in male breast cancer, we analyzed a population-based series of 25 male breast cancer cases from Florence, Central Italy. We combined mutational screening with the study of germ-line allele transcript levels and of tumor-associated losses of heterozygosity. Screening by protein truncation test and single-strand conformational polymorphism assay, followed by sequencing, revealed 4 pathogenetic mutations (4 of 25 = 16%; 95% confidence interval, 5–37%), 1 in BRCA1 and 3 in BRCA2, including mutations recurring in Central Italy (BRCA1 3345delAG and BRCA2 6696delTC). The a priori probability of carrying a mutation, estimated using BRCAPRO software, showed a good agreement between expected and observed mutations (14% versus 16%). A 7-fold association between germ-line mutations and family history of breast-ovarian cancer emerged. To investigate associations between BRCA1/BRCA2 status and clinicopathological characteristics, we analyzed the histopathological and immunophenotypic parameters of the tumors. A significant association emerged between mutation carrier status and high histological grade (P = 0.02). Furthermore, one BRCA2 carrier was affected with Paget’s disease, an extremely rare male breast cancer histotype. Overall, BRCA1/2 mutations were observed to be strongly associated with positive c-erbB-2 immunostaining (P = 0.004). To evaluate germ-line allele expression, we used primer extension assays targeting frequent BRCA1 and BRCA2 polymorphisms. A BRCA2 allele transcript imbalance was found in one of four heterozygotes tested, all of them negative for germ-line mutations. BRCA1 transcript imbalances were not detected in nine heterozygotes analyzed. Losses of heterozygosity at one or more of nine loci in the BRCA2 region were found in 8 of 22 tumors tested. Interestingly, a case that was negative for BRCA1/BRCA2 germ-line mutations and that had a priori mutation probability <10% showed loss of heterozygosity at all three of the intragenic BRCA2 markers analyzed, which could be related to a somatic involvement of BRCA2. No losses of heterozygosity were detected at BRCA1. In conclusion, constitutional BRCA1/BRCA2 mutations accounted for 16% of the male breast cancer cases in this area of Central Italy. The detection of a BRCA2 germ-line transcript imbalance and of a somatic loss of BRCA2 among the cases that resulted negative for germ-line mutations suggests a role of this gene more relevant than indicated by conventional mutational analysis. A distinct pattern of characteristics indicative of aggressive behavior, including high-grade and c-erbB-2 expression, was evident in tumors from germ-line BRCA2 mutation carriers. This suggests that phenotypic characteristics may contribute to the identification of hereditary BRCA2-related male breast cancers and that these tumors might share a unique molecular pathway of cancer progression.

This article has been cited by other articles:

				A. W. Kurian, G. D. Gong, E. M. John, A. Miron, A. Felberg, A. I. Phipps, D. W. West, and A. S. Whittemore Performance of Prediction Models for BRCA Mutation Carriage in Three Racial/Ethnic Groups: Findings from the Northern California Breast Cancer Family Registry Cancer Epidemiol. Biomarkers Prev., April 1, 2009; 18(4): 1084 - 1091. [Abstract] [Full Text] [PDF]

				A. W. Kurian, G. D. Gong, N. M. Chun, M. A. Mills, A. D. Staton, K. E. Kingham, B. B. Crawford, R. Lee, S. Chan, S. S. Donlon, et al. Performance of BRCA1/2 Mutation Prediction Models in Asian Americans J. Clin. Oncol., October 10, 2008; 26(29): 4752 - 4758. [Abstract] [Full Text] [PDF]

				D. C. Allain Genetic Counseling and Testing for Common Hereditary Breast Cancer Syndromes: A Paper from the 2007 William Beaumont Hospital Symposium on Molecular Pathology J. Mol. Diagn., September 1, 2008; 10(5): 383 - 395. [Abstract] [Full Text] [PDF]

				S. H. Giordano A Review of the Diagnosis and Management of Male Breast Cancer Oncologist, August 1, 2005; 10(7): 471 - 479. [Abstract] [Full Text] [PDF]

				J. R. Weiss, K. B. Moysich, and H. Swede Epidemiology of Male Breast Cancer Cancer Epidemiol. Biomarkers Prev., January 1, 2005; 14(1): 20 - 26. [Abstract] [Full Text] [PDF]

				N. Chunder, S. Mandal, A. Roy, S. Roychoudhury, and C. K. Panda Differential Association of BRCA1 and BRCA2 Genes with Some Breast Cancer-Associated Genes in Early and Late Onset Breast Tumors Ann. Surg. Oncol., December 1, 2004; 11(12): 1045 - 1055. [Abstract] [Full Text] [PDF]

				A. Liede, B. Y. Karlan, and S. A. Narod Cancer Risks for Male Carriers of Germline Mutations in BRCA1 or BRCA2: A Review of the Literature J. Clin. Oncol., February 15, 2004; 22(4): 735 - 742. [Abstract] [Full Text] [PDF]