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BRCA1/BRCA2 mutation status and clinical-pathologic features of 108 male breast cancer cases from Tuscany: a population-based study in central Italy

  • Epidemiology
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Abstract

Background Male breast cancer (MBC) is a rare and scarcely investigated disease. The strongest genetic risk factor for MBC is represented by inherited BRCA2 mutations, whereas the association between MBC and BRCA1 mutations is less clear. MBC appears to be biologically similar to breast cancer in females, however the phenotypic characteristics of BRCA1/2-related MBCs are not yet well elucidated. Objective To investigate the genetic and phenotypic characteristics of MBC in a large and well-characterized population-based series of 108 MBCs from Tuscany (Central Italy) and to evaluate associations between BRCA1/BRCA2 mutation status and clinical-pathological features including breast/ovarian cancer first-degree family history, tumor histology and grade, proliferative activity, estrogen/progesterone receptors (ER/PR) and epidermal growth factor receptor 2 (HER2) expression. Results BRCA1/BRCA2 mutations were identified in ten MBCs, in particular, two cases (1.9%) carried BRCA1 and eight cases (7.4%) carried BRCA2 mutations. The same BRCA1 mutation (3347delAG) was detected in two unrelated MBC cases. Three novel BRCA2 pathogenic mutations were found. Statistically significant associations emerged between BRCA2-related tumors and absence of PR expression (P = 0.008), HER2 over-expression (P = 0.002) and high tumor grade (P = 0.005). Conclusions Here, we (i) reported that in our population about 9% of MBC cases are accounted for by BRCA1/BRCA2 mutations; (ii) enlarged the BRCA2 mutational spectrum and (iii) characterized a specific phenotype associated with BRCA2-related MBCs suggestive of aggressive behavior. Overall, our results may have important implications on clinical management for this rare disease.

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References

  1. NCI, SEER (Surveillance Epidemiology and End Results) database 2007

  2. Speirs V, Shaaban AM (2008) The rising incidence of male breast cancer. Breast Cancer Res Treat (Epub ahead of print)

  3. Fentiman IS, Fourquet A, Hortobagyi GN (2006) Male breast cancer. Lancet 367:595–604. doi:10.1016/S0140-6736(06)68226-3

    Article  PubMed  Google Scholar 

  4. Zanetti R, Gafà L, Pannelli F, Conti E, Rosso S (eds) (2001) Il cancro in Italia 3. I dati dei Registri Tumori. Volume terzo: 1993–1998. Il Pensiero Scientifico Editore, Roma

  5. Agrawal A, Ayantunde AA, Rampaul R, Robertson JF (2007) Male breast cancer: a review of clinical management. Breast Cancer Res Treat 103:11–21. doi:10.1007/s10549-006-9356-z

    Article  PubMed  CAS  Google Scholar 

  6. Giordano SH (2005) A review of the diagnosis and management of male breast cancer. Oncologist 10:471–479. doi:10.1634/theoncologist.10-7-471

    Article  PubMed  Google Scholar 

  7. Ferla R, Calo V, Cascio S (2007) Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol 18(Suppl 6):vi93–vi98. doi:10.1093/annonc/mdm234

    Article  PubMed  Google Scholar 

  8. Baudi F, Quaresima B, Grandinetti C, Cuda G, Faniello C, Tassone P et al (2001) Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer. Hum Mutat 18:163–164. doi:10.1002/humu.1167

    Article  PubMed  CAS  Google Scholar 

  9. Pisano M, Cossu A, Persico I, Palmieri G, Angius A, Casu G et al (2000) Identification of a founder BRCA2 mutation in Sardinia. Br J Cancer 82:553–559. doi:10.1054/bjoc.1999.0963

    Article  PubMed  CAS  Google Scholar 

  10. Russo A, Calo V, Bruno L, Schiro V, Agnese V, Cascio S et al (2008) Is BRCA1-5083del19, identified in breast cancer patients of Sicilian origin, a Calabrian founder mutation? Breast Cancer Res Treat (Epub ahead of print)

  11. Malacrida S, Agata S, Callegaro M, Casella C, Barana D, Scaini MC et al (2008) BRCA1 p.Val1688del is a deleterious mutation that recurs in breast and ovarian cancer families from Northeast Italy. J Clin Oncol 26:26–31. doi:10.1200/JCO.2007.13.2118

    Article  PubMed  CAS  Google Scholar 

  12. Tournier I, Paillerets BB, Sobol H, Stoppa-Lyonnet D, Lidereau R, Barrois M et al (2004) Significant contribution of germline BRCA2 rearrangements in male breast cancer families. Cancer Res 64:8143–8147. doi:10.1158/0008-5472.CAN-04-2467

    Article  PubMed  CAS  Google Scholar 

  13. Woodward AM, Davis TA, Silva AG, Kirk JA, Leary JA (2005) kConFab investigators. Large genomic rearrangements of both BRCA2 and BRCA1 are a feature of the inherited breast/ovarian cancer phenotype in selected families. J Med Genet 42:e31. doi:10.1136/jmg.2004.027961

    Article  PubMed  CAS  Google Scholar 

  14. Gutierrez-Enriquez S, de La Hoya M, Martinez-Bouzas C, De Abajo AS, Cajal TR, Llort G et al (2006) Screening for large rearrangements of the BRCA2 gene in Spanish families with breast/ovarian cancer. Breast Cancer Res Treat 103:103–107. doi:10.1007/s10549-006-9376-8

    Article  PubMed  Google Scholar 

  15. Machado PM, Brandao RD, Cavaco BM, Eugenio J, Bento S, Nave M et al (2007) Screening for a BRCA2 rearrangement in high-risk breast/ovarian cancer families: evidence for a founder effect and analysis of the associated phenotypes. J Clin Oncol 25:2027–2034. doi:10.1200/JCO.2006.06.9443

    Article  PubMed  CAS  Google Scholar 

  16. Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J et al (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379–1388. doi:10.1001/jama.295.12.1379

    Article  PubMed  CAS  Google Scholar 

  17. Falchetti M, Lupi R, Rizzolo P, Ceccarelli K, Zanna I, Calò V et al (2008) BRCA1/2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases. Breast Cancer Res Treat 110:161–167. doi:10.1007/s10549-007-9689-2

    Article  PubMed  CAS  Google Scholar 

  18. Nahleh ZA, Srikantiah R, Safa M, Jazieh AR, Muhleman A, Komrokji R (2007) Male breast cancer in the veterans affairs population: a comparative analysis. Cancer 109:1471–1477. doi:10.1002/cncr.22589

    Article  PubMed  Google Scholar 

  19. Honrado E, Osorio A, Palacios J, Benitez J (2006) Pathology and gene expression of hereditary breast tumors associated with BRCA1, BRCA2 and CHEK2 gene mutations. Oncogene 25:5837–5845. doi:10.1038/sj.onc.1209875

    Article  PubMed  CAS  Google Scholar 

  20. Bane AL, Beck JC, Bleiweiss I, Buys SS, Catalano E, Daly MB et al (2007) BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays. Am J Surg Pathol 31:121–128. doi:10.1097/01.pas.0000213351.49767.0f

    Article  PubMed  Google Scholar 

  21. Kwiatkowska E, Teresiak M, Filas V, Karczewska A, Breborowicz D, Mackiewicz A (2003) BRCA2 mutations and androgen receptor expression as independent predictors of outcome of male breast cancer patients. Clin Cancer Res 9(12):4452–4459

    PubMed  CAS  Google Scholar 

  22. Burga AM, Fadare O, Lininger RA, Tavassoli FA (2006) Invasive carcinomas of the male breast: a morphologic study of the distribution of histologic subtypes and metastatic patterns in 778 cases. Virchows Arch 449:507–512. doi:10.1007/s00428-006-0305-3

    Article  PubMed  Google Scholar 

  23. Evans DG, Bulman M, Young K, Howard E, Bayliss S, Wallace A et al (2008) BRCA1/2 mutation analysis in male breast cancer families from North West England. Fam Cancer 7:113–117. doi:10.1007/s10689-007-9153-9

    Article  PubMed  CAS  Google Scholar 

  24. Syrjäkoski K, Kuukasjärvi T, Waltering K, Haraldsson K, Auvinen A, Borg A et al (2004) BRCA2 mutations in 154 finnish male breast cancer patients. Neoplasia 6:541–545. doi:10.1593/neo.04193

    Article  PubMed  Google Scholar 

  25. Ottini L, Masala G, D’Amico C, Mancini B, Saieva C, Aceto G et al (2003) BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res 63:342–347

    PubMed  CAS  Google Scholar 

  26. Parmigiani G, Berry DA, Aguilar O (1998) Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62:145–158. doi:10.1086/301670

    Article  PubMed  CAS  Google Scholar 

  27. Bianchi S, Palli D, Falchetti M, Saieva C, Masala G, Mancini B et al (2006) ErbB-receptors expression and survival in breast carcinoma: a 15-year follow-up study. J Cell Physiol 206:702–708. doi:10.1002/jcp.20535

    Article  PubMed  CAS  Google Scholar 

  28. Dakin Haché K, Gray S, Barnes PJ, Dewar R, Younis T, Rayson D (2007) Clinical and pathological correlations in male breast cancer: intratumoral aromatase expression via tissue microarray. Breast Cancer Res Treat 105:169–175. doi:10.1007/s10549-006-9448-9

    Article  PubMed  Google Scholar 

  29. Basham VM, Lipscombe JM, Ward JM, Gayther SA, Ponder BA, Easton DF et al (2002) BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 4:R2. doi:10.1186/bcr419

    Article  PubMed  CAS  Google Scholar 

  30. Chodick G, Struewing JP, Ron E, Rutter JL, Iscovich J (2008) Similar prevalence of founder BRCA1 and BRCA2 mutations among Ashkenazi and non-Ashkenazi men with breast cancer: evidence from 261 cases in Israel, 1976–1999. Eur J Med Genet 51:141–147. doi:10.1016/j.ejmg.2007.11.001

    Article  PubMed  Google Scholar 

  31. Papi L, Putignano AL, Congregati C, Zanna I, Sera F, Morrone D et al (2008) Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy. Breast Cancer Res Treat (in press). doi:10.1007/s10549-008-0190-3

  32. Capalbo C, Buffone A, Vestri A, Ricevuto E, Rinaldi C, Zani M et al (2007) Does the search for large genomic rearrangements impact BRCAPRO carrier prediction? J Clin Oncol 25:2632–2634. doi:10.1200/JCO.2007.11.4330

    Article  PubMed  Google Scholar 

  33. Miolo G, Puppa LD, Santarosa M, De Giacomi C, Veronesi A, Bidoli E et al (2006) Phenotypic features and genetic characterization of male breast cancer families: identification of two recurrent BRCA2 mutations in North-east of Italy. BMC Cancer 6:156. doi:10.1186/1471-2407-6-156

    Article  PubMed  Google Scholar 

  34. Pich A, Chiusa L, Margarina E (1994) Proliferative activity is a significant prognostic factor in male breast carcinoma. Am J Pathol 145:481–489

    PubMed  CAS  Google Scholar 

  35. Muñoz de Toro MM, Maffini MV, Kass L, Luque EH (1998) Proliferative activity and steroid hormone receptor status in male breast carcinoma. J Steroid Biochem Mol Biol 67:333–339. doi:10.1016/S0960-0760(98)00124-1

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Authors are grateful to all patients, their families and their caring physicians for participating in this study. Authors wish also to thank Mr. Massimo Zani and Mr. Sergio Ferraro for expert technical assistance, and all the colleagues of the Pathology Departments of several hospitals in the study area (Drs. Carmelo Urso, Augusto Giannini, Lavinia Puglisi, Tiziana Megha, Michela Stumpo, Federica Zolfanelli, Francesco Mirri, Lidia La Magra, and Mauro Biancalani) for their active collaboration in providing tissue samples. The study was supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC) to Laura Ottini and by Regione Toscana in the frame of the High-Risk Cancer Family Project.

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Authors and Affiliations

  1. Department of Experimental Medicine, University of Rome “La Sapienza”, Viale Regina Elena, 324, 00161, Rome, Italy

    Laura Ottini, Piera Rizzolo, Mario Falchetti, Ketty Ceccarelli, Alberto Gulino & Giuseppe Giannini

  2. Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute – ISPO, 50139, Florence, Italy

    Ines Zanna, Giovanna Masala, Francesco Sera & Domenico Palli

  3. Department of Pathology, University of Florence, 50100, Florence, Italy

    Vania Vezzosi & Simonetta Bianchi

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  1. Laura Ottini
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  2. Piera Rizzolo
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Correspondence to Laura Ottini.

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Ottini, L., Rizzolo, P., Zanna, I. et al. BRCA1/BRCA2 mutation status and clinical-pathologic features of 108 male breast cancer cases from Tuscany: a population-based study in central Italy. Breast Cancer Res Treat 116, 577–586 (2009). https://doi.org/10.1007/s10549-008-0194-z

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