Advertisement

Breast Cancer Research and Treatment

, Volume 110, Issue 1, pp 161–167 | Cite as

BRCA1/BRCA2 rearrangements and CHEK2 common mutations are infrequent in Italian male breast cancer cases

  • Mario Falchetti
  • Ramona Lupi
  • Piera Rizzolo
  • Ketty Ceccarelli
  • Ines Zanna
  • Valentina Calò
  • Stefania Tommasi
  • Giovanna Masala
  • Angelo Paradiso
  • Alberto Gulino
  • Giuseppe Giannini
  • Antonio Russo
  • Domenico Palli
  • Laura OttiniEmail author
Epidemiology

Abstract

Male breast cancer (MBC) is a rare and poorly known disease. Germ-line mutations of BRCA2 and, to lesser extent, BRCA1 genes are the highest risk factors associated with MBC. Interestingly, BRCA2 germ-line rearrangements have been described in high-risk breast/ovarian cancer families which included at least one MBC case. Germ-line mutations of CHEK2 gene have been also implicated in inherited MBC predisposition. The CHEK2 1100delC mutation has been shown to increase the risk of breast cancer in men lacking BRCA1/BRCA2 mutations. Intriguingly, two other CHEK2 mutations (IVS2+1G>A and I157T) and a CHEK2 large genomic deletion (del9-10) have been associated with an elevated risk for prostate cancer. Here, we investigated the contribution of BRCA1, BRCA2 and CHEK2 alterations to MBC predisposition in Italy by analysing a large series of MBC cases, unselected for breast cancer family history and all negative for BRCA1/BRCA2 germ-line mutations. A total of 102 unrelated Italian MBC cases were screened for deletions/duplications of BRCA1, BRCA2 and CHEK2 by multiplex ligation-dependent probe amplification. No BRCA1, BRCA2 and CHEK2 genomic rearrangements, including the CHEK2 del9-10, were found in the series analysed. Furthermore, none of the MBC cases and 263 male population controls, also included in this study, carried the CHEK2 1100delC, IVS2+1G>A and I157T common mutations. Overall, our data suggest that screening of BRCA1/2 rearrangements is not advantageous in MBC cases not belonging to high-risk breast cancer families and that common CHEK2 mutations play an irrelevant role in MBC predisposition in Italy.

Keywords

Male breast cancer BRCA1 BRCA2 CHEK2 Germ-line mutations Large genomic rearrangements MLPA 

Notes

Acknowledgement

The study was supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC) to Laura Ottini.

References

  1. 1.
    Weiss JR, Moysich KB, Swede H (2005) Epidemiology of male breast cancer. Cancer Epidemiol Biomarkers Prev 14:20–26PubMedCrossRefGoogle Scholar
  2. 2.
    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. RomaGoogle Scholar
  3. 3.
    Fentiman IS, Fourquet A, Hortobagyi GN (2006) Male breast cancer. Lancet 367(9510):595–604PubMedCrossRefGoogle Scholar
  4. 4.
    Giordano SH (2005) A review of the diagnosis and management of male breast cancer. Oncologist 10(7):471–479PubMedCrossRefGoogle Scholar
  5. 5.
    Ford D, Easton DF, Stratton M, Narod S, Goldgar D, Devilee P, Bishop DT, Weber B, Lenoir G, Chang-Claude J et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 Genes in breast cancer families. Am J Hum Genet 62:676–689PubMedCrossRefGoogle Scholar
  6. 6.
    Ottini L, Masala G, D’Amico C, Mancini B, Saieva C, Aceto G, Gestri D, Vezzosi V, Falchetti M, De Marco M et al (2003) BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: a population-based study in Italy. Cancer Res 63(2):342–347PubMedGoogle Scholar
  7. 7.
    Hartmann C, John AL, Klaes R, Hofmann W, Bielen R, Koehler R et al (2004) Large BRCA1 gene deletions are found in 3% of German high-risk breast cancer families. Hum Mutat 24:534PubMedCrossRefGoogle Scholar
  8. 8.
    Mazoyer S (2005) Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat 25:415–422PubMedCrossRefGoogle Scholar
  9. 9.
    Hendrickson BC, Judkins T, Ward BD, Eliason K, Deffenbaugh AE, Burbidge LA et al (2005) Prevalence of five previously reported and recurrent BRCA1 genetic rearrangement mutations in 20,000 patients from hereditary breast/ovarian cancer families. Genes Chromosomes Cancer 43:309–313PubMedCrossRefGoogle Scholar
  10. 10.
    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:e31PubMedCrossRefGoogle Scholar
  11. 11.
    Casilli F, Tournier I, Sinilnikova OM, Coulet F, Soubrier F, Houdayer C, Hardouin A, Berthet P, Sobol H, Bourdon V et al (2006) The contribution of germline rearrangements to the spectrum of BRCA2 mutations. J Med Genet 43(9):e49PubMedCrossRefGoogle Scholar
  12. 12.
    Walsh T, Casadei S, Coats KH, Swisher E, Stray SM, Higgins J, Roach KC, Mandell J, Lee MK, Ciernikova S et al (2006) Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295:1379–1388PubMedCrossRefGoogle Scholar
  13. 13.
    Agata S, Viel A, Della Puppa L, Cortesi L, Fersini G, Callegaro M, Dalla Palma M, Dolcetti R, Federico M, Venuta S et al (2006) Prevalence of BRCA1 genomic rearrangements in a large series of Italian breast and breast/ovarian cancer families without detectable BRCA1 and BRCA2 point mutations. Genes Chromosomes Cancer 45(9):791–797PubMedCrossRefGoogle Scholar
  14. 14.
    Gutierrez-Enriquez S, de La Hoya M, Martinez-Bouzas C, de Abajo AS, Cajal TR, Llort G, Blanco I, Beristain E, Diaz-Rubio E, Alonso C et al (2006) Screening for large rearrangements of the BRCA2 gene in Spanish families with breast/ovarian cancer. Breast Cancer Res Treat 103(1):103–107PubMedCrossRefGoogle Scholar
  15. 15.
    Moisen AM, Fortin J, Dumont M, Samson C, Bessette P, Chiquette J, Laframboise R, Lepine J, Lesperance B, Pichette R et al (2006) No evidence of BRCA1/2 genomic rearrangements in high-risk French-Canadian breast/ovarian cancer families. Genet Test 10:104–115CrossRefGoogle Scholar
  16. 16.
    Preisler-Adams S, Schonbuchner I, Fiebig B, Welling B, Dworniczak B, Weber BH (2006) Gross rearrangements in BRCA1 but not BRCA2 play a notable role in predisposition to breast and ovarian cancer in high-risk families of German origin. Cancer Genet Cytogenet 168:44–49PubMedCrossRefGoogle Scholar
  17. 17.
    Thomassen M, Gerdes AM, Cruger D, Jensen PK, Kruse TA (2006) Low frequency of large genomic rearrangements of BRCA1 and BRCA2 in western Denmark. Cancer Genet Cytogenet 168(2):168–171PubMedCrossRefGoogle Scholar
  18. 18.
    Buffone A, Capalbo C, Ricevuto E, Sidoni T, Ottini L, Falchetti M, Cortesi E, Marchetti P, Scambia G, Tomao S et al (2007) Prevalence of BRCA1 and BRCA2 genomic rearrangements in a cohort of consecutive Italian breast and/or ovarian cancer families. Breast Cancer Res Treat Feb 28 [Epub ahead of print]Google Scholar
  19. 19.
    Machado PM, Brandao RD, Cavaco BM, Eugenio J, Bento S, Nave M, Rodrigues P, Fernandes A, Vaz F (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(15):2027–2034PubMedCrossRefGoogle Scholar
  20. 20.
    Tournier I, Paillerets BB, Sobol H, Stoppa-Lyonnet D, Lidereau R, Barrois M, Mazoyer S, Coulet F, Hardouin A, Chompret A et al (2004) Significant contribution of germline BRCA2 rearrangements in male breast cancer families. Cancer Res 64:8143–8147PubMedCrossRefGoogle Scholar
  21. 21.
    Karhu R, Laurila E, Kallioniemi A, Syrjakoski K (2006) Large genomic BRCA2 rearrangements and male breast cancer. Cancer Detect Prev 30(6):530–534PubMedCrossRefGoogle Scholar
  22. 22.
    Meijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, Hollestelle A, Houben M, Crepin E, van Veghel-Plandsoen M, Elstrodt F, van Duijn C, Bartels C, Meijers C, Schutte M, McGuffog L, Thompson D, Easton D, Sodha N, Seal S, Barfoot R, Mangion J, Chang-Claude J, Eccles D, Eeles R, Evans DG, Houlston R, Murday V, Narod S, Peretz T, Peto J, Phelan C, Zhang HX, Szabo C, Devilee P, Goldgar D, Futreal PA, Nathanson KL, Weber B, Rahman N, Stratton MR; CHEK2-Breast Cancer Consortium (2002) Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31(1):55–59Google Scholar
  23. 23.
    Neuhausen S, Dunning A, Steele L, Yakumo K, Hoffman M, Szabo C et al (2004) Role of CHEK2*1100delC in unselected series of non-BRCA1/2 male breast cancers. Int J Cancer 108:477–478PubMedCrossRefGoogle Scholar
  24. 24.
    Ohayon T, Gal I, Baruch RG, Szabo C, Friedman E (2004) CHEK2*1100-delC and male breast cancer risk in Israel. Int J Cancer 108:479–480PubMedCrossRefGoogle Scholar
  25. 25.
    Syrjäkoski K, Kuukasjärvi T, Auvinen A, Kallioniemi OP (2004) CHEK2 1100delC is not a risk factor for male breast cancer population. Int J Cancer 108(3):475–476PubMedCrossRefGoogle Scholar
  26. 26.
    Martinez-Bouzas C, Beristain E, Guerra I, Gorostiaga J, Mendizabal JL, De-Pablo JL, Garcia-Alegria E, Sanz-Parra A, Tejada MI (2007) CHEK2 1100delC is present in familial breast cancer cases of the Basque Country. Breast Cancer Res Treat 103(1):111–113PubMedCrossRefGoogle Scholar
  27. 27.
    Narod SA, Lynch HT (2007) CHEK2 mutation and hereditary breast cancer. J Clin Oncol 25(1):6–7PubMedCrossRefGoogle Scholar
  28. 28.
    Caligo MA, Agata S, Aceto G, Crucianelli R, Manoukian S, Peissel B, Scaini MC, Sensi E, Veschi S, Cama A, Radice P, Viel A, D’Andrea E, Montagna M (2004) The CHEK2 c.1100delC mutation plays an irrelevant role in breast cancer predisposition in Italy. Hum Mutat 24(1):100–101PubMedCrossRefGoogle Scholar
  29. 29.
    Kilpivaara O, Vahteristo P, Falck J, Syrjakoski K, Eerola H, Easton D, Bartkova J, Lukas J, Heikkila P, Aittomaki K, Holli K, Blomqvist C, Kallioniemi OP, Bartek J, Nevanlinna H (2004) CHEK2 variant I157T may be associated with increased breast cancer risk. Int J Cancer 111:543–547PubMedCrossRefGoogle Scholar
  30. 30.
    Bogdanova N, Enssen-Dubrowinskaja N, Feshchenko S, Lazjuk GI, Rogov YI, Dammann O, Bremer M, Karstens JH, Sohn C, Dork T (2005) Association of two mutations in the CHEK2 gene with breast cancer. Int J Cancer 116:263–266PubMedCrossRefGoogle Scholar
  31. 31.
    Dong X, Wang L, Taniguchi K, Wang X, Cunningham JM, McDonnell SK, Qian C, Marks AF, Slager SL, Peterson BJ, Smith DI, Cheville JC, Blute ML, Jacobsen SJ, Schaid DJ, Tindall DJ, Thibodeau SN, Liu W (2003) Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet 72:270–280PubMedCrossRefGoogle Scholar
  32. 32.
    Seppala EH, Ikonen T, Mononen N, Autio V, Rokman A, Matikainen MP, Tammela TL, Schleutker J (2003) CHEK2 variants associate with hereditary prostate cancer. Br J Cancer 89:1966–1970PubMedCrossRefGoogle Scholar
  33. 33.
    Schutte M, Seal S, Barfoot R, Meijers-Heijboer H, Wasielewski M, Evans DG, Eccles D, Meijers C, Lohman F, Klijn J, van den Ouweland A, Futreal PA, Nathanson KL, Weber BL, Easton DF, Stratton MR, Rahman N. Breast Cancer Linkage Consortium (2003) Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am J Hum Genet 72:1023–1028Google Scholar
  34. 34.
    Baynes C, Healey CS, Pooley KA, Scollen S, Luben RN, Thompson DJ, Pharoah PD, Easton DF, Ponder BA, Dunning AM; SEARCH breast cancer study (2007) Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk. Breast Cancer Res 9(2):R27Google Scholar
  35. 35.
    Cybulski C, Wokolorczyk D, Huzarski T, Byrski T, Gronwald J, Gorski B, Debniak T, Masojc B, Jakubowska A, van de Wetering T, Narod SA, Lubinski J (2006) A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat 102(1):119–122PubMedCrossRefGoogle Scholar
  36. 36.
    Cybulski C, Wokolorczyk D, Huzarski T, Byrski T, Gronwald J, Gorski B, Debniak T, Masojc B, Jakubowska A, Gliniewicz B, Sikorski A, Stawicka M, Godlewski D, Kwias Z, Antczak A, Krajka K, Lauer W, Sosnowski M, Sikorska-Radek P, Bar K, Klijer R, Zdrojowy R, Malkiewicz B, Borkowski A, Borkowski T, Szwiec M, Narod SA, Lubinski J (2006) A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer. J Med Genet 43(11):863–866PubMedCrossRefGoogle Scholar
  37. 37.
    Russo A, Calo V, Agnese V, Bruno L, Corsale S, Augello C, Gargano G, Barbera F, Cascio S, Intrivici C, Rinaldi G, Gulotta G, Macaluso M, Surmacz E, Giordano A, Gebbia N, Bazan V (2007) BRCA1 genetic testing in 106 breast and ovarian cancer families from southern Italy (Sicily): a mutation analyses. Breast Cancer Res Treat Jan 13 [Epub ahead of print]Google Scholar
  38. 38.
    Gutierrez-Enriquez S, Balmana J, Baiget M, Diez O (2007) Detection of the CHEK2 1100delC mutation by MLPA BRCA1/2 analysis: a worthwhile strategy for its clinical applicability in 1100delC low-frequency populations? Breast Cancer Res Treat Apr 26 [Epub ahead of print]Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Mario Falchetti
    • 1
  • Ramona Lupi
    • 1
  • Piera Rizzolo
    • 1
  • Ketty Ceccarelli
    • 1
  • Ines Zanna
    • 2
  • Valentina Calò
    • 3
  • Stefania Tommasi
    • 4
  • Giovanna Masala
    • 2
  • Angelo Paradiso
    • 4
  • Alberto Gulino
    • 1
  • Giuseppe Giannini
    • 1
  • Antonio Russo
    • 3
  • Domenico Palli
    • 2
  • Laura Ottini
    • 1
    Email author
  1. 1.Department of Experimental MedicineUniversity of Rome “La Sapienza”RomeItaly
  2. 2.Molecular and Nutritional Epidemiology UnitCSPO-Scientific Institute of TuscanyFlorenceItaly
  3. 3.Department of Surgical and Oncological Sciences, Section of Medical Oncology, Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary TumorsUniversity of PalermoPalermoItaly
  4. 4.Clinical Experimental Oncology LaboratoryNational Cancer Institute “Giovanni Paolo II”BariItaly

Personalised recommendations