Skip to main content

Advertisement

SpringerLink
Log in

BRCA1 genetic testing in 106 breast and ovarian cancer families from southern Italy (Sicily): a mutation analyses

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the contribution of germline BRCA1 mutations in the incidence of hereditary and familial Breast Cancer (BC) and/or Ovarian Cancer (OC) in patients from Southern Italy (in the region of Sicily) and to identify a possible association between the higher frequency of BRCA1 mutations and a specific familial profile.

Experimental design

A consecutive series of 650 patients with BC and/or OC diagnosed between 1999 and 2005 were recruited from the Southern Italian region of Sicily, after interview at the “Regional Reference Centre for the Characterization and Genetic Screening of Hereditary Tumors” at the University of Palermo. Genetic counselling allowed us to recruit a total of 106 unrelated families affected with breast and/or ovarian cancer screened for mutations occurring in the whole BRCA1 gene by automatic direct sequencing.

Results

Germline BRCA1 mutations were found in 17 of 106 (16%) Sicilian families. The HBOC profile had a major frequency (66%) of mutations (P < 0.01). A total of 28 sequence variants was identified. Seven of these were pathogenic, 5 unknown biological variant (UV) and 16 polymorphisms. We also identified a pathological mutation (4843delC) as a possible Sicilian founder mutation.

Conclusions

The present study is the first BRCA1 disease-associated mutations analysis in Southern Italian families. The early age of onset of such tumors and the association with the HBOC familial profile could be two valid screening factors for the identification of BRCA1 mutation carriers. Finally, we identified a BRCA1 mutation with a possible founder effect.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Miki Y, Swensen J, Shattuck-Eidens D et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71

    Article  PubMed  CAS  Google Scholar 

  2. Ford D, Easton DF, Stratton M et al and Breast Cancer linkage Consortium (1998) Genetic heterogenicity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62:676–689

    Google Scholar 

  3. Pharoah PD, Antoniou A, Bobrow M et al (2002) Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet 31:33–36

    Article  PubMed  CAS  Google Scholar 

  4. Callebaut I, Mornon JP. (1997) From BRCA1 to Rap1: a widespread BRCT module closely associated with DNA repair. FEBS Lett 400(1):25–30

    Article  PubMed  CAS  Google Scholar 

  5. Brose MS, Rebbeck TR, Calzone KA et al (2002) Cancer risk estimates for BRCA1 mutation carriers identifìed in a risk evaluation program. J Natl Cancer Inst 9418:1365–1372

    Google Scholar 

  6. Ford D, Easton DF, Bishop DT et al (1994) Breast Cancer Linkage Consortium. Lancet 343:692–695

    Article  PubMed  CAS  Google Scholar 

  7. Lynch HT, Watson P, Narod SA (1999) The genetic epidemiology of male breast carcinoma. Cancer 86(5):744–746

    Article  PubMed  CAS  Google Scholar 

  8. Nkondjock A, Ghadirian P. (2004) Epidemiology of breast cancer among BRCA mutation carriers: an overview. Cancer Lett 2051:1–8

    Article  Google Scholar 

  9. Takahashi H, Behbakht K, McGovern PE et al (1995) Mutation analysis of the BRCA1 gene in ovarian cancers. Cancer Res 55:2998–3002

    PubMed  CAS  Google Scholar 

  10. Easton DF, Hopper JL, Thomas DC et al (2004) Breast cancer risks for BRCA1/2 carriers. Science 306:2187–2188

    Article  PubMed  CAS  Google Scholar 

  11. Antoniou A, Pharoah PD, Narod S et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130

    Article  PubMed  CAS  Google Scholar 

  12. Marroni F, Aretini P, D’Andrea E et al (2004 )Penetrance of breast ad ovarian cancer in a large series of families tested for BRCA1/2 mutations. Eur J Hum Genet 12:899–906

    Article  PubMed  CAS  Google Scholar 

  13. Cipollini G, Tommasi S, Paradiso A et al (2004) Genetic alteration in hereditary breast cancer. Ann Oncol 15:7–13

    Article  Google Scholar 

  14. Szabo CI, King MC. (1997) Population genetics of BRCA1 and BRCA2. Am J Hum Genet 60:1013–1020

    PubMed  CAS  Google Scholar 

  15. Peelen T, van Vliet M, Petrij-Bosch A et al (1997). A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet 60:1041–1049

    PubMed  CAS  Google Scholar 

  16. Einbeigi Z, Bergman A, Kindblom LG et al (2001) A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer. Eur J Cancer 37:1904–1909

    Article  PubMed  CAS  Google Scholar 

  17. Pisano M, Cossu A, Persico I et al (2000) Identification of a founder BRCA2 mutation in Sardinia. Br J Cancer 82:553–559

    Article  PubMed  CAS  Google Scholar 

  18. Baudi F, Quaresima B, Grandinetti C et al (2001)Evidence of a founder mutation of BRCA1 gene in a highly homogeneous population from southern Italy with breast/ ovarian cancer. Hum Mut 18:163–164

    Article  PubMed  CAS  Google Scholar 

  19. Breast Cancer Information Core (BIC) (2002) An open access on line breast cancer mutation database. Retrived from http://www.hhgri.nih.gov/Intramural_transfer/Bic/

  20. Judkins T, Hendrickson BC, Deffenbaugh MA et al (2005) Single nucleotide polymorphisms in clinical genetic testing: the characterization of the clinical significance of genetic variants and their application in clinical research for BRCA1. Mut Res 573:168–179

    CAS  Google Scholar 

  21. Goldgard DE, Easton DF, Deffenbaugh AM et al (2004) Breast Cancer Information Core (BIC) Sterring Committee. Integrated evaluation of DNA sequence variants of unknown clinical significance: application to BRCA1 and BRCA2. Am J Hum Genet 75:535–544

    Article  Google Scholar 

  22. Phelan CM, Dapic V, Tice B et al (2004) Classification of BRCA1 missense variants of unknown clinical significance. Am J Hum Genet 75:535–544

    Article  Google Scholar 

  23. ASCO (1996) Statement of the American Society of Clinical Oncology, genetic testing for cancer susceptibility, Adopted on Febbruary 20, 1996. J Clin Oncol 14:1730–1740

    Google Scholar 

  24. ASCO (2003) American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol 21:2397–2406

    Article  Google Scholar 

  25. Friedman LS, Ostermeyer EA, Szabo CI et al (1994) Confirmation of BRCA 1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet 8:399–404

    Article  PubMed  CAS  Google Scholar 

  26. Caligo MA, Ghimenti C, Cipollini G et al (1996) BRCA1 germline mutation spectrum in Italian families from Tuscany: a high frequency of novel mutations. Oncogene 13:1483–1488.

    PubMed  CAS  Google Scholar 

  27. Antonarakis SE. (1998) Recommendations for a nomenclature system for human gene mutations. Nomenclature Working Group. Hum Mutat 11(1):1–3

    Article  PubMed  CAS  Google Scholar 

  28. Augello C, Gregorio V, Bazan V et al (2006) TP53 and p16INK4A, but not H-KI-Ras, are involved in tumorigenesis and progression of pleomorphic adenomas. J Cell Physiol Jun 207(3):654–659

    Article  CAS  Google Scholar 

  29. Ottini L, D’Amico C, Noviello C et al (2000) BRCA1 and BRCA2 mutations in central and southern Italian patients. Breast Cancer Res 2:307–310

    Article  PubMed  CAS  Google Scholar 

  30. Cortesi L, Turchetti D, Bertoni C, et al (2000) Comparison between genotype and phenotype identifies a high-risk population carryng BRCA1 mutations. Genes Chromosomes Cancer 27:130–135

    Article  PubMed  CAS  Google Scholar 

  31. Turchetti D, Cortesi L, Federico M et al (2000) BRCA1 mutations and clinicopathological features in a sample of Italian women with early-onset breast cancer. Eur J Cancer 36:2083–2089

    Article  PubMed  CAS  Google Scholar 

  32. Malone KE, Daling JR, Thompson JD et al (1998) BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before 45 years with first-degree family hystory. J Am Med Assoc 279:922–929

    Article  CAS  Google Scholar 

  33. Capalbo C, Ricevuto E, Vestri A et al (2006) BRCA1 and BRCA2 genetic testing in Italian breast and/or ovarian cancer families: mutation spectrum and prevalence and analysis of mutation prediction models. Ann Oncol; 17(7):vii34–vii40

    Article  PubMed  Google Scholar 

  34. Malander S, Ridderheim M, Masback A et al (2004) One in 10 ovarian cancer patients carry germ line BRCA1 or BRCA2 mutations: results of a prospective study in Southern Sweden. Eur J Cancer 40:422–428

    Article  PubMed  CAS  Google Scholar 

  35. Johannesdottir G, Gudmundsson J, Bergthorsson JT et al (1996) High prevalence of the 999del5 mutation in Icelandic breast cancer patients. Cancer Res 56:3663–3665

    PubMed  CAS  Google Scholar 

  36. Struewing JP, Coriaty ZM, Ron E et al (1999) Founder BRCA1/2mutations among male patients with breast cancer in Israel. Am J Hum Genet 65:1800–1802

    Article  PubMed  CAS  Google Scholar 

  37. Basham VM, Lipscombe JM, Ward JM et al (2002) BRCA1 and BRCA2 mutations in a population-based study of male breast cancer. Breast Cancer Res 4(1):R2

    Article  PubMed  CAS  Google Scholar 

  38. De La Hoya M, Osorio A, Godino J et al (2002) Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: implications for genetic testing. Int J Cancer 97:466–471

    Article  Google Scholar 

  39. Ottini L, Masala G, D’Amico C 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 

  40. Iau PTC, M. Marafie A. Ali et al (2004) Are medullary breast cancers an indication for BRCA1 mutation screening? A mutation analysis of 42 cases of medullary breast cancer. Breast Cancer Res Treatment 85:81–88

    Article  CAS  Google Scholar 

  41. Crook T, Brooks LA, Crossland S et al (1998) P53 mutations with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2- associated breast tumours. Oncogene 17:1682–1689

    Article  Google Scholar 

  42. Eisinger F, Jacquemier J, Charpin C et al (1998) Mutations at BRCA1: the medullary breast carcinoma revisited. Cancer Res 58:1588–1592

    PubMed  CAS  Google Scholar 

  43. Vezina H, Durocher F, Dumont M et al (2005) Molecular and genealogical characterization of the R1443X BRCA1 mutation in high-risk French-Canadian breast-ovarian cancer families. Hum Genet 117:119–132

    Article  PubMed  CAS  Google Scholar 

  44. Muller D, Bonaiti-Pellie C, Abecassis J et al (2004) BRCA1 testing in breast ad/or ovarian cancer families from north-eastern France identifies two common mutations with a founder effect. Familial Cancer 3:15–20

    Article  PubMed  CAS  Google Scholar 

  45. Calo V, Agnese V, Gargano G et al (2005) A new germline mutation in a Sicilian family with ovarian cancer. Breast Cancer Res Treat 22:1–4

    Google Scholar 

  46. Morris JR, Pangon L, Boutell C et al (2006) Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility. Human Mol Genet 15(4):599–606

    Article  CAS  Google Scholar 

  47. Fleming MA, Potter JD, Ramirez CJ et al (2003) Understanding missense mutations in the BRCA1 gene: An evolutionary approach. PNAS 100(3):1151–1156

    Article  PubMed  CAS  Google Scholar 

  48. Abkevich V, Zharkikh A, Deffenbaugh AM et al (2004) Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet 41: 492–507

    Article  PubMed  CAS  Google Scholar 

  49. Augello C, Bruno L, Bazan V et al (2006) Y179C, F486L and N550H are BRCA1 variants that may be associated with breast cancer in a Sicilian family: results of a 5-year GOIM (Gruppo Oncologico dell’Italia Meridionale) prospective study. Ann Oncol 17(Suppl 7):vii30–vii33

    Article  PubMed  Google Scholar 

  50. Tavtigian SV, Deffenbaugh AM, Yin L et al (2006) Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 43:295–305

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Pamela Gardner for help in the preparation of the text and Girolama Quattrocchi and Anna Zingone for nursery assistance, and Salvatore Madonia Ferraro for laboratory technician assistance.

Author information

Authors and Affiliations

  1. Interdepartmental Center of Clinical Oncology; Regional Reference Center for the Biomolecular Characterization and Genetic Screening of Hereditary Tumors, Università di Palermo, Via del Vespro 127, 90127, Palermo, Italy

    Antonio Russo, Valentina Calò, Valentina Agnese, Loredana Bruno, Simona Corsale, Claudia Augello, Grazia Gargano, Floriana Barbera, Sandra Cascio, Chiara Intrivici, Gaetana Rinaldi, Nicola Gebbia & Viviana Bazan

  2. Sbarro Institute for Cancer Research and Molecular Medicine, College of Science, Temple University, Philadelphia, USA

    Marcella Macaluso, Eva Surmacz & Antonio Giordano

  3. Department of Surgical Oncology, Università di Palermo, Palermo, Italy

    Gaspare Gulotta

Authors
  1. Antonio Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valentina Calò
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valentina Agnese
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Loredana Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Simona Corsale
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Claudia Augello
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Grazia Gargano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Floriana Barbera
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sandra Cascio
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chiara Intrivici
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gaetana Rinaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Gaspare Gulotta
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Marcella Macaluso
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Eva Surmacz
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Antonio Giordano
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Nicola Gebbia
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Viviana Bazan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antonio Russo.

Additional information

Antonio Russo and Valentina Calò contributed equally to this work

Rights and permissions

Reprints and permissions

About this article

Cite this article

Russo, A., Calò, V., Agnese, V. et al. BRCA1 genetic testing in 106 breast and ovarian cancer families from southern Italy (Sicily): a mutation analyses. Breast Cancer Res Treat 105, 267–276 (2007). https://doi.org/10.1007/s10549-006-9456-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-006-9456-9

Keywords

Search

Navigation