Analysis of FANCB and FANCN/PALB2 Fanconi Anemia genes in BRCA1/2-negative Spanish breast cancer families (original) (raw)

Abstract

Recent reports have shown that mutations in the FANCJ/BRIP1 and FANCN/PALB2 Fanconi Anemia (FA) genes confer a moderate breast cancer risk. Discussion has been raised on the phenotypic characteristics of the _PALB2-_associated families and tumors. The role of FANCB in breast cancer susceptibility has not been tested to date. Likewise PALB2 mutation frequency has not been studied in Spanish population. We analyzed the complete coding sequence and splicing sites of FANCB and PALB2 in 95 index cases of _BRCA1/2_-negative Spanish breast cancer families. We also performed an exhaustive screening of three previously described rare but recurrent PALB2 mutations in 725 additional probands. Pathogenic changes were not detected in FANCB. We found a novel PALB2 truncating mutation c.1056_1057delGA (p.K353IfsX7) in one of the 95 screened patients, accounting for a mutation frequency of 1% in our series. Further comprehensive screening of the novel mutation and of previously reported rare but recurrent PALB2 mutations did not reveal any carrier patient. We report the first example of LOH occurring in a _PALB2_-associated tumor. Our results rule out a major contribution of FANCB to hereditary breast cancer. Our data are consistent with the notion of individually rare PALB2 mutations, lack of mutational hot-spots in the gene and existence of between-population disease-allele heterogeneity. We show evidence that PALB2 loss of function might also conform to the inactivation model of a classic tumor-suppressor gene and present data that adds to the clinically relevant discussion about the existence of a _PALB2_-breast cancer phenotype.

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Acknowledgements

We are grateful to Prof. Nazneen Rahman for kindly providing us with DNA samples from carriers of the previously described c.3113G>A, c.3116delA and c.3549C>G PALB2 mutations used as positive controls in our screening; G. Ribas for valuable advise on DHPLC conditions and for helpful discussions; O. Díez and M. Baiget (Department of Genetics, La Santa Creu i Sant Pau Hospital) for their contribution in the ascertainment of part of the families included in the study; S.M. Rodríguez-Pinilla and M. Cañamero for histopathological revision of the PALB2 tumor and definition of areas for further macrodisecction; R.L. Milne for biostatistical support; S. Carilla for his contribution to this project; F. Fernández, C. Alonso and L. Moreno for excellent technical assistance. M.J. García is supported by the Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain. This work was partially supported by the Fancogene Project (Fundación Genoma España) Pharmamar and the Spanish Network of Cancer (Grant RTICC 06/0020/0021).

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Authors and Affiliations

  1. Group of Human Genetics, Human Cancer Genetics Program, Spanish National Cancer Centre (CNIO), C/ Melchor Fernández Almagro 3, 28029, Madrid, Spain
    María J. García, Victoria Fernández, Ana Osorio, Alicia Barroso, Miguel Urioste & Javier Benítez
  2. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
    María J. García & Javier Benítez
  3. Genetic Counseling Unit, Prevention and Cancer Control Department, Catalan Institute of Oncology (ICO), 08907, L’Hospitalet, Barcelona, Spain
    Gemma LLort & Ignacio Blanco
  4. Translational Research Laboratory, Catalan Institute of Oncology (ICO), 08907, L’Hospitalet, Barcelona, Spain
    Conxi Lázaro
  5. Laboratory of Molecular Oncology, San Carlos University Hospital, 28040, Madrid, Spain
    Trinidad Caldés & Miguel de la Hoya
  6. Service of Medical Oncology, La Santa Creu i Sant Pau Hospital, 08025, Barcelona, Spain
    Teresa Ramón y Cajal & Carmen Alonso
  7. Molecular Genetics Laboratory, Cruces Hospital, 48903, Baracaldo, Bilbao, Spain
    María-Isabel Tejada
  8. Genetics Department, Ramón y Cajal Hospital, 28034, Madrid, Spain
    Carlos San Román
  9. Oncology Department, Doce de Octubre Hospital, 28041, Madrid, Spain
    Luis Robles-Díaz

Authors

  1. María J. García
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  2. Victoria Fernández
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  3. Ana Osorio
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  4. Alicia Barroso
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  5. Gemma LLort
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  6. Conxi Lázaro
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  7. Ignacio Blanco
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  8. Trinidad Caldés
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  9. Miguel de la Hoya
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  10. Teresa Ramón y Cajal
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  11. Carmen Alonso
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  12. María-Isabel Tejada
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  13. Carlos San Román
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  14. Luis Robles-Díaz
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  15. Miguel Urioste
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  16. Javier Benítez
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Corresponding author

Correspondence toJavier Benítez.

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García, M.J., Fernández, V., Osorio, A. et al. Analysis of FANCB and FANCN/PALB2 Fanconi Anemia genes in _BRCA1/2_-negative Spanish breast cancer families.Breast Cancer Res Treat 113, 545–551 (2009). https://doi.org/10.1007/s10549-008-9945-0

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