Breast Cancer Research and Treatment

, Volume 113, Issue 3, pp 545–551

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

  • María J. García
  • Victoria Fernández
  • Ana Osorio
  • Alicia Barroso
  • Gemma LLort
  • Conxi Lázaro
  • Ignacio Blanco
  • Trinidad Caldés
  • Miguel de la Hoya
  • Teresa Ramón y Cajal
  • Carmen Alonso
  • María-Isabel Tejada
  • Carlos San Román
  • Luis Robles-Díaz
  • Miguel Urioste
  • Javier Benítez
Epidemiology

DOI: 10.1007/s10549-008-9945-0

Cite this article as:
García, M.J., Fernández, V., Osorio, A. et al. Breast Cancer Res Treat (2009) 113: 545. doi:10.1007/s10549-008-9945-0

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.

Keywords

FANCN/PALB2FANCBFanconi AnemiaGenotypic–phenotypic correlationHereditary breast cancerPALB2 tumor

Supplementary material

10549_2008_9945_MOESM1_ESM.pdf (695 kb)
(PDF 694 kb)

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • María J. García
    • 1
    • 2
  • Victoria Fernández
    • 1
  • Ana Osorio
    • 1
  • Alicia Barroso
    • 1
  • Gemma LLort
    • 3
  • Conxi Lázaro
    • 4
  • Ignacio Blanco
    • 3
  • Trinidad Caldés
    • 5
  • Miguel de la Hoya
    • 5
  • Teresa Ramón y Cajal
    • 6
  • Carmen Alonso
    • 6
  • María-Isabel Tejada
    • 7
  • Carlos San Román
    • 8
  • Luis Robles-Díaz
    • 9
  • Miguel Urioste
    • 1
  • Javier Benítez
    • 1
    • 2
  1. 1.Group of Human GeneticsHuman Cancer Genetics Program, Spanish National Cancer Centre (CNIO)MadridSpain
  2. 2.Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER)Instituto de Salud Carlos IIIMadridSpain
  3. 3.Genetic Counseling Unit, Prevention and Cancer Control DepartmentCatalan Institute of Oncology (ICO)L’Hospitalet, BarcelonaSpain
  4. 4.Translational Research LaboratoryCatalan Institute of Oncology (ICO)L’Hospitalet, BarcelonaSpain
  5. 5.Laboratory of Molecular OncologySan Carlos University HospitalMadridSpain
  6. 6.Service of Medical OncologyLa Santa Creu i Sant Pau HospitalBarcelonaSpain
  7. 7.Molecular Genetics LaboratoryCruces HospitalBaracaldo, BilbaoSpain
  8. 8.Genetics DepartmentRamón y Cajal HospitalMadridSpain
  9. 9.Oncology DepartmentDoce de Octubre HospitalMadridSpain