Research Article

Silencing of tumor suppressor genes RASSF1A, SLIT2, and WIF1 by promoter hypermethylation in hereditary breast cancer

  1. Carolina Alvarez1,
  2. Teresa Tapia1,
  3. Valeria Cornejo2,
  4. Wanda Fernandez2,
  5. Alex Muñoz3,
  6. Mauricio Camus4,
  7. Manuel Alvarez5,
  8. Luigi Devoto3,
  9. Dr. Pilar Carvallo1,*

Article first published online: 7 FEB 2012

DOI: 10.1002/mc.21881

Additional Information

How to Cite

Alvarez, C., Tapia, T., Cornejo, V., Fernandez, W., Muñoz, A., Camus, M., Alvarez, M., Devoto, L. and Carvallo, P. (2012), Silencing of tumor suppressor genes RASSF1A, SLIT2, and WIF1 by promoter hypermethylation in hereditary breast cancer. Mol. Carcinog.. doi: 10.1002/mc.21881

Author Information

  1. 1

    Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

  2. 2

    Unidad de Anatomía Patológica, Hospital San Borja Arriarán, Santiago, Chile

  3. 3

    Instituto de Investigaciones Materno Infantil (IDIMI); Facultad de Medicina; Universidad de Chile Santiago, Chile

  4. 4

    Centro de Cáncer, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

  5. 5

    Centro Clínico del Cáncer, Clínica Las Condes, Santiago, Chile

*Departamento de Biología Celular y Molecular Facultad de Ciencias Biológicas Pontificia Universidad Católica de Chile Casilla 114-D Santiago, Chile.

Publication History

  1. Article first published online: 7 FEB 2012
  2. Manuscript Accepted: 10 JAN 2012
  3. Manuscript Revised: 26 OCT 2011
  4. Manuscript Received: 5 MAY 2011

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Keywords:

  • hereditary breast cancer;
  • BRCAX;
  • biopsies;
  • tumor suppressor gene;
  • promoter hypermethylation;
  • protein expression

Abstract

Promoter hypermethylation is gaining strength as one of the main mechanisms through which tumor suppressor genes are silenced during tumor progression. Three tumor suppressor genes are frequently found methylated in their promoter, in concordance with absence of expression, RASSF1A, SLIT2, and WIF1. In addition, a previous array-CGH analysis from our group showed that these genes are found in deleted genomic regions observed in hereditary breast cancer tumors. In the present work we analyzed the methylation status of these three tumor suppressor gene promoters in 47 hereditary breast cancer tumors. Promoter methylation status analysis of hereditary breast tumors revealed high methylation frequencies for the three genes (67% RASSF1A, 80% SLIT2, and 72% WIF1). Additionally, the presence of methylated PCR products was associated with absence of protein expression for the three genes and statistically significant for RASSF1A and WIF1. Interestingly, methylation of all the three genes was found in 4 out of 6 grade I invasive ductal carcinoma tumors. Association between RASSF1A methylation and DCIS tumors was found. These results suggest that silencing of these tumor suppressor genes is an early event in hereditary breast cancer, and could be a marker for pre-malignant phenotypes. © 2012 Wiley Periodicals, Inc.

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