Methylation of tumor suppressor genes is related with copy number aberrations in breast cancer

Autores de IIS La Fe

• Rosa María Murria Estal

  Autor

• Sarai Palanca Suela

  Autor

• Inmaculada De Juan Jiménez

  Autor

• Maria Zaida Garcia Casado

  Autor

• Ana Beatriz Sanchez Heras

  Autor

• Ana Santaballa Bertrán

  Autor

• Isabel Chirivella Gonzalez

  Autor

• Ángel Agustín Segura Huerta

  Autor

• David Hervás Marín

  Autor

• Marta Llop García

  Autor

• Eva Barragán González

  Autor

• Pascual Bolufer Gilabert

  Autor

Participantes ajenos a IIS La Fe

• Egoavil C
• Alenda C
• Juan MJ

Grupos

• Hematología y Hemoterapia

• Investigación Clínica y Traslacional en Cáncer

Abstract

This study investigates the relationship of promoter methylation in tumor suppressor genes with copynumber aberrations (CNA) and with tumor markers in breast cancer (BCs). The study includes 98 formalin fixed paraffin-embedded BCs in which promoter methylation of 24 tumour suppressor genes were assessed by Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA), CNA of 20 BC related genes by MLPA and ER, PR, HER2, CK5/6, CK18, EGFR, Cadherin-E, P53, Ki-67 and PARP expression by immunohistochemistry (IHC). Cluster analysis classed BCs in two groups according to promoter methylation percentage: the highly-methylated group (16 BCs), containing mostly hyper-methylated genes, and the sparsely-methylated group (82 BCs) with hypomethylated genes. ATM, CDKN2A, VHL, CHFR and CDKN2B showed the greatest differences in the mean methylation percentage between these groups. We found no relationship of the IHC parameters or pathological features with methylation status, except for Catherin-E (p = 0.008). However the highly methylated BCs showed higher CNA proportion than the sparsely methylated BCs (p < 0.001, OR = 1.62; IC 95% [1.26, 2.07]). CDC6, MAPT, MED1, PRMD14 and AURKA showed the major differences in the CNA percentage between the two groups, exceeding the 22%. Methylation in RASSF1, CASP8, DAPK1 and GSTP1 conferred the highest probability of harboring CNA. Our results show a new link between promoter methylation and CNA giving support to the importance of methylation events to establish new BCs subtypes. Our findings may be also of relevance in personalized therapy assessment, which could benefit the hyper methylated BC patients group.

Keywords

• Breast cancer; promoter methylation; copy number aberrations; immunochemistry