title: Methylation of tumor suppressor genes is related with copy number aberrations in breast cancer.
abstract: This study investigates the relationship of promoter methylation in tumor suppressor genes with copy-number 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 hypo-methylated 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.
authors: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe Valencia, Spain.
authors: Rosa
authors: R
authors: Murria
authors: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe Valencia, Spain.
authors: Sarai
authors: S
authors: Palanca
authors: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe Valencia, Spain.
authors: Inmaculada
authors: I
authors: de Juan
authors: Department of Pathology, University General Hospital Alicante, Spain.
authors: Cecilia
authors: C
authors: Egoavil
authors: Department of Pathology, University General Hospital Alicante, Spain.
authors: Cristina
authors: C
authors: Alenda
authors: Laboratory of Molecular Biology, IVO Valencia, Spain.
authors: Zaida
authors: Z
authors: García-Casado
authors: Department of Oncology, IVO Valencia, Spain.
authors: María J
authors: MJ
authors: Juan
authors: Genetic Counseling Unit, Elche Hospital Alicante, Spain.
authors: Ana B
authors: AB
authors: Sánchez
authors: Department of Oncology, University Hospital La Fe Valencia, Spain.
authors: Ana
authors: A
authors: Santaballa
authors: Genetic Counseling Unit, Clinic University Hospital Valencia, Spain.
authors: Isabel
authors: I
authors: Chirivella
authors: Genetic Counseling Unit, University Hospital La Fe Valencia, Spain.
authors: Ángel
authors: Á
authors: Segura
authors: Biostatistics Service, Health Research Institute La Fe Valencia, Spain.
authors: David
authors: D
authors: Hervás
authors: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe Valencia, Spain.
authors: Marta
authors: M
authors: Llop
authors: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe Valencia, Spain.
authors: Eva
authors: E
authors: Barragán
authors: Laboratory of Molecular Biology, Service of Clinical Analysis, University Hospital La Fe Valencia, Spain.
authors: Pascual
authors: P
authors: Bolufer
keywords: Breast cancer; copy number aberrations; immunochemistry; promoter methylation
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