BRCA2 carriers with male breast cancer show elevated tumour methylation

BMC Cancer

Research Article

kConFab Investigators¹  Elena A. Takano²  Jia-Min B. Pang²  David J. Byrne²  Alexander Dobrovic³  Siddhartha Deb⁴  Stephen B. Fox⁵  Kylie L. Gorringe⁶ 

[1] Kathleen Cuningham Foundation Consortium for research into Familial Breast Cancer, Peter MacCallum Cancer Centre, 3000, Melbourne, Australia;Molecular Pathology Research and Development Laboratory, Department of Pathology, Peter MacCallum Cancer Centre, 3000, Melbourne, VIC, Australia;Molecular Pathology Research and Development Laboratory, Department of Pathology, Peter MacCallum Cancer Centre, 3000, Melbourne, VIC, Australia;Department of Pathology, University of Melbourne, 3012, Parkville, VIC, Australia;Translational Genomics and Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, 3084, Heidelberg, VIC, Australia;School of Cancer Medicine, La Trobe University, 3084, Bundoora, VIC, Australia;Molecular Pathology Research and Development Laboratory, Department of Pathology, Peter MacCallum Cancer Centre, 3000, Melbourne, VIC, Australia;Sir Peter MacCallum Department of Oncology, The University of Melbourne, Vic, 3010, Parkville, Australia;Molecular Pathology Research and Development Laboratory, Department of Pathology, Peter MacCallum Cancer Centre, 3000, Melbourne, VIC, Australia;Sir Peter MacCallum Department of Oncology, The University of Melbourne, Vic, 3010, Parkville, Australia;Department of Pathology, University of Melbourne, 3012, Parkville, VIC, Australia;School of Cancer Medicine, La Trobe University, 3084, Bundoora, VIC, Australia;Sir Peter MacCallum Department of Oncology, The University of Melbourne, Vic, 3010, Parkville, Australia;Cancer Genomics Program, Peter MacCallum Cancer Centre, 3000, Melbourne, VIC, Australia;Department of Pathology, University of Melbourne, 3012, Parkville, VIC, Australia;

关键词: Male breast cancer;    Familial breast cancer;    Methylation;    BRCA1;    BRCA2;    Promoter methylation;   

DOI  :  10.1186/s12885-017-3632-7

 received in 2017-03-08, accepted in 2017-08-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundMale breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer. However, recent studies demonstrate biological and molecular differences likely to impact on tumour behaviour and therefore patient outcome. The aim of this study was to investigate methylation of a panel of commonly methylated breast cancer genes in familial MBCs.Methods60 tumours from 3 BRCA1 and 25 BRCA2 male mutation carriers and 32 males from BRCAX families were assessed for promoter methylation by methylation-sensitive high resolution melting in a panel of 10 genes (RASSF1A, TWIST1, APC, WIF1, MAL, RARβ, CDH1, RUNX3, FOXC1 and GSTP1). An average methylation index (AMI) was calculated for each case comprising the average of the methylation of the 10 genes tested as an indicator of overall tumour promoter region methylation. Promoter hypermethylation and AMI were correlated with BRCA carrier mutation status and clinicopathological parameters including tumour stage, grade, histological subtype and disease specific survival.ResultsTumours arising in BRCA2 mutation carriers showed significantly higher methylation of candidate genes, than those arising in non-BRCA2 familial MBCs (average AMI 23.6 vs 16.6, p = 0.01, 45% of genes hypermethylated vs 34%, p < 0.01). RARβ methylation and AMI-high status were significantly associated with tumour size (p = 0.01 and p = 0.02 respectively), RUNX3 methylation with invasive carcinoma of no special type (94% vs 69%, p = 0.046) and RASSF1A methylation with coexistence of high grade ductal carcinoma in situ (33% vs 6%, p = 0.02). Cluster analysis showed MBCs arising in BRCA2 mutation carriers were characterised by RASSF1A, WIF1, RARβ and GTSP1 methylation (p = 0.02) whereas methylation in BRCAX tumours showed no clear clustering to particular genes. TWIST1 methylation (p = 0.001) and AMI (p = 0.01) were prognostic for disease specific survival.ConclusionsIncreased methylation defines a subset of familial MBC and with AMI may be a useful prognostic marker. Methylation might be predictive of response to novel therapeutics that are currently under investigation in other cancer types.

【 授权许可】

CC BY   
© The Author(s). 2017