Identification of BRCA1-like triple-negative breast cancers by quantitative multiplex-ligation-dependent probe amplification (MLPA) analysis of BRCA1-associated chromosomal regions: a validation study

BMC Cancer

Research Article

Harm van Tinteren¹  Sandra Raab²  Manfred Schmitt²  Corinna Propping²  Zhou Li²  Alfons Meindl²  Marion Kiechle²  Apostolos Gkazepis²  Christina Meul²  Eva Gross²  Petra M. Nederlof³  Esther H. Lips⁴  Michaela Aubele⁵  Stefanie Avril⁶  Nadja Laddach⁷ 

[1] Biometrics Department, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands;Department of Gynecology and Obstetrics, Technische Universität München, Ismaninger Strasse 22, D-81675, Munich, Germany;Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands;Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands;Department of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands;Helmholtz Zentrum München, Institute of Pathology, Ingolstädter Landstrasse 1, D-85764, Neuherberg, Germany;Institute of Pathology, Technische Universität München, Ismaninger Strasse 22, D-81675, Munich, Germany;Present address: Department of Pathology, Case Western Reserve University School of Medicine, University Hospitals Case Medical Center, Cleveland, OH, USA;MRC-Holland, Willem Schoutenstraat 6, 1057 DN, Amsterdam, The Netherlands;

关键词: BRCA1;    BRCAness;    DNA repair;    PARP1;    MLPA assay;    Triple-negative breast cancer;   

DOI  :  10.1186/s12885-016-2848-2

 received in 2015-08-27, accepted in 2016-10-07,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundTriple-negative breast cancer (TNBC) with a BRCA1-like molecular signature has been demonstrated to remarkably respond to platinum-based chemotherapy and might be suited for a future treatment with poly(ADP-ribose)polymerase (PARP) inhibitors. In order to rapidly assess this signature we have previously developed a multiplex-ligation-dependent probe amplification (MLPA)-based assay. Here we present an independent validation of this assay to confirm its important clinical impact.MethodsOne-hundred-forty-four TNBC tumor specimens were analysed by the MLPA-based “BRCA1-like” test. Classification into BRCA1-like vs. non-BRCA1-like samples was performed by our formerly established nearest shrunken centroids classifier. Data were subsequently compared with the BRCA1-mutation/methylation status of the samples. T-lymphocyte infiltration and expression of the main target of PARP inhibitors, PARP1, were assessed on a subset of samples by immunohistochemistry. Data acquisition and interpretation was performed in a blinded manner.ResultsIn the studied TNBC cohort, 63 out of 144 (44 %) tumors were classified into the BRCA1-like category. Among these, the MLPA test correctly predicted 15 out of 18 (83 %) samples with a pathogenic BRCA1-mutation and 20 of 22 (91 %) samples exhibiting BRCA1-promoter methylation. Five false-negative samples were observed. We identified high lymphocyte infiltration as one possible basis for misclassification. However, two falsely classified BRCA1-mutated tumors were also characterized by rather non-BRCA1-associated histopathological features such as borderline ER expression. The BRCA1-like vs. non-BRCA1-like signature was specifically enriched in high-grade (G3) cancers (90 % vs. 58 %, p = 0.0004) and was also frequent in tumors with strong (3+) nuclear PARP1 expression (37 % vs. 16 %; p = 0.087).ConclusionsThis validation study confirmed the good performance of the initial MLPA assay which might thus serve as a valuable tool to select patients for platinum-based chemotherapy regimens. Moreover, frequent PARP1 upregulation in BRCA1-like tumors may also point to susceptibility to treatment with PARP inhibitors. Limitations are the requirement of high tumor content and high-quality DNA.

【 授权许可】

CC BY   
© The Author(s). 2016