Research Papers:

Mutational profiles in triple-negative breast cancer defined by ultradeep multigene sequencing show high rates of PI3K pathway alterations and clinically relevant entity subgroup specific differences

Mark Kriegsmann _, Volker Endris, Thomas Wolf, Nicole Pfarr, Albrecht Stenzinger, Sibylle Loibl, Carsten Denkert, Andreas Schneeweiss, Jan Budczies, Peter Sinn and Wilko Weichert

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Oncotarget. 2014; 5:9952-9965. https://doi.org/10.18632/oncotarget.2481

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Mark Kriegsmann1, Volker Endris1,2, Thomas Wolf1, Nicole Pfarr1, Albrecht Stenzinger1, Sibylle Loibl3, Carsten Denkert4,6, Andreas Schneeweiss5,6, Jan Budczies4,6, Peter Sinn1 and Wilko Weichert1,5,6

1 Institute of Pathology, University of Heidelberg, Germany

2 German Cancer Research Center, Heidelberg, Germany

3 German Breast Group, Neu-Isenburg, Germany

4 Institute of Pathology, University Hospital Charité Berlin, Germany

5 National Center for Tumor Diseases, Heidelberg, Germany

6 German Cancer Consortium (DKTK), Germany


Mark Kriegsmann, email:

Keywords: triple-negative breast cancer, next generation sequencing, immunohistochemistry, mutation profiling

Received: July 09, 2014 Accepted: September 15, 2014 Published: September 16, 2014


Mutational profiling of triple-negative breast cancer (TNBC) by whole exome sequencing (WES) yielded a landscape of genomic alterations in this tumor entity. However, the clinical significance of these findings remains enigmatic. Further, integration of WES in routine diagnostics using formalin-fixed paraffin-embedded (FFPE) material is currently not feasible.

Therefore, we designed and validated a breast cancer specific gene panel for semiconductor-based sequencing comprising 137 amplicons covering mutational hotspots in 44 genes and applied this panel on a cohort of 104 well-characterized FFPE TNBC with complete clinical follow-up.

TP53 mutations were present in more than 80% of cases. PI3K pathway alterations (29.8%) comprising mainly PIK3CA mutations (22.1%) but also mutations and/or amplifications/deletions in other PI3K-associated genes (7.7%) were far more frequently observed, when compared to WES data. Alterations in MAPK signaling genes (8.7%) and cell-cycle regulators (14.4%) were also frequent. Mutational profiles were linked to TNBC subgroups defined by morphology and immunohistochemistry. Alterations in cell-cycle pathway regulators were linked with better overall (p=0.053) but not disease free survival.

Taken together, we could demonstrate that breast cancer targeted hotspot sequencing is feasible in a routine setting and yields reliable and clinically meaningful results. Mutational spectra were linked to clinical and immunohistochemically defined parameters.

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