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Oncotarget. 2014 Oct 30;5(20):9952-65.

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.

Author information

1
Institute of Pathology, University of Heidelberg, Germany.
2
Institute of Pathology, University of Heidelberg, Germany. German Cancer Research Center, Heidelberg, Germany.
3
German Breast Group, Neu-Isenburg, Germany.
4
Institute of Pathology, University Hospital Charité Berlin, Germany. German Cancer Consortium (DKTK), Germany.
5
National Center for Tumor Diseases, Heidelberg, Germany. German Cancer Consortium (DKTK), Germany.
6
Institute of Pathology, University of Heidelberg, Germany. National Center for Tumor Diseases, Heidelberg, Germany. German Cancer Consortium (DKTK), Germany.

Abstract

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.

PMID:
25296970
PMCID:
PMC4259450
DOI:
10.18632/oncotarget.2481
[Indexed for MEDLINE]
Free PMC Article

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