title: 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.
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.
authors.affiliation: Institute of Pathology, University of Heidelberg, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Kriegsmann
authors.affiliation: Institute of Pathology, University of Heidelberg, Germany. German Cancer Research Center, Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.affiliation: Institute of Pathology, University of Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wolf
authors.affiliation: Institute of Pathology, University of Heidelberg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pfarr
authors.affiliation: Institute of Pathology, University of Heidelberg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
authors.affiliation: German Breast Group, Neu-Isenburg, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.affiliation: Institute of Pathology, University Hospital Charité Berlin, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Denkert
authors.affiliation: National Center for Tumor Diseases, Heidelberg, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schneeweiss
authors.affiliation: Institute of Pathology, University Hospital Charité Berlin, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Budczies
authors.affiliation: Institute of Pathology, University of Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Sinn
authors.affiliation: Institute of Pathology, University of Heidelberg, Germany. National Center for Tumor Diseases, Heidelberg, Germany. German Cancer Consortium (DKTK), Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
mesh_terms: D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D016158:Genes, p53; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D005810:Multigene Family; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000145:classification / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases