title: Copy number changes of clinically actionable genes in melanoma, non-small cell lung cancer and colorectal cancer-A survey across 822 routine diagnostic cases.
abstract: Targeted deep massive parallel sequencing has been implemented in routine molecular diagnostics for high-throughput genetic profiling of formalin-fixed paraffin-embedded (FFPE) cancer samples. This approach is widely used to interrogate simple somatic mutations but experience with the analysis of copy number variations (CNV) is limited. Here, we retrospectively analyzed CNV in 822 cancer cases (135 melanoma, 468 non-small cell lung cancers (NSCLC), 219 colorectal cancers (CRC)). We observed a decreasing frequency of CNV in clinically actionable genes from melanoma to NSCLC to CRC. The overall cohort displayed 168 (20%) amplifications in 17 druggable targets. The majority of BRAF mutant melanomas (54%) showed co-occurring CNV in other genes, mainly affecting CDKN2A. Subsets showed clustered deletions in ABL1, NOTCH1, RET or STK11, GNA11, and JAK3. Most NRAS mutant melanomas (49%) harbored CNVs in other genes with CDKN2A and FGFR3 being most frequently affected. Five BRAF/NRASwt tumors had co-amplifications of KDR, KIT, PDGFRA and another six mutated KIT. Among all NSCLC, we identified 14 EGFRamp (with ten EGFRmut) and eight KRASamp (with seven KRASmut). KRASmut tumors displayed frequent amplifications of MYC (n = 10) and MDM2 (n = 5). Fifteen KRAS/EGFR/BRAFwt tumors had MET mutations/amplifications. In CRC, amplified IGF2 was most prevalent (n = 13) followed by MYC (n = 9). Two cases showed amplified KRAS wildtype alleles. Two of the KRASmut cases harbored amplifications of NRAS and three KRASwt cases amplification of EGFR. In conclusion, we demonstrate that our approach i) facilitates detection of CNV, ii) enables detection of known CNV patterns, and iii) uncovers new CNV of clinically actionable genes in FFPE tissue samples across cancers. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Institute of Pathology, Technical University Munich (TUM), Munich, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pfarr
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.affiliation: Institute of Pathology, Charité University Hospital, Berlin, Germany.
authors.forename: Frederick
authors.initials: F
authors.lastname: Klauschen
authors.affiliation: Institute of Pathology, Charité University Hospital, Berlin, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Heim
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Regine
authors.initials: R
authors.lastname: Brandt
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kazdal
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Institute of Pathology, Technical University Munich (TUM), Munich, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Jesinghaus
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|German Center for Lung Research (DZL), Heidelberg, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Warth
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.|Institute of Pathology, Technical University Munich (TUM), Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|National Center for Tumor Diseases (NCT), Heidelberg, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Endris
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. albrecht.stenzinger@med.uni-heidelberg.de.|German Cancer Consortium (DKTK), Heidelberg, Germany. albrecht.stenzinger@med.uni-heidelberg.de.|National Center for Tumor Diseases (NCT), Heidelberg, Germany. albrecht.stenzinger@med.uni-heidelberg.de.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Stenzinger
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D003581:Cytodiagnosis; D056915:DNA Copy Number Variations / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008545:Melanoma / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins