title: Seeking the driver in tumours with apparent normal molecular profile on comparative genomic hybridization and targeted gene panel sequencing: what is the added value of whole exome sequencing?
abstract: BACKGROUND
  Molecular tumour profiling technologies have become increasingly important in the era of precision medicine, but their routine use is limited by their accessibility, cost, and tumour material availability. It is therefore crucial to assess their relative added value to optimize the sequence and combination of such technologies.
  
  
  METHODS
  Within the MOSCATO-01 trial, we investigated the added value of whole exome sequencing (WES) in patients that did not present any molecular abnormality on array comparative genomic hybridization (aCGH) and targeted gene panel sequencing (TGPS) using cancer specific panels. The pathogenicity potential and actionability of mutations detected on WES was assessed.
  
  
  RESULTS
  Among 420 patients enrolled between December 2011 and December 2013, 283 (67%) patients were analysed for both TGPS and aCGH. The tumour sample of 25 (8.8%) of them presented a flat (or low-dynamic) aCGH profile and no pathogenic mutation on TGPS. We selected the first eligible 10 samples-corresponding to a heterogeneous cohort of different tumour types-to perform WES. This allowed identifying eight mutations of interest in two patients: FGFR3, PDGFRB, and CREBBP missense single-nucleotide variants (SNVs) in an urothelial carcinoma; FGFR2, FBXW7, TP53, and MLH1 missense SNVs as well as an ATM frameshift mutation in a squamous cell carcinoma of the tongue. The FGFR3 alteration had been previously described as an actionable activating mutation and might have resulted in treatment by an FGFR inhibitor. CREBBP and ATM alterations might also have suggested a therapeutic orientation towards epigenetic modifiers and ataxia-telangectasia and Rad3-related inhibitors, respectively.
  
  
  CONCLUSIONS
  The therapeutic added value of performing WES on tumour samples that do not harbour any genetic abnormality on TGPS and aCGH might be limited and variable according to the histotype. Alternative techniques, including RNASeq and methylome analysis, might be more informative in selected cases.
authors.affiliation: Drug Development Unit, Gustave Roussy Department of Medical Oncology, Faculté de medicine Paris-Sud XI, Kremlin-Bicêtre sophie.postel-vinay@gustaveroussy.fr.
authors.forename: S
authors.initials: S
authors.lastname: Postel-Vinay
authors.affiliation: Bioinformatic platform, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy.
authors.forename: Y
authors.initials: Y
authors.lastname: Boursin
authors.affiliation: Drug Development Unit, Gustave Roussy Department of Medical Oncology, Faculté de medicine Paris-Sud XI, Kremlin-Bicêtre.
authors.forename: C
authors.initials: C
authors.lastname: Massard
authors.affiliation: Drug Development Unit, Gustave Roussy Department of Medical Oncology, Faculté de medicine Paris-Sud XI, Kremlin-Bicêtre.
authors.forename: A
authors.initials: A
authors.lastname: Hollebecque
authors.affiliation: Drug Development Unit, Gustave Roussy.
authors.forename: E
authors.initials: E
authors.lastname: Ileana
authors.affiliation: Sanofi, Translational Medicine, Oncology Unit, Vitry-sur-Seine, France.
authors.forename: M
authors.initials: M
authors.lastname: Chiron
authors.affiliation: Sanofi, Translational Medicine, Oncology Unit, Cambridge, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jung
authors.affiliation: Sanofi, Translational Medicine, Oncology Unit, Cambridge, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Laboratory of Translational Research and Biological Resource Center, AMMICA, INSERM US23/CNRS UMS3655 Department of Medical Biology and Pathology, Gustave Roussy, France.
authors.forename: Z
authors.initials: Z
authors.lastname: Balogh
authors.affiliation: Laboratory of Translational Research and Biological Resource Center, AMMICA, INSERM US23/CNRS UMS3655 Department of Medical Biology and Pathology, Gustave Roussy, France.
authors.forename: J
authors.initials: J
authors.lastname: Adam
authors.affiliation: Laboratory of Translational Research and Biological Resource Center, AMMICA, INSERM US23/CNRS UMS3655 Department of Medical Biology and Pathology, Gustave Roussy, France.
authors.forename: P
authors.initials: P
authors.lastname: Vielh
authors.affiliation: Drug Development Unit, Gustave Roussy.
authors.forename: E
authors.initials: E
authors.lastname: Angevin
authors.affiliation: Laboratory of Translational Research and Biological Resource Center, AMMICA, INSERM US23/CNRS UMS3655 Department of Medical Biology and Pathology, Gustave Roussy, France.
authors.forename: L
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: Drug Development Unit, Gustave Roussy Department of Medical Oncology, Faculté de medicine Paris-Sud XI, Kremlin-Bicêtre.
authors.forename: J-C
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D016172:DNA Fingerprinting; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D011446:Prospective Studies; D017422:Sequence Analysis, DNA
keywords: array comparative genomic hybridization; flat profile; precision medicine; targeted gene panel sequencing; whole exome sequencing