title: High number of kinome-mutations in non-small cell lung cancer is associated with reduced immune response and poor relapse-free survival.
abstract: Lung cancer is the leading cause of cancer related death, and the past years' improved insight into underlying molecular events has significantly improved outcome for specific subsets of patients. In particular, several new therapies that target protein kinases have been implemented, and many more are becoming available. We have investigated lung cancer specimens for somatic mutations in a targeted panel of 612 human genes, the majority being protein kinases. The somatic mutation profiles were correlated to profiles of immune cell infiltration as well as relapse-free survival. Targeted deep sequencing was performed on 117 tumour/normal pairs using the SureSelect Human Kinome kit (Agilent Technologies), with capture probes targeting 3.2 Mb of the human genome, including exons and untranslated regions of all known kinases, kinase receptors and selected cancer-related genes (612 genes in total). CD8 staining was determined using Ventana Benchmark. Survival analyses were performed using SPSS. The number of mutations per sample ranged from 0 to 50 (within the 612 genes tested), with a median of nine. The prognosis was worse for patients with more than the median number of mutations. A significant correlation was found between mutations in one of selected DNA-repair genes and the total number of mutations in that tumour (p < 0.001). There was a significant inverse correlation between the number of infiltrating stromal CD8+ lymphocytes and the presence of EGFR mutations.
authors.affiliation: Department of Cancer Genetics, Oslo University Hospital - Radium Hospital, Oslo, Norway.|Department of Oncology, Oslo University Hospital - Radium Hospital, Oslo, Norway.|Institute of Clinical Medicine, University of Oslo, Norway.
authors.forename: Å
authors.identifier: 0000-0002-5520-0275
authors.initials: Å
authors.lastname: Helland
authors.affiliation: Department of Cancer Genetics, Oslo University Hospital - Radium Hospital, Oslo, Norway.|Department of Oncology, Oslo University Hospital - Radium Hospital, Oslo, Norway.
authors.forename: O T
authors.initials: OT
authors.lastname: Brustugun
authors.affiliation: Norwegian Cancer Genomics Consortium, Institute for Cancer Research, Oslo University Hospital -Radium Hospital, Oslo, Norway.|Department of Tumor Biology, Oslo University Hospital, Radium Hospital, Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Nakken
authors.affiliation: Department of Cancer Genetics, Oslo University Hospital - Radium Hospital, Oslo, Norway.
authors.forename: A R
authors.initials: AR
authors.lastname: Halvorsen
authors.affiliation: Institute of Clinical Medicine, UiT - The Arctic University of Tromsø, Norway.|Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway.
authors.forename: T
authors.initials: T
authors.lastname: Dønnem
authors.affiliation: Institute of Clinical Medicine, UiT - The Arctic University of Tromsø, Norway.|Department of Oncology, University Hospital of Northern Norway, Tromsø, Norway.
authors.forename: R
authors.initials: R
authors.lastname: Bremnes
authors.affiliation: Institute of Medical Biology, The Arctic University of Norway, Tromsø, Norway.|Department of Pathology, University Hospital of Northern Norway, Tromsø, Norway.
authors.forename: L T
authors.initials: LT
authors.lastname: Busund
authors.affiliation: Norwegian Cancer Genomics Consortium, Institute for Cancer Research, Oslo University Hospital -Radium Hospital, Oslo, Norway.|Department of Tumor Biology, Oslo University Hospital, Radium Hospital, Oslo, Norway.
authors.forename: J
authors.initials: J
authors.lastname: Sun
authors.affiliation: Norwegian Cancer Genomics Consortium, Institute for Cancer Research, Oslo University Hospital -Radium Hospital, Oslo, Norway.|Department of Tumor Biology, Oslo University Hospital, Radium Hospital, Oslo, Norway.
authors.forename: S
authors.initials: S
authors.lastname: Lorenz
authors.affiliation: Departement of Thoracic Surgery, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
authors.forename: S K
authors.initials: SK
authors.lastname: Solberg
authors.affiliation: Departement of Thoracic Surgery, Oslo University Hospital - Rikshospitalet, Oslo, Norway.
authors.forename: L H
authors.initials: LH
authors.lastname: Jørgensen
authors.affiliation: Norwegian Cancer Genomics Consortium, Institute for Cancer Research, Oslo University Hospital -Radium Hospital, Oslo, Norway.|Department of Tumor Biology, Oslo University Hospital, Radium Hospital, Oslo, Norway.
authors.forename: D
authors.initials: D
authors.lastname: Vodak
authors.affiliation: Norwegian Cancer Genomics Consortium, Institute for Cancer Research, Oslo University Hospital -Radium Hospital, Oslo, Norway.|Department of Tumor Biology, Oslo University Hospital, Radium Hospital, Oslo, Norway.
authors.forename: O
authors.initials: O
authors.lastname: Myklebost
authors.affiliation: Norwegian Cancer Genomics Consortium, Institute for Cancer Research, Oslo University Hospital -Radium Hospital, Oslo, Norway.|Department of Tumor Biology, Oslo University Hospital, Radium Hospital, Oslo, Norway.|Department of Informatics, University of Oslo, Oslo, Norway.|Institute of Cancer Genetics and informatics, Radium Hospital, Oslo, Norway.
authors.forename: E
authors.initials: E
authors.lastname: Hovig
authors.affiliation: Norwegian Cancer Genomics Consortium, Institute for Cancer Research, Oslo University Hospital -Radium Hospital, Oslo, Norway.|Department of Tumor Biology, Oslo University Hospital, Radium Hospital, Oslo, Norway.
authors.forename: L A
authors.initials: LA
authors.lastname: Meza-Zepeda
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use
chemical_list: D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D010770:Phosphotransferases
keywords: kinome; lung cancer; mutations; prognosis; sequencing