Analysis of the Genomic Landscape in ALK plus NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes
MOLECULAR CANCER THERAPEUTICS
Authors: du Tertre, Mathilde Couetoux; Marques, Maud; Tremblay, Lise; Bouchard, Nicole; Diaconescu, Razvan; Blais, Normand; Couture, Christian; Pelsser, Vincent; Wang, Hangjun; Higenell, Valerie; Izzi, Luisa; Gambaro, Karen; Hoffert, Cyrla; Srivastava, Archana; Spatz, Alan; Rousseau, Caroline; McNamara, Suzan; Cohen, Victor; Batist, Gerald; Agulnik, Jason
Abstract
Rearrangements in the anaplastic lymphoma kinase (ALK) gene are found in approximately 5% of non-small cell lung carcinoma (NSCLC) here, we present a comprehensive genomic landscape of 11 patients with ALK+ NSCLC and investigate its relationship with response to crimtinib. Using whole-exome sequencing and RNAseq data, we identified four rare ALK fusion partners (HIP1, GCC2, ERC1, and SLC16A7) and one novel partner (CEP55). At the mutation level, TP53 was the most frequently mutated gene and was only observed in patients with the shortest progression-free survival (PFS). Of note, only 4% of the genes carrying mutations are present in more than 1 patient. Analysis of somatic copy number aberrations (SCNA) demonstrated that a gain in EML4 was associated with longer PFS, and a loss of ALK or gain in EGFR was associated with shorter PFS. This study is the first to report a comprehensive view of the ALK+ NSCI,C copy number landscape and to identify SCNA regions associated with clinical outcome. Our data show the presence of TP53 mutation as a strong prognostic indication of poor clinical response in ALK+ NSCLC. Furthermore, new and rare ALK fusion partners were observed in this cohort, expanding our knowledge in ALK+ NSCLC.
Antibodies to active zone protein ERC1 in Lambert-Eaton myasthenic syndrome
HUMAN IMMUNOLOGY
Authors: Huijbers, Maartje G.; Lipka, Alexander F.; Potman, Marko; Hensbergen, Paul J.; Titulaer, Maarten J.; Niks, Erik H.; van der Maarel, Silvere M.; Klooster, Rinse; Verschuuren, Jan J.
Abstract
Lambert Eaton myasthenic syndrome (LEMS) is characterized by fluctuating muscle weakness and autonomic dysfunction. In 90% of the LEMS patients the disease is associated with auto-antibodies against the voltage-gated calcium channels (VGCC). Several auto-immune responses against other antigenic targets have been described to (co)-occur in LEMS patients. To identify new LEMS associated small cell lung cancer (SCLC) markers immunoprecipitation with a SCLC cell line was performed. We discovered strong immunoreactivity against the 120 kDa large ERC1 protein in one tumor-negative VGCC-positive LEMS patient. A recombinant ELISA assay and a cellular assay expressing GFP-tagged full length ERC1 were used to confirm the presence of auto-antibodies against ERC1 in this patient. Additional testing of 58 LEMS patients including 9 VGCC auto-antibody negative LEMS patients, 48 myasthenia gravis patients, 84 control patients with other diseases and 12 healthy controls revealed no other cases. ERC1 is therefore a new, but rare, antigen in LEMS. (c) 2013 American Society for Histocompatibility and Immunogenetics. Published byElsevier Inc. All rights reserved.