Genomic Aberrations in Lung Adenocarcinoma in Never Smokers

PLoS One

Paul Hofman¹  Pierre Fouret²  Ludovic Lacroix²  Alain Bernheim²  Sophie Camilleri-Broët³  Michèle Beau-Faller⁴  Julien Mazières⁵  Julien Laffaire⁶  Philippe Dessen⁷  Bastien Job⁸  Saloua Toujani⁹  Philippe Girard^1,10  for the LG Investigators^1,10 

[1] Département Thoracique, Institut Mutualiste Montsouris, Paris, France;INSERM Génétique des tumeurs U985, INSERM, Villejuif, France;INSERM JE2492, INSERM, Kremlin-Bicêtre, France;Laboratoire de Biochimie et de Biologie Moléculaire (Hôpital de Hautepierre), CHU Strasbourg, Strasbourg, France;Laboratoire de Pathologie Clinique et Expérimentale (Hôpital Pasteur), CHU Nice, Nice, France;Laboratoire de Recherche Translationnelle, Institut de cancérologie Gustave-Roussy, Villejuif, France;Ligue Nationale contre le Cancer, Paris, France;Plate-forme de Biologie intégrée, Institut de recherche intégrée en Cancérologie à Villejuif, Villejuif, France;Unité de Cancérologie Cervico Thoracique (Hôpital Larrey), CHU Toulouse, Toulouse, France;Université Paris-Sud, Kremlin-Bicêtre, France

关键词: Lung and intrathoracic tumors;    Adenocarcinoma of the lung;    Adenocarcinomas;    Molecular genetics;    Oncogenes;    Secondary lung tumors;    Gene amplification;    Tumor suppressor genes;   

DOI  :  10.1371/journal.pone.0015145

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Background Lung cancer in never smokers would rank as the seventh most common cause of cancer death worldwide. Methods and Findings We performed high-resolution array comparative genomic hybridization analysis of lung adenocarcinoma in sixty never smokers and identified fourteen new minimal common regions (MCR) of gain or loss, of which five contained a single gene (MOCS2, NSUN3, KHDRBS2, SNTG1 and ST18). One larger MCR of gain contained NSD1. One focal amplification and nine gains contained FUS. NSD1 and FUS are oncogenes hitherto not known to be associated with lung cancer. FISH showed that the amplicon containing FUS was joined to the next telomeric amplicon at 16p11.2. FUS was over-expressed in 10 tumors with gain of 16p11.2 compared to 30 tumors without that gain. Other cancer genes present in aberrations included ARNT, BCL9, CDK4, CDKN2B, EGFR, ERBB2, MDM2, MDM4, MET, MYC and KRAS. Unsupervised hierarchical clustering with adjustment for false-discovery rate revealed clusters differing by the level and pattern of aberrations and displaying particular tumor characteristics. One cluster was strongly associated with gain of MYC. Another cluster was characterized by extensive losses containing tumor suppressor genes of which RB1 and WRN. Tumors in that cluster frequently harbored a central scar-like fibrosis. A third cluster was associated with gains on 7p and 7q, containing ETV1 and BRAF, and displayed the highest rate of EGFR mutations. SNP array analysis validated copy-number aberrations and revealed that RB1 and WRN were altered by recurrent copy-neutral loss of heterozygosity. Conclusions The present study has uncovered new aberrations containing cancer genes. The oncogene FUS is a candidate gene in the 16p region that is frequently gained in never smokers. Multiple genetic pathways defined by gains of MYC, deletions of RB1 and WRN or gains on 7p and 7q are involved in lung adenocarcinoma in never smokers.

【 授权许可】

CC BY