Journal Article

Comprehensive genomic profiles of small cell lung cancer

Choi, Chang-min, Travis, William D., Chen, Yuan, Jovanovic, Dragana, Haas, Stefan A., Pinther, Berit, Park, Kwon-Sik, Menon, Roopika, Altmüller, Janine, Wright, Gavin M., Dahmen, Ilona, Muscarella, Lucia A., Jakopovic, Marko, Tsuta, Koji, Pastorino, Ugo, Castaños-Vélez, Esmeralda, Kontic, Milica, Vlasic, Ignacija, Sage, Julien, Yokota, Jun, Kohno, Takashi, Schuler, Martin, Ansén, Sascha, Salvesen, Helga B., Büttner, Reinhard, Jahchan, Nadine S., Vaka, Dedeepya, Knezevic, Jelena, Lim, Jing Shan, Kim, Yong-Hee, Russell, Prudence A., Schneider, Peter M., Kim, Deokhoon, Field, John K., Brambilla, Elisabeth, Becker, Christian, Fernández-Cuesta, Lynnette, Hoffmann, Hans, Achter, Viktor, Zander, Thomas, Lang, Ulrich, Seidel, Danila, Korbel, Jan O., Massion, Pierre P., Reinhardt, Christian, Karnezis, Anthony N., Pützer, Brigitte, Schaub, Philipp, Bosco, Graziella, Lund-Iversen, Marius, George, Julie, Wang, Maia Segura, Köhler, Jens, Bos, Marc, Zou, Yong, Jang, Se Jin, Thunnissen, Erik, Sandelin, Martin, Leenders, Frauke, Müller, Christian, Soltermann, Alex, Botling, Johan, Koch, Ina, Yatabe, Yasushi, Wilkerson, Matt, Tho

2015

Overview

We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3 . In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer. Genomic sequencing of 110 human small cell lung cancers identifies genomic signatures including nearly ubiquitous bi-allelic inactivation of TP53 and RB1 , a role for NOTCH family genes, and somatic rearrangements that create an oncogenic version of TP73 . Genetic causes of small cell lung cancer Whole-genome sequencing of 110 small cell lung cancers reveals a characteristic bi-allelic inactivation of the tumour suppressor genes TP53 and RB1 in almost all cases. In the only two specimens with no alterations in TP53 and RB1 , chromothripsis activates cyclin D1, leading to the same molecular effect. In addition, 25% of tumours carry inactivating mutations in NOTCH family genes, and the authors show that activation of Notch signalling in a pre-clinical mouse model reduces the number of tumours and extends the survival of the mutant mice. This work highlights possible drug targets in one of the deadliest of human cancers.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/51 / 45/22 / 45/23 / 45/77 / 45/90 / 45/91 / 631/67/69 / 64/110 / 96/63 / Alleles / Analysis / Animals / Cancer / Cancer therapies / Cell Line, Tumor / Chromosome Breakpoints / Cyclin D1 - genetics / Deregulation / Disease Models, Animal / DNA-Binding Proteins - genetics / Drug therapy / Exome sequencing / Female / Gene expression / Gene Expression Profiling / Gene mutations / Genetic aspects / Genome, Human - genetics / Genomes / Genomics / Humanities and Social Sciences / Humans / Inactivation / Kinases / Lung cancer / Lung cancer, Small cell / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Male / Mice / multidisciplinary / Mutation / Mutation - genetics / Neurosecretory Systems - metabolism / Neurosecretory Systems - pathology / Nuclear Proteins - genetics / Pathogenesis / Receptors, Notch - genetics / Receptors, Notch - metabolism / Retinoblastoma Protein - genetics / Science / Signal Transduction - genetics / Small Cell Lung Carcinoma - genetics / Small Cell Lung Carcinoma - metabolism / Small Cell Lung Carcinoma - pathology / Tumor Protein p73 / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Proteins - genetics / Tumors