RGD Reference Report - Comprehensive genomic profiles of small cell lung cancer. - Rat Genome Database

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Comprehensive genomic profiles of small cell lung cancer.

Authors: George, Julie  Lim, Jing Shan  Jang, Se Jin  Cun, Yupeng  Ozretić, Luka  Kong, Gu  Leenders, Frauke  Lu, Xin  Fernández-Cuesta, Lynnette  Bosco, Graziella  Müller, Christian  Dahmen, Ilona  Jahchan, Nadine S  Park, Kwon-Sik  Yang, Dian  Karnezis, Anthony N  Vaka, Dedeepya  Torres, Angela  Wang, Maia Segura  Korbel, Jan O  Menon, Roopika  Chun, Sung-Min  Kim, Deokhoon  Wilkerson, Matt  Hayes, Neil  Engelmann, David  Pützer, Brigitte  Bos, Marc  Michels, Sebastian  Vlasic, Ignacija  Seidel, Danila  Pinther, Berit  Schaub, Philipp  Becker, Christian  Altmüller, Janine  Yokota, Jun  Kohno, Takashi  Iwakawa, Reika  Tsuta, Koji  Noguchi, Masayuki  Muley, Thomas  Hoffmann, Hans  Schnabel, Philipp A  Petersen, Iver  Chen, Yuan  Soltermann, Alex  Tischler, Verena  Choi, Chang-min  Kim, Yong-Hee  Massion, Pierre P  Zou, Yong  Jovanovic, Dragana  Kontic, Milica  Wright, Gavin M  Russell, Prudence A  Solomon, Benjamin  Koch, Ina  Lindner, Michael  Muscarella, Lucia A  la Torre, Annamaria  Field, John K  Jakopovic, Marko  Knezevic, Jelena  Castaños-Vélez, Esmeralda  Roz, Luca  Pastorino, Ugo  Brustugun, Odd-Terje  Lund-Iversen, Marius  Thunnissen, Erik  Köhler, Jens  Schuler, Martin  Botling, Johan  Sandelin, Martin  Sanchez-Cespedes, Montserrat  Salvesen, Helga B  Achter, Viktor  Lang, Ulrich  Bogus, Magdalena  Schneider, Peter M  Zander, Thomas  Ansén, Sascha  Hallek, Michael  Wolf, Jürgen  Vingron, Martin  Yatabe, Yasushi  Travis, William D  Nürnberg, Peter  Reinhardt, Christian  Perner, Sven  Heukamp, Lukas  Büttner, Reinhard  Haas, Stefan A  Brambilla, Elisabeth  Peifer, Martin  Sage, Julien  Thomas, Roman K 
Citation: George J, etal., Nature. 2015 Aug 6;524(7563):47-53. doi: 10.1038/nature14664. Epub 2015 Jul 13.
RGD ID: 151347582
Pubmed: PMID:26168399   (View Abstract at PubMed)
PMCID: PMC4861069   (View Article at PubMed Central)
DOI: DOI:10.1038/nature14664   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TP73Humanlung small cell carcinoma  IAGP DNA:mutations:multiple: (human)RGD 
Tp73Ratlung small cell carcinoma  ISOTP73 (Homo sapiens)DNA:mutations:multiple: (human)RGD 
Trp73Mouselung small cell carcinoma  ISOTP73 (Homo sapiens)DNA:mutations:multiple: (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
TP73HumanSmall cell lung carcinoma  IAGP DNA:mutations:multiple:RGD 
Objects Annotated

Genes (Rattus norvegicus)
Tp73  (tumor protein p73)

Genes (Mus musculus)
Trp73  (transformation related protein 73)

Genes (Homo sapiens)
TP73  (tumor protein p73)


Additional Information