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Comprehensive genomic profiles of small cell lung cancer

2015-07-13 00:01:19

NATURE; 13 July 2015: DOI:10.1038/nature14664


Julie George, Jing Shan Lim, Se Jin Jang, Yupeng Cun, Luka Ozreti?, Gu Kong, Frauke Leenders, Xin Lu, Lynnette Fernández-Cuesta, Graziella Bosco, Christian Müller, Ilona Dahmen, Nadine S. Jahchan, Kwon-Sik Park, Dian Yang, Anthony N. Karnezis, Dedeepya Vaka, Angela Torres, Maia Segura Wang, Jan O. Korbel, Roopika Menon, Sung-Min Chun, Deokhoon Kim, Matt Wilkerson, Neil Hayes, et al.



Abstract


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.



Introduction


Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, arises in heavy smokers, and the tumour cells express neuroendocrine markers. Although chemotherapy is initially effective in the treatment of SCLC, recurrence arises rapidly in the vast majority of cases, usually killing the patient within only a few months. SCLC is rarely treated by surgery and few specimens are available for genomic characterization. Previous studies applying mostly exome sequencing in a limited number of tumour specimens have revealed only a few recurrently mutated genes.



We hypothesized that complex genomic rearrangements, which are undetectable by exome sequencing, might further contribute to the pathogenesis of SCLC and thus performed whole-genome sequencing of 110 human SCLC specimens. One of the hallmarks of SCLC is the high frequency of mutations in TP53 and RB1. As mice lacking Trp53 and Rb1 in the lung develop SCLC8, we also sequenced 8 of these murine SCLC tumours in order to identify mutations that may promote SCLC development following loss of Trp53 and Rb1 and that may overlap with such accessory genes in human SCLC.



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Key Words


Cancer Genomics