Comprehensive genomic profiles of small cell lung cancer
Top Cited Papers
Open Access
- 13 July 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 524 (7563), 47-53
- https://doi.org/10.1038/nature14664
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.Keywords
This publication has 52 references indexed in Scilit:
- Genome‐wide identification of genes with amplification and/or fusion in small cell lung cancerGenes, Chromosomes and Cancer, 2013
- Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancerNature Genetics, 2012
- Comprehensive molecular characterization of human colon and rectal cancerNature, 2012
- Possible roles of DLK1 in the Notch pathway during development and diseaseBiochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2012
- A continuum model for tumour suppressionNature, 2011
- Loss of p130 Accelerates Tumor Development in a Mouse Model for Human Small-Cell Lung CarcinomaCancer Research, 2010
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- A census of human cancer genesNature Reviews Cancer, 2004
- Achaete–scute homolog-1 and Notch in lung neuroendocrine development and cancerCancer Letters, 2004
- Gain-of-Function Mutations of c- kit in Human Gastrointestinal Stromal TumorsScience, 1998