Comprehensive genomic profiles of small cell lung cancer

Nature. 2015 Aug 6;524(7563):47-53. doi: 10.1038/nature14664. Epub 2015 Jul 13.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Cell Line, Tumor
  • Chromosome Breakpoints
  • Cyclin D1 / genetics
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Female
  • Gene Expression Profiling
  • Genome, Human / genetics*
  • Genomics*
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mutation / genetics*
  • Neurosecretory Systems / metabolism
  • Neurosecretory Systems / pathology
  • Nuclear Proteins / genetics
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Retinoblastoma Protein / genetics
  • 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

Substances

  • DNA-Binding Proteins
  • Nuclear Proteins
  • Receptors, Notch
  • Retinoblastoma Protein
  • TP53 protein, human
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • p73 protein, human
  • Cyclin D1

Associated data

  • GEO/GSE69091