Comprehensive genomic profiles of small cell lung cancer.

Authors:
Professor John K Field, PhD, BDS, FRCPath
Professor John K Field, PhD, BDS, FRCPath
University of Liverpool
Professor
United Kingdom
Dr. Philipp A Schnabel, MD, PhD
Dr. Philipp A Schnabel, MD, PhD
University Clinics Homburg/Saar
Ltd. Oberarzt
Homburg/Saar, Saarland | Germany
Mr. Philipp Schnabel, MD, PhD
Mr. Philipp Schnabel, MD, PhD
University Clinics Homburg/Saar
Priv.-Doz. Dr. med.
Homburg/Saar, Saarland | Germany

Nature 2015 Aug 13;524(7563):47-53. Epub 2015 Jul 13.

1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany.

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.

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http://dx.doi.org/10.1038/nature14664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861069PMC
August 2015
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