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Nat Commun. 2018 Sep 17;9(1):3787. doi: 10.1038/s41467-018-06162-9.

Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer.

Author information

1
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63108, USA.
2
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.
3
Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, 63110, USA.
4
Saint Luke's Health System, Kansas City, MO, USA.
5
ICCE Institute, Washington University School of Medicine, St. Louis, MO, 63110, USA.
6
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
7
Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA.
8
Intermountain Healthcare BioRepository and Department of Pathology, Intermountain Healthcare, Salt Lake City, UT, 84103, USA.
9
Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
10
Nationwide Children's Hospital, Columbus, OH, USA.
11
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63108, USA. mgriffit@wustl.edu.
12
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. mgriffit@wustl.edu.
13
Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, 63110, USA. mgriffit@wustl.edu.
14
Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA. mgriffit@wustl.edu.
15
McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, 63108, USA. obigriffith@wustl.edu.
16
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. obigriffith@wustl.edu.
17
Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, 63110, USA. obigriffith@wustl.edu.
18
Department of Genetics, Washington University School of Medicine, St. Louis, MO, 63110, USA. obigriffith@wustl.edu.
19
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. rgovindan@wustl.edu.
20
Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, 63110, USA. rgovindan@wustl.edu.

Abstract

Nearly all patients with small cell lung cancer (SCLC) eventually relapse with chemoresistant disease. The molecular mechanisms driving chemoresistance in SCLC remain un-characterized. Here, we describe whole-exome sequencing of paired SCLC tumor samples procured at diagnosis and relapse from 12 patients, and unpaired relapse samples from 18 additional patients. Multiple somatic copy number alterations, including gains in ABCC1 and deletions in MYCL, MSH2, and MSH6, are identifiable in relapsed samples. Relapse samples also exhibit recurrent mutations and loss of heterozygosity in regulators of WNT signaling, including CHD8 and APC. Analysis of RNA-sequencing data shows enrichment for an ASCL1-low expression subtype and WNT activation in relapse samples. Activation of WNT signaling in chemosensitive human SCLC cell lines through APC knockdown induces chemoresistance. Additionally, in vitro-derived chemoresistant cell lines demonstrate increased WNT activity. Overall, our results suggest WNT signaling activation as a mechanism of chemoresistance in relapsed SCLC.

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