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.

Details

Title
Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer
Author
Wagner, Alex H 1   VIAFID ORCID Logo  ; Devarakonda, Siddhartha 2 ; Skidmore, Zachary L 1 ; Krysiak, Kilannin 3   VIAFID ORCID Logo  ; Ramu, Avinash 1   VIAFID ORCID Logo  ; Trani, Lee 1 ; Kunisaki, Jason 1 ; Masood, Ashiq 4 ; Waqar, Saiama N 2 ; Spies, Nicholas C 1 ; Morgensztern, Daniel 2 ; Waligorski, Jason 1 ; Ponce, Jennifer 1 ; Fulton, Robert S 1 ; Maggi, Leonard B, Jr 5 ; Weber, Jason D 5 ; Watson, Mark A 6 ; Christopher J O’Conor 7 ; Ritter, Jon H 7 ; Olsen, Rachelle R 8 ; Cheng, Haixia 8 ; Mukhopadhyay, Anandaroop 8 ; Ismail, Can 8   VIAFID ORCID Logo  ; Cessna, Melissa H 9 ; Oliver, Trudy G 8 ; Mardis, Elaine R 10 ; Wilson, Richard K 10 ; Griffith, Malachi 11 ; Griffith, Obi L 11   VIAFID ORCID Logo  ; Ramaswamy Govindan 2 

1  McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA 
2  Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, USA 
3  McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA 
4  Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, USA; Saint Luke’s Health System, Kansas City, MO, USA 
5  Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, USA; ICCE Institute, Washington University School of Medicine, St. Louis, MO, USA 
6  Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, USA 
7  Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA 
8  Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA 
9  Intermountain Healthcare BioRepository and Department of Pathology, Intermountain Healthcare, Salt Lake City, UT, USA 
10  McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA; Nationwide Children’s Hospital, Columbus, OH, USA 
11  McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, USA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Alvin J Siteman Cancer Center, Washington University, St. Louis, MO, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA 
Pages
1-11
Publication year
2018
Publication date
Sep 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-06162-9
ProQuest document ID
2108206326
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.