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

Author

Listed:
  • Alex H. Wagner

    (Washington University School of Medicine)

  • Siddhartha Devarakonda

    (Washington University School of Medicine
    Washington University)

  • Zachary L. Skidmore

    (Washington University School of Medicine)

  • Kilannin Krysiak

    (Washington University School of Medicine
    Washington University School of Medicine)

  • Avinash Ramu

    (Washington University School of Medicine)

  • Lee Trani

    (Washington University School of Medicine)

  • Jason Kunisaki

    (Washington University School of Medicine)

  • Ashiq Masood

    (Washington University School of Medicine
    Washington University
    Saint Luke’s Health System)

  • Saiama N. Waqar

    (Washington University School of Medicine
    Washington University)

  • Nicholas C. Spies

    (Washington University School of Medicine)

  • Daniel Morgensztern

    (Washington University School of Medicine
    Washington University)

  • Jason Waligorski

    (Washington University School of Medicine)

  • Jennifer Ponce

    (Washington University School of Medicine)

  • Robert S. Fulton

    (Washington University School of Medicine)

  • Leonard B. Maggi

    (Washington University School of Medicine
    Washington University
    Washington University School of Medicine)

  • Jason D. Weber

    (Washington University School of Medicine
    Washington University
    Washington University School of Medicine)

  • Mark A. Watson

    (Washington University)

  • Christopher J. O’Conor

    (Washington University School of Medicine)

  • Jon H. Ritter

    (Washington University School of Medicine)

  • Rachelle R. Olsen

    (Huntsman Cancer Institute)

  • Haixia Cheng

    (Huntsman Cancer Institute)

  • Anandaroop Mukhopadhyay

    (Huntsman Cancer Institute)

  • Ismail Can

    (Huntsman Cancer Institute)

  • Melissa H. Cessna

    (Intermountain Healthcare)

  • Trudy G. Oliver

    (Huntsman Cancer Institute)

  • Elaine R. Mardis

    (Washington University School of Medicine
    Washington University
    Washington University School of Medicine
    Nationwide Children’s Hospital)

  • Richard K. Wilson

    (Washington University School of Medicine
    Washington University
    Washington University School of Medicine
    Nationwide Children’s Hospital)

  • Malachi Griffith

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University
    Washington University School of Medicine)

  • Obi L. Griffith

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University
    Washington University School of Medicine)

  • Ramaswamy Govindan

    (Washington University School of Medicine
    Washington University)

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.

Suggested Citation

  • Alex H. Wagner & Siddhartha Devarakonda & Zachary L. Skidmore & Kilannin Krysiak & Avinash Ramu & Lee Trani & Jason Kunisaki & Ashiq Masood & Saiama N. Waqar & Nicholas C. Spies & Daniel Morgensztern , 2018. "Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06162-9
    DOI: 10.1038/s41467-018-06162-9
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    Cited by:

    1. Kelsy C. Cotto & Yang-Yang Feng & Avinash Ramu & Megan Richters & Sharon L. Freshour & Zachary L. Skidmore & Huiming Xia & Joshua F. McMichael & Jason Kunisaki & Katie M. Campbell & Timothy Hung-Po Ch, 2023. "Integrated analysis of genomic and transcriptomic data for the discovery of splice-associated variants in cancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Maximilian W. Schenk & Sam Humphrey & A. S. Md Mukarram Hossain & Mitchell Revill & Sarah Pearsall & Alice Lallo & Stewart Brown & Samuel Bratt & Melanie Galvin & Tine Descamps & Cong Zhou & Simon P. , 2021. "Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Ming Chen & Runzhe Chen & Ying Jin & Jun Li & Xin Hu & Jiexin Zhang & Junya Fujimoto & Shawna M. Hubert & Carl M. Gay & Bo Zhu & Yanhua Tian & Nicholas McGranahan & Won-Chul Lee & Julie George & Xiao , 2021. "Cold and heterogeneous T cell repertoire is associated with copy number aberrations and loss of immune genes in small-cell lung cancer," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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