TY - JOUR
T1 - Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer
AU - Wagner, Alex H.
AU - Devarakonda, Siddhartha
AU - Skidmore, Zachary L.
AU - Krysiak, Kilannin
AU - Ramu, Avinash
AU - Trani, Lee
AU - Kunisaki, Jason
AU - Masood, Ashiq
AU - Waqar, Saiama N.
AU - Spies, Nicholas C.
AU - Morgensztern, Daniel
AU - Waligorski, Jason
AU - Ponce, Jennifer
AU - Fulton, Robert S.
AU - Maggi, Leonard B.
AU - Weber, Jason D.
AU - Watson, Mark A.
AU - O’Conor, Christopher J.
AU - Ritter, Jon H.
AU - Olsen, Rachelle R.
AU - Cheng, Haixia
AU - Mukhopadhyay, Anandaroop
AU - Can, Ismail
AU - Cessna, Melissa H.
AU - Oliver, Trudy G.
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
AU - Griffith, Malachi
AU - Griffith, Obi L.
AU - Govindan, Ramaswamy
N1 - Funding Information:
The authors would like to thank Erica Barnell, Irena Lanc, and Lynzey Kujan for their assistance with manual review of variants. A.H.W. was supported by a fellowship (F32CA206247) and traineeship (T32CA113275) from the NCI. S.D. was supported by a fellowship award from the International Association for Study of Lung Cancer (IASLC). T.G.O. was supported by the Huntsman Cancer Foundation (P30CA042014) and in part by the NIH (R01CA187487, R21CA216504) and the American Lung Association (LCD-506758). M.G. was supported by the NHGRI under award R00HG007940. O.L.G. was supported by the NCI under award numbers K22CA188163 and U01CA209936. R.G. was supported by a grant from the Lung Cancer Connection foundation.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85053390711&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-06162-9
DO - 10.1038/s41467-018-06162-9
M3 - Article
C2 - 30224629
AN - SCOPUS:85053390711
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3787
ER -