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

• DOI: 10.1038/s41467-018-06162-9
• Publication Date: 2018-09-11T13:45:55Z
• Authors: Alex H. Wagner; Siddhartha Devara...; Zachary L. Skidmore; Kilannin Krysiak; Avinash Ramu; Lee Trani; Jason Kunisaki; Ashiq Masood; Saiama N. Waqar; Nicholas C. Spies; Daniel Morgensztern; Jason Waligorski; Jennifer Ponce; Robert S. Fulton; Leonard B. Maggi; Jason D. Weber; Mark A. Watson; Christopher J. O’...; Jon H. Ritter; Rachelle R. Olsen; Haixia Cheng; Anandaroop Mukhop...; Ismail Can; Melissa H. Cessna; Trudy G. Oliver; Elaine R. Mardis; Richard K. Wilson; Malachi Griffith; Obi L. Griffith; Ramaswamy Govindan
• Keywords: MSH6; MSH2

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