Circulating tumor DNA analysis depicts subclonal architecture and genomic evolution of small cell lung cancer
Jingying Nong, Yuhua Gong, Yanfang Guan, Xin Yi, Yuting Yi, Lianpeng Chang, Ling Yang, Jialin Lv, Zhirong Guo, Hongyan Jia, Yuxing Chu, Tao Liu, Ming Chen, Lauren Byers, Emily Roarty, Vincent K Lam, Vassiliki A Papadimitrakopoulou, Ignacio Wistuba, John V Heymach, Bonnie Glisson, Zhongxing Liao, J Jack Lee, P Andrew Futreal, Shucai Zhang, Xuefeng Xia, Jianjun Zhang, Jinghui Wang, Jingying Nong, Yuhua Gong, Yanfang Guan, Xin Yi, Yuting Yi, Lianpeng Chang, Ling Yang, Jialin Lv, Zhirong Guo, Hongyan Jia, Yuxing Chu, Tao Liu, Ming Chen, Lauren Byers, Emily Roarty, Vincent K Lam, Vassiliki A Papadimitrakopoulou, Ignacio Wistuba, John V Heymach, Bonnie Glisson, Zhongxing Liao, J Jack Lee, P Andrew Futreal, Shucai Zhang, Xuefeng Xia, Jianjun Zhang, Jinghui Wang
Abstract
Subclonal architecture and genomic evolution of small-cell lung cancer (SCLC) under treatment has not been well studied primarily due to lack of tumor specimens, particularly longitudinal samples acquired during treatment. SCLC is characterized by early hematogenous spread, which makes circulating cell-free tumor DNA (ctDNA) sequencing a promising modality for genomic profiling. Here, we perform targeted deep sequencing of 430 cancer genes on pre-treatment tumor biopsies, as well as on plasma samples collected prior to and during treatment from 22 SCLC patients. Similar subclonal architecture is observed between pre-treatment ctDNA and paired tumor DNA. Mean variant allele frequency of clonal mutations from pre-treatment ctDNA is associated with progression-free survival and overall survival. Pre- and post-treatment ctDNA mutational analysis demonstrate that mutations of DNA repair and NOTCH signaling pathways are enriched in post-treatment samples. These data suggest that ctDNA sequencing is promising to delineate genomic landscape, subclonal architecture, and genomic evolution of SCLC.
Conflict of interest statement
The authors declare the following competing interests: Y.H.G., Y.F.G., X.Y., Y.T.Y., L.P.C., L.Y., Y.X.C., and T.L. are current employees of Geneplus-Beijing. X.Y. and L.Y. hold leadership positions and stocks of Geneplus-Beijing. J.V.H. is a consultant for AstraZeneca, Abbvie, Boehringer Ingelheim, Bristol-Myers Squibb, Medivation, ARIAD, Synta, Oncomed, Novartis, Genentech, and Calithera Biosciences, holds stock in Cardinal Spine LLC and Bio-Tree, and has received funding from AstraZeneca. J.Z. is a consultant for AstraZeneca and receives honoraria from Bristol-Myers Squibb. I.I.W. receives honoraria from Roche/Genentech, Ventana, GlaxoSmithKline, Celgene, Bristol-Myers Squibb, Synta Pharmaceuticals, Boehringer Ingelheim, Medscape, Clovis, AstraZeneca, and Pfizer, and research support from Roche/Genentech, Oncoplex, and HGT. The remaining authors declare no competing interests.
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