Circulating tumor DNA analysis depicts subclonal architecture and genomic evolution of small cell lung cancer

Jingying Nong,Vincent K Lam,Jianjun Zhang,Shucai Zhang,Ming Chen,P Andrew Futreal,Jialin Lv,Yuhua Gong,Ling Yang,Vassiliki A Papadimitrakopoulou,Zhirong Guo,John V Heymach,Yanfang Guan,Ignacio I Wistuba ,Lauren A Byers ,John Lee ,Bonnie S Glisson ,Emily Roarty,Xin Yi,Hongyan Jia,Yuxing Chu,Zhongxing Liao,Yuting Yi,Lianpeng Chang,Xuefeng Xia,Tao Liu,Jinghui Wang

doi:10.1038/s41467-018-05327-w

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.

Highlights

Small-cell lung cancer (SCLC) accounts for ~15% of newly diagnosed lung cancers
About 1/3 of patients presented with limited-stage disease (LD) that can be treated with chemoradiation, while the remaining patients presented with extensive-stage disease (ED), which are usually treated with palliative chemotherapy
SCLC is a rapidly proliferating malignancy with early hematogenous spread[5], suggesting that cell-free tumor DNA (ctDNA) might be readily detectable in SCLC patients, regardless of stage

Summary

Introduction

Small-cell lung cancer (SCLC) accounts for ~15% of newly diagnosed lung cancers. SCLC is a very aggressive malignancy characterized by rapid growth and early hematogenous spread. Given the pattern of initial response to chemotherapy and/or radiotherapy and nearly invariable relapse, it has been speculated that treatment-naive SCLC harbors subclones of inherently refractory (resistant) cancer cells that give rise to the relapse in these patients. Compared to many other solid tumors, there have been only a few studies investigating the genomic landscape of SCLC10–12 This is primarily due to the lack of adequate tumor tissues because the majority of SCLC patients are not treated with surgical resection. Since ctDNA sequencing is noninvasive and “real-time”, it could be an ideal tool for investigating genomic evolution of SCLC over time, during treatment. We show that circulating tumor DNA sequencing is promising to delineate genomic landscape, subclonal architecture and investigate genomic evolution of small-cell lung cancer under therapy

Methods

Results

Conclusion