Whole exome sequencing (WES) analysis of transformed small cell lung cancer (SCLC) from lung adenocarcinoma (LUAD)

Tongji Xie; Yan Li; Jianming Ying; Weijing Cai; Junling Li; Kye Young Lee; Biagio Ricciuti; Jose Pacheco; Puyuan Xing

doi:10.21037/tlcr-20-1278

Whole exome sequencing (WES) analysis of transformed small cell lung cancer (SCLC) from lung adenocarcinoma (LUAD)

Transl Lung Cancer Res. 2020 Dec;9(6):2428-2439. doi: 10.21037/tlcr-20-1278.

Authors

Tongji Xie¹, Yan Li¹, Jianming Ying¹, Weijing Cai², Junling Li¹, Kye Young Lee³, Biagio Ricciuti^{4

5}, Jose Pacheco⁶, Puyuan Xing¹

Affiliations

¹ National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Shanghai Tongshu Biotechnology Co., Ltd, Shanghai, China.
³ Precision Medicine Lung Cancer Center, Konkuk University Medical Center and Department of Pulmonary Medicine, Konkuk University School of Medicine, 120-1 Neungdong-ro, Gwangjin-Gu, Seoul, 05030 Republic of Korea.
⁴ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
⁵ Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
⁶ University of Colorado Anschutz Cancer Center, Aurora, CO, USA.

Abstract

Background: Histologic transformation of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is a rare mechanism of acquired resistance to epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors. However, the SCLC transformation has also been observed in non.

Egfr: mutant NSCLC. In these cases, whether SCLC initially co-exists with NSCLC or originates from initial NSCLC remains to be determined.

Methods: Whole exome sequencing was performed on 10 samples from 5 patients with SCLC transformation from lung adenocarcinoma (LUAD), a main subtype of NSCLC. Somatic mutations and copy number variations (CNVs) were analyzed to explore the differences between initial LUAD and transformed SCLC, as well as the origin of transformed SCLC.

Results: After SCLC transformation, the mutation spectrum changed, with decreased C>T and increased C>A. Compared with initial LUAD, the CNV burden of transformed SCLC was greatly increased (39.0 vs. 61.1, Wilcoxon P=0.4). The higher the CNV burden of LUAD, the shorter the time to SCLC transformation was observed to be; and the higher the CNV burden of transformed SCLC, the shorter the overall survival (OS) after transformation. Clonal evolution analysis showed different clonal components between initial LUAD and transformed SCLC.

Conclusions: The transformation of LUAD into SCLC may be promoted by CNV events rather than mutational events. CNV burden was associated with the time to SCLC transformation and with the OS of patients following SCLC transformation. Transformed SCLC did not evolve directly from the initial LUAD but branched off from LUAD before the time of initial diagnosis.

Keywords: Next generation sequencing (NGS); clonal evolution analysis; copy number variation (CNV) burden; prognostic predictor; single nucleotide variants (SNVs).