Profiling of 520 Candidate Genes in 50 Surgically Treated Chinese Small Cell Lung Cancer Patients

Ting Yuan; Xin Wang; Sijin Sun; Zheng Cao; Xiaoli Feng; Yibo Gao

doi:10.3389/fonc.2021.644434

Profiling of 520 Candidate Genes in 50 Surgically Treated Chinese Small Cell Lung Cancer Patients

Front Oncol. 2021 Jun 8:11:644434. doi: 10.3389/fonc.2021.644434. eCollection 2021.

Authors

Ting Yuan¹, Xin Wang², Sijin Sun², Zheng Cao¹, Xiaoli Feng¹, Yibo Gao^{2

3}

Affiliations

¹ Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
³ State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Abstract

Small cell lung cancer (SCLC) is one of the severe malignancies with high mortality. Surgically resected tumor tissues from 50 Chinese SCLC patients were collected for next-generation sequencing to detect 520 cancer-related genes. The most frequently altered genes were TP53 (94.0%), RB1 (86.0%), LRP1B (44.0%), SPTA1 (26.0%) and KMT2D (24.0%). We detected that NOTCH2, JAK2 and CDK12 (P<0.05) had a significantly higher mutation frequency in Chinese SCLC compared to the Cologne and MSKCC. The single nucleotide variation (SNV) is dominated by C>A (34.1%). We found a significant association between TMB-H (≥10.3muts/Mb) and ATM (P=0.023), CREBBP (P=0.010), KMT2D(P=0.050) and LRP1B (P=0.005) gene mutations in Chinese SCLC patients. Immunostaining was performed using the following antibodies: TTF-1, CgA, CD56, Syn, and Ki-67. Correlation analysis between the expression of 6 markers and mutations in signaling pathways showed that Syn and CgA expression were associated with 4 (cGMP-PKG, Chemokine, TGF-β and Phospholipase D) and 2 (cGMP-PKG and Phosphatidylinositol) signaling pathway mutations. Kaplan-Meier curve showed that age<55 years, mutant ARID2 and high TMB (≥7muts/Mb) were associated with a better prognosis, while the prognosis of patients with mutations in the Ras pathway was significantly improved. High TMB is an important prognostic factor for SCLC patients showed by multivariate analysis. In the combined cohort composed of current and two previous studies, survival analysis showed that SCLC patients with mutant LRP1B demonstrated better OS (P=0.0017). Patients with a high TMB (≥7muts/Mb) have a better prognosis (P=0.0053), consistent with our results in the Chinese cohort. We characterized the genomic alterations profile of Chinese SCLC patients and analyzed the correlation between genomic changes and immunohistochemical phenotypes at the signaling pathway level. Our data might provide useful information in the diagnosis and treatment for Chinese SCLC patients.

Keywords: immunohistochemistry; next generation sequencing; signaling pathway; small cell lung cancer (SCLC); tumor mutation burden (TMB).