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.
Highlights
Lung cancer is the leading cause of cancer-related deaths worldwide
Small cell lung cancer (SCLC) is characterized by a shorter tumor doubling time, and a higher rate of early distant metastasis compared to non-small cell lung cancer (NSCLC)
We identified some unique genetic variant features in Chinese SCLC patients and found that somatic co‐occurring TP53/RB1 mutations were frequent in Chinese SCLC patients
Summary
Lung cancer is the leading cause of cancer-related deaths worldwide. In China, there are approximately 787,000 newly diagnosed lung cancer and 631,000 deaths annually (1). SCLC is characterized by a shorter tumor doubling time, and a higher rate of early distant metastasis compared to non-small cell lung cancer (NSCLC). U.S Food and Drug Administration (FDA) approved Atezolizumab in combination with carboplatin and etoposide as first-line treatment for patients with ED-SCLC. This is the first immune checkpoint inhibitor (ICI) approved as a first-line treatment for SCLC (4, 5). Based on nextgeneration sequencing (NGS) technology, comprehensive genomic profiling of tumors can detect genetic changes from point mutations to large structural variations. Univariate and multivariate analyses were performed to determine patient survival These results might be helpful in the diagnosis and treatment of Chinese SCLC patients
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