Comprehensive genomic profiling of small cell lung cancer in Chinese patients and the implications for therapeutic potential

Hu, Jing; Wang, Yu; Zhang, Yuan; Yu, Yafeng; Chen, Hui; Liu, Kuai; Yao, Ming; Wang, Kai; Gu, Weiguang; Shou, Tao

doi:10.1002/cam4.2199

Cited by 47 publications

(26 citation statements)

References 28 publications

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“…It was suggested in a previous study that Notch1 was highly expressed in Chinese patients with small cell LC 15. It was also pointed out that overexpression of Notch1 could promote the proliferation, invasion, and migration of NCI-H358 cells and H1299 cells 16,17.…”

Section: Resultsmentioning

confidence: 93%

<p>Ultrasound-microbubbles-mediated microRNA-449a inhibits lung cancer cell growth via the regulation of Notch1</p>

Ling-wu

Yuan

Zhu

et al. 2019

OTT

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BackgroundThe application of gene-loaded microbubbles (MBs) combined with ultrasound that results in increased delivery efficiency may be an excellent method of gene delivery. This study aimed to discuss the effects of ultrasound-MB-mediated microRNA (miR)-449a on lung cancer (LC) development by targeting Notch1.MethodsInitially, miR-449a expression in LC tissues, paracancerous tissues, LC cell lines, and lung epithelial cells was detected and its association with LC patients’ clinical characteristics was analyzed. The gain-of-function studies were performed to probe the roles of miR-449a and ultrasound-MB-mediated miR-449a in LC progression. Then, RT-qPCR combined with Western blot analysis was applied to verify the levels of miR-449a, Notch1, proliferation- and apoptosis-related proteins. Moreover, xenograft tumors in nude mice were also applied for in vivo experiments.ResultsPoorly expressed miR-449a was observed in LC, and its expression was associated with clinical staging, differentiation and lymph node metastasis of LC patients. Overexpression of miR-449a suppressed LC cell proliferation and promoted G2/M arrest and apoptosis. Ultrasound-MB-mediated miR-449a strengthened inhibitory effects of miR-449a on cell growth and resistance to apoptosis. miR-449a inhibited H1299 cell activity by targeting Notch1.ConclusionOur data supported that miR-449a overexpression inhibited LC cell growth, and ultrasound-MB-mediated miR-449a reinforced the repressive effects of miR-449a on LC progression. This investigation may offer new insight for LC treatment.

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Section: Resultsmentioning

confidence: 93%

<p>Ultrasound-microbubbles-mediated microRNA-449a inhibits lung cancer cell growth via the regulation of Notch1</p>

Ling-wu

Yuan

Zhu

et al. 2019

OTT

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“…However, the most common genetic alterations include inactivation of the tumor suppressor genes TP53 and RB1 [16,17]. Hu et al demonstrated that the most frequently altered genes in small cell lung cancer were as followed: TP53 (93.4%), RB1 (78.7%), LRP1B(18.9%), KMT2D (15.6%), FAT1 (11.5%), KMT2C (11.5%),STK24 (11.5%), FAM135B (10.7%), and NOTCH1 (10.7%) [10]. The results were derived from genomic pro ling of 122 Chinese patients.…”

Section: Discussionmentioning

confidence: 99%

“…The genes were captured and sequenced with a mean depth of 800X, using Illumina NextSeq 500 (Illumina, Inc). Genomic alterations (GAs) were identi ed by the alignment of sequences from tissues and matched normal lung tissue, following the previously reported methods [10]. Tumor mutation burden (TMB) was estimated by counting the somatic mutations, containing SNVs and Indels, per megabase of the sequence examined on each patient.…”

Section: Next-generation Sequencingmentioning

confidence: 99%

Tumor Mutation Burden May be a Prognostic Biomarker of Long-Term Survival in Resected Small-Cell Lung Cancer

Qin¹,

Pan²,

Wang³

et al. 2020

Preprint

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BackgroundSmall cell lung cancer (SCLC) has a poor prognosis. The majority of SCLC patients do not survive within a few months of diagnosis, however, a sub-group of patients have a long-term survival. Individual differences in prognosis remain elusive. We present the first comprehensive comparative genomic profiling and tumor mutation burden (TMB) analyses of SCLC on patients with long-term survival (LTS) and short-term survival (STS) after surgery.MethodsThe present study included 52 patients with SCLC who underwent surgery in Zhejiang Cancer Hospital from April 2008 to December 2017. A total of 6 LTS patients (≥4 years) with stage IIB or IIIA SCLC and 5 STS patients (<2 years) with stage IA or IB SCLC were included. The latter subjects were used as control subjects. All subjects underwent resection without neoadjuvant therapy. We assessed their genomic profile and calculated TMB using next-generation sequencing (NGS). Moreover, we assessed the correlation between TMB and prognosis. Subsequently, we analyzed and compared the molecular characteristics of LTS and STS.ResultsThe data indicated that the LTS harbored high TMB. The median TMB for LTS was approximately 16.4 Mutations/Mb, while STS harbored low TMB which was approximately 8.5 Mutations/Mb. A differential trend on the median TMB was revealed between LTS and STS (p = 0.08). Moreover, we discovered that TMB exhibited significant effects on the survival of the patients (p=0.007). In the LTS group, the median number was 10 (range: 6-13) in mutated genes per sample and the samples harbored collectively 60 gene mutations in the following 28 genes: TP53 (n=6), RB1 (n=4), FAT3 (n=4), KMT2D (n=3), NOTCH1 (n=3), FAM135B (n=3), LRP1B (n=3), CDKN2C (n=3), H3F3A (n=3) . In the mutated genes per sample of STS, the median number was 7 (range: 3-8) and 30 mutations were found in the 17 genes as followed: TP53 (n=5), RB1 (n=4), KMT2D (n=2), NOTCH1 (n=2), FAT4 (n=2), MUC16 (n=2), PTEN (n=2), FAM135B (n=1), LRP1B (n=1), KMT2C (n=1). Gene alteration represented the survival difference between the two groups. The FAT3 gene was only noted in LTS and the P-value was 0.06 as determined by the Fisher’s exact test. Interestingly, the FAT3 gene could impact the patients’ survival (p=0.11) though no significant difference were noted.ConclusionsHigh nonsynonymous TMB was associated with improved prognosis on patients with resected SCLC. The FAT3 gene may impact disease prognosis. The data may provide valuable information of differences between individuals in terms of prognosis and guide treatment. Studies involving larger groups are required to confirm these findings.

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“…Of them, two patients were detected with concurrent TP53 and RB1 mutations, which are typical molecular features of SCLC. 10 The remaining patient harbored concurrent TP53 p.Arg342* and PIK3CA p.Glu542Lys, which were detected from both his plasma and SLN-FNA samples.…”

Section: F I G U R Ementioning

confidence: 98%

Liquid‐based cell suspension of supraclavicular lymph node fine‐needle aspirate as an alternative specimen for NGS‐based genomic profiling in advanced lung cancer

Zhang

Chen

Chu

et al. 2020

Clinical & Translational Med

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Our study demonstrates the clinical utility of liquidbased cell suspension of fine-needle aspirates (FNA) of supraclavicular lymph node (SLN) stored in 10% neutral buffered formalin (NBF) as a source of tumor-derived DNA for next-generation sequencing (NGS)-based mutation profiling and guides therapeutic decisions of patients with advanced lung cancer. Over the past decade, various targeted therapies have dramatically improved the survival of patients with advanced lung cancer harboring actionable genetic mutations, making it essential to implement NGS-based molecular profiling in clinical practice to simultaneously interrogate and identify potential tyrosine kinase inhibitor-sensitizing mutations for treatment planning. 1-3 The use of specimens obtained in a less invasive manner, including cytology specimens collected through FNA biopsy has been extensively explored for NGS assays. 2,4-6 SLN metastasis occurs in 26-42% of advanced lung cancer. 7 SLN-FNA prepared as cytospin or formalin-fixed paraffinembedded (FFPE) cell blocks have been reported in PCRbased EGFR mutation testing. 8 Compared to conventional smears, liquid-based cytology maintains the morphology of the collected cells, which preserves DNA integrity and minimizes DNA degradation, thereby improving the quantity and quality of DNA extracted for subsequent molecular assays. 9 Moreover, liquid-based cytology stored in 10% NBF is more convenient for molecular testing applications than FFPE cell blocks by skipping the laborious paraffinization/deparaffinization sample processing steps. SLN-FNA samples stored in 10% NBF were obtained from 54 lung cancer patients with pathologically confirmed metastatic SLNs diagnosed between January 2018 and December 2019 at Fudan University Shanghai Cancer Center, 53 of whom also had paired plasma samples (Figure 1A). The baseline characteristics of these patients were listed in Table S1. DNA from the SLN-FNA samples and This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Comprehensive genomic profiling of small cell lung cancer in Chinese patients and the implications for therapeutic potential

Cited by 47 publications

References 28 publications

<p>Ultrasound-microbubbles-mediated microRNA-449a inhibits lung cancer cell growth via the regulation of Notch1</p>

<p>Ultrasound-microbubbles-mediated microRNA-449a inhibits lung cancer cell growth via the regulation of Notch1</p>

Tumor Mutation Burden May be a Prognostic Biomarker of Long-Term Survival in Resected Small-Cell Lung Cancer

Liquid‐based cell suspension of supraclavicular lymph node fine‐needle aspirate as an alternative specimen for NGS‐based genomic profiling in advanced lung cancer

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