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An Accurate and Comprehensive Clinical Sequencing Assay for Cancer Targeted and Immunotherapies.
Oncologist 2019; 24(12):e1294-e1302O

Abstract

BACKGROUND

Incorporation of next-generation sequencing (NGS) technology into clinical utility in targeted and immunotherapies requires stringent validation, including the assessment of tumor mutational burden (TMB) and microsatellite instability (MSI) status by NGS as important biomarkers for response to immune checkpoint inhibitors.

MATERIALS AND METHODS

We designed an NGS assay, Cancer Sequencing YS panel (CSYS), and applied algorithms to detect five classes of genomic alterations and two genomic features of TMB and MSI.

RESULTS

By stringent validation, CSYS exhibited high sensitivity and predictive positive value of 99.7% and 99.9%, respectively, for single nucleotide variation; 100% and 99.9%, respectively, for short insertion and deletion (indel); and 95.5% and 100%, respectively, for copy number alteration (CNA). Moreover, CSYS achieved 100% specificity for both long indel (50-3,000 bp insertion and deletion) and gene rearrangement. Overall, we used 33 cell lines and 208 clinical samples to validate CSYS's NGS performance, and genomic alterations in clinical samples were also confirmed by fluorescence in situ hybridization, immunohistochemistry, and polymerase chain reaction (PCR). Importantly, the landscape of TMB across different cancers of Chinese patients (n = 3,309) was studied. TMB by CSYS exhibited a high correlation (Pearson correlation coefficient r = 0.98) with TMB by whole exome sequencing (WES). MSI measurement showed 98% accuracy and was confirmed by PCR. Application of CSYS in a clinical setting showed an unexpectedly high occurrence of long indel (6.3%) in a cohort of tumors from Chinese patients with cancer (n = 3,309), including TP53, RB1, FLT3, BRCA2, and other cancer driver genes with clinical impact.

CONCLUSION

CSYS proves to be clinically applicable and useful in disclosing genomic alterations relevant to cancer target therapies and revealing biomarkers for immune checkpoint inhibitors.

IMPLICATIONS FOR PRACTICE

The study describes a specially designed sequencing panel assay to detect genomic alterations and features of 450 cancer genes, including its overall workflow and rigorous clinical and analytical validations. The distribution of pan-cancer tumor mutational burden, microsatellite instability, gene rearrangement, and long insertion and deletion mutations was assessed for the first time by this assay in a broad array of Chinese patients with cancer. The Cancer Sequencing YS panel and its validation study could serve as a blueprint for developing next-generation sequencing-based assays, particularly for the purpose of clinical application.

Authors+Show Affiliations

Department of Hepatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, Kunming, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.Program of Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.OrigiMed, Shanghai, People's Republic of China.Department of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, People's Republic of China.Department of Hepatobiliary Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China.Department of Hepatobiliary Surgery, Shandong Tumor Hospital, Jinan, People's Republic of China.Department of General Surgery, The First Affiliated Hospital, Jiaxing College of Medicine, Jiangxi, People's Republic of China.Department of Chemotherapy, Meizhou People's Hospital, Meizhou, People's Republic of China.Department of Oncology, Dongguan People's Hospital, Dongguan, People's Republic of China.Department of Medical Oncology-Chest, Hunan Cancer Hospital, Changsha, People's Republic of China.OrigiMed, Shanghai, People's Republic of China. Zhejiang University International Hospital, Hangzhou, People's Republic of China.Department of Thoracic Surgery, The Third Affiliated Hospital of Kunming Medical University, Yunnan Tumor Hospital, Kunming, People's Republic of China gaofeng_li2016@sina.com shiww@origimed.com.OrigiMed, Shanghai, People's Republic of China gaofeng_li2016@sina.com shiww@origimed.com. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People's Republic of China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31409745

Citation

Cao, Jingyu, et al. "An Accurate and Comprehensive Clinical Sequencing Assay for Cancer Targeted and Immunotherapies." The Oncologist, vol. 24, no. 12, 2019, pp. e1294-e1302.
Cao J, Chen L, Li H, et al. An Accurate and Comprehensive Clinical Sequencing Assay for Cancer Targeted and Immunotherapies. Oncologist. 2019;24(12):e1294-e1302.
Cao, J., Chen, L., Li, H., Chen, H., Yao, J., Mu, S., ... Shi, W. (2019). An Accurate and Comprehensive Clinical Sequencing Assay for Cancer Targeted and Immunotherapies. The Oncologist, 24(12), pp. e1294-e1302. doi:10.1634/theoncologist.2019-0236.
Cao J, et al. An Accurate and Comprehensive Clinical Sequencing Assay for Cancer Targeted and Immunotherapies. Oncologist. 2019;24(12):e1294-e1302. PubMed PMID: 31409745.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An Accurate and Comprehensive Clinical Sequencing Assay for Cancer Targeted and Immunotherapies. AU - Cao,Jingyu, AU - Chen,Lijuan, AU - Li,Heng, AU - Chen,Hui, AU - Yao,Jicheng, AU - Mu,Shuo, AU - Liu,Wenjin, AU - Zhang,Peng, AU - Cheng,Yuwei, AU - Liu,Binbin, AU - Hu,Zhongxiang, AU - Chen,Donglin, AU - Kang,Hui, AU - Hu,Jinwei, AU - Wang,Aodi, AU - Wang,Weifeng, AU - Yao,Ming, AU - Chrin,Gungwei, AU - Wang,Xiaoting, AU - Zhao,Wei, AU - Li,Lei, AU - Xu,Luping, AU - Guo,Weixin, AU - Jia,Jun, AU - Chen,Jianhua, AU - Wang,Kai, AU - Li,Gaofeng, AU - Shi,Weiwei, Y1 - 2019/08/13/ PY - 2019/04/02/received PY - 2019/05/25/accepted PY - 2019/8/15/pubmed PY - 2019/8/15/medline PY - 2019/8/15/entrez KW - Gene rearrangement KW - Long insertion and deletion KW - Microsatellite instability KW - Next‐generation sequencing‐based assay KW - Targeted therapies and immunotherapies KW - Tumor mutational burden SP - e1294 EP - e1302 JF - The oncologist JO - Oncologist VL - 24 IS - 12 N2 - BACKGROUND: Incorporation of next-generation sequencing (NGS) technology into clinical utility in targeted and immunotherapies requires stringent validation, including the assessment of tumor mutational burden (TMB) and microsatellite instability (MSI) status by NGS as important biomarkers for response to immune checkpoint inhibitors. MATERIALS AND METHODS: We designed an NGS assay, Cancer Sequencing YS panel (CSYS), and applied algorithms to detect five classes of genomic alterations and two genomic features of TMB and MSI. RESULTS: By stringent validation, CSYS exhibited high sensitivity and predictive positive value of 99.7% and 99.9%, respectively, for single nucleotide variation; 100% and 99.9%, respectively, for short insertion and deletion (indel); and 95.5% and 100%, respectively, for copy number alteration (CNA). Moreover, CSYS achieved 100% specificity for both long indel (50-3,000 bp insertion and deletion) and gene rearrangement. Overall, we used 33 cell lines and 208 clinical samples to validate CSYS's NGS performance, and genomic alterations in clinical samples were also confirmed by fluorescence in situ hybridization, immunohistochemistry, and polymerase chain reaction (PCR). Importantly, the landscape of TMB across different cancers of Chinese patients (n = 3,309) was studied. TMB by CSYS exhibited a high correlation (Pearson correlation coefficient r = 0.98) with TMB by whole exome sequencing (WES). MSI measurement showed 98% accuracy and was confirmed by PCR. Application of CSYS in a clinical setting showed an unexpectedly high occurrence of long indel (6.3%) in a cohort of tumors from Chinese patients with cancer (n = 3,309), including TP53, RB1, FLT3, BRCA2, and other cancer driver genes with clinical impact. CONCLUSION: CSYS proves to be clinically applicable and useful in disclosing genomic alterations relevant to cancer target therapies and revealing biomarkers for immune checkpoint inhibitors. IMPLICATIONS FOR PRACTICE: The study describes a specially designed sequencing panel assay to detect genomic alterations and features of 450 cancer genes, including its overall workflow and rigorous clinical and analytical validations. The distribution of pan-cancer tumor mutational burden, microsatellite instability, gene rearrangement, and long insertion and deletion mutations was assessed for the first time by this assay in a broad array of Chinese patients with cancer. The Cancer Sequencing YS panel and its validation study could serve as a blueprint for developing next-generation sequencing-based assays, particularly for the purpose of clinical application. SN - 1549-490X UR - https://www.unboundmedicine.com/medline/citation/31409745/An_Accurate_and_Comprehensive_Clinical_Sequencing_Assay_for_Cancer_Targeted_and_Immunotherapies_ L2 - https://doi.org/10.1634/theoncologist.2019-0236 DB - PRIME DP - Unbound Medicine ER -