Oncotarget

Research Papers:

Noninvasive genotyping and monitoring of anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer by capture-based next-generation sequencing

Ye Wang, Pan-Wen Tian, Wei-Ya Wang, Ke Wang, Zhou Zhang, Bo-Jiang Chen, Yan-Qi He, Lei Li, Hao Liu, Shannon Chuai and Wei-Min Li _

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Oncotarget. 2016; 7:65208-65217. https://doi.org/10.18632/oncotarget.11569

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Abstract

Ye Wang1,2,*, Pan-Wen Tian1,2,*, Wei-Ya Wang3,*, Ke Wang1,2, Zhou Zhang4, Bo-Jiang Chen1, Yan-Qi He1, Lei Li1, Hao Liu4, Shannon Chuai4, Wei-Min Li1

1Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

2Lung Cancer Treatment Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

3Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China

4Burning Rock Biotech, Guangzhou, Guangdong Province, China

*These authors contributed equally to this work and shared joint first authorship

Correspondence to:

Wei-Min Li, email: weimi003@yahoo.com

Keywords: capture-based next-generation sequencing, ALK fusion, ALK rearrangements, cell-free DNA, non-small cell lung cancer

Received: January 27, 2016     Accepted: August 13, 2016     Published: August 24, 2016

ABSTRACT

Noninvasive genotyping of driver genes and monitoring of tumor dynamics help make better personalized therapeutic decisions. However, neither PCR-based assays nor amplicon-based targeted sequencing can detect fusion genes like anaplastic lymphoma kinase (ALK) rearrangements in blood samples. To investigate the feasibility and performance of capture-based sequencing on ALK fusion detection, we developed a capture-based targeted sequencing panel to detect and quantify rearrangement events, along with other driver mutation variants in plasma. In this perspective study, we screened 364 patients with advanced non-small cell lung cancer (NSCLC) for ALK rearrangements, and collected blood samples from 24 of them with confirmed ALK rearrangements based on their tissue biopsies. ALK rearrangements were successfully detected in 19 of 24 patients at baseline with 79.2% (95% CI 57.9%, 92.9%) sensitivity and 100% (36/36) specificity. Among the 24 patients, we obtained longitudinal blood samples from 7 of them after either chemotherapy and/or Crizotinib treatment for disease monitoring. The by-sample detection rate of ALK rearrangements after treatment drops to 69.2% (9 of 13). In addition to detecting ALK rearrangements, we also detected 3 Crizotinib resistant mutations, ALK L1152R, ALK I1171T and ALK L1196M from patient P4. ctDNA concentration correlates with responses and disease progression, reflecting its ability as a biomarker. Our findings suggest capture-based sequencing can detect and quantify ALK rearrangements as well as other somatic mutations, including mutations mediated drug resistance, in plasma with high sensitivity, paving the way for its application in identifying driver fusion genes and monitoring tumor dynamics in the clinic.


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