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Combining targeted sequencing and ultra-low-pass whole-genome sequencing for accurate somatic copy number alteration detection

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Abstract

This study investigated the feasibility of combining targeted sequencing and ultra-low-pass whole-genome sequencing (ULP-WGS) for improved somatic copy number alteration (SCNA) detection, due to its role in tumorigenesis and prognosis. Cerebrospinal fluid and matched blood samples were obtained from 29 patients with brain metastasis derived from lung cancer. Samples were subjected to targeted sequencing (genomic coverage: 300 kb) and 2×ULP-WGS. The SCNA was detected by the CTLW_CNV, Control-FreeC, and CNVkit methods and their accuracy was analyzed. Eighteen tumor samples showed consistent SCNA results between the three methods, while a small fraction of samples resulted in different SCNA estimations. Further analysis indicated that consistency of SCNA highly correlated with the difference of baseline depth (normalized depth of regions without SCNA events) estimation between methods. Conflict Index showed that CTLW_CNV significantly improved the accuracy of SCNA detection through precise baseline depth estimation. CTLW_CNV combines targeted sequencing and ULP-WGS for improved SCNA detection. The improvement in detection accuracy is mainly due to a refined baseline depth estimation, guided by single-nucleotide polymorphism allele frequencies within the deeply sequenced region (targeted sequencing). This method is especially suitable for tumor samples with biased aneuploidy, a previously under-estimated genomic characteristic across different cancer types.

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Authors and Affiliations

  1. Department of Thoracic Surgery, The Second Hospital of Dalian Medical University, No.467 Zhongshan Road, Shahekou District, Dalian, 116000, Liaoning Province, China

    Junfeng Fu, Zhenyang Lv, Yu Wang, Ze Wang, Zhe Fan & Ting Lei

  2. Genetron Health (Beijing) Co. Ltd., Beijing, 102206, China

    Weihua Guo & Cheng Yan

Authors
  1. Junfeng Fu
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  2. Weihua Guo
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  3. Cheng Yan
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  4. Zhenyang Lv
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  5. Yu Wang
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  6. Ze Wang
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  7. Zhe Fan
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  8. Ting Lei
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Contributions

Conception and design of the research: TL, JF, WG, and CY; acquisition of data: HF, ZL, YW, ZW, and ZF; analysis and interpretation of data: JF, WG, and CY; statistical analysis: WG and CY; drafting the manuscript: JF; revision of manuscript for important intellectual content: TL, WG, and CY. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Ting Lei.

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This study was approved by the ethics committee of The Second Hospital of Dalian Medical University (Dalian, China). Informed consent was obtained from each patient.

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The authors declare no competing interests.

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Fu, J., Guo, W., Yan, C. et al. Combining targeted sequencing and ultra-low-pass whole-genome sequencing for accurate somatic copy number alteration detection. Funct Integr Genomics 21, 161–169 (2021). https://doi.org/10.1007/s10142-021-00767-y

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  • DOI: https://doi.org/10.1007/s10142-021-00767-y

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