Comparison of Structural and Short Variants Detected by Linked-Read and Whole-Exome Sequencing in Multiple Myeloma

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Kumar , A , Adhikari , S , Kankainen , M & Heckman , C A 2021 , ' Comparison of Structural and Short Variants Detected by Linked-Read and Whole-Exome Sequencing in Multiple Myeloma ' , Cancers , vol. 13 , no. 6 , 1212 . https://doi.org/10.3390/cancers13061212

Title: Comparison of Structural and Short Variants Detected by Linked-Read and Whole-Exome Sequencing in Multiple Myeloma
Author: Kumar, Ashwini; Adhikari, Sadiksha; Kankainen, Matti; Heckman, Caroline A.
Contributor organization: Institute for Molecular Medicine Finland
Helsinki Institute of Life Science HiLIFE
University of Helsinki
Digital Precision Cancer Medicine (iCAN)
HUSLAB
Department of Medical and Clinical Genetics
Helsinki University Hospital Area
TRIMM - Translational Immunology Research Program
Date: 2021-03
Language: eng
Number of pages: 20
Belongs to series: Cancers
ISSN: 2072-6694
DOI: https://doi.org/10.3390/cancers13061212
URI: http://hdl.handle.net/10138/329650
Abstract: Simple Summary The wide variety of next-generation sequencing technologies requires thorough evaluation and understanding of their advantages and shortcomings of these different approaches prior to their implementation in a precision medicine setting. Here, we compared the performance of two DNA sequencing methods, whole-exome and linked-read exome sequencing, to detect large structural variants (SVs) and short variants in eight multiple myeloma (MM) patient cases. For three patient cases, matched tumor-normal samples were sequenced with both methods to compare somatic SVs and short variants. The methods' clinical relevance was also evaluated, and their sensitivity and specificity to detect MM-specific cytogenetic alterations and other short variants were measured. Thus, this study systematically demonstrates and evaluates the performance of whole-exome and linked-read exome sequencing technologies for detecting genetic alterations to aid in selecting the optimal method for clinical application. Linked-read sequencing was developed to aid the detection of large structural variants (SVs) from short-read sequencing efforts. We performed a systematic evaluation to determine if linked-read exome sequencing provides more comprehensive and clinically relevant information than whole-exome sequencing (WES) when applied to the same set of multiple myeloma patient samples. We report that linked-read sequencing detected a higher number of SVs (n = 18,455) than WES (n = 4065). However, linked-read predictions were dominated by inversions (92.4%), leading to poor detection of other types of SVs. In contrast, WES detected 56.3% deletions, 32.6% insertions, 6.7% translocations, 3.3% duplications and 1.2% inversions. Surprisingly, the quantitative performance assessment suggested a higher performance for WES (AUC = 0.791) compared to linked-read sequencing (AUC = 0.766) for detecting clinically validated cytogenetic alterations. We also found that linked-read sequencing detected more short variants (n = 704) compared to WES (n = 109). WES detected somatic mutations in all MM-related genes while linked-read sequencing failed to detect certain mutations. The comparison of somatic mutations detected using linked-read, WES and RNA-seq revealed that WES and RNA-seq detected more mutations than linked-read sequencing. These data indicate that WES outperforms and is more efficient than linked-read sequencing for detecting clinically relevant SVs and MM-specific short variants.
Subject: genomics
NGS
linked-read sequencing
whole-exome sequencing
RNA sequencing
structural variants
short variants
FISH
multiple myeloma
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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