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 .

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)
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
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
linked-read sequencing
whole-exome sequencing
RNA sequencing
structural variants
short variants
multiple myeloma
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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