Clinical cancer genomic profiling by three-platform sequencing of whole genome, whole exome and transcriptome

Michael Rusch, Joy Nakitandwe, Sheila Shurtleff, Scott Newman, Zhaojie Zhang, Michael N. Edmonson, Matthew Parker, Yuannian Jiao, Xiaotu Ma, Yanling Liu, Jiali Gu, Michael F. Walsh, Jared Becksfort, Andrew Thrasher, Yongjin Li, James McMurry, Erin Hedlund, Aman Patel, John Easton, Donald Yergeau, Bhavin Vadodaria, Ruth G. Tatevossian, Susana Raimondi, Dale Hedges, Xiang Chen, Kohei Hagiwara, Rose McGee, Giles W. Robinson, Jeffery M. Klco, Tanja A. Gruber, David W. Ellison (), James R Downing () and Jinghui Zhang ()
Additional contact information
Michael Rusch: St. Jude Children’s Research Hospital
Joy Nakitandwe: St. Jude Children’s Research Hospital
Sheila Shurtleff: St. Jude Children’s Research Hospital
Scott Newman: St. Jude Children’s Research Hospital
Zhaojie Zhang: St. Jude Children’s Research Hospital
Michael N. Edmonson: St. Jude Children’s Research Hospital
Matthew Parker: University of Sheffield
Yuannian Jiao: St. Jude Children’s Research Hospital
Xiaotu Ma: St. Jude Children’s Research Hospital
Yanling Liu: St. Jude Children’s Research Hospital
Jiali Gu: St. Jude Children’s Research Hospital
Michael F. Walsh: St. Jude Children’s Research Hospital
Jared Becksfort: St. Jude Children’s Research Hospital
Andrew Thrasher: St. Jude Children’s Research Hospital
Yongjin Li: St. Jude Children’s Research Hospital
James McMurry: St. Jude Children’s Research Hospital
Erin Hedlund: St. Jude Children’s Research Hospital
Aman Patel: St. Jude Children’s Research Hospital
John Easton: St. Jude Children’s Research Hospital
Donald Yergeau: St. Jude Children’s Research Hospital
Bhavin Vadodaria: St. Jude Children’s Research Hospital
Ruth G. Tatevossian: St. Jude Children’s Research Hospital
Susana Raimondi: St. Jude Children’s Research Hospital
Dale Hedges: St. Jude Children’s Research Hospital
Xiang Chen: St. Jude Children’s Research Hospital
Kohei Hagiwara: St. Jude Children’s Research Hospital
Rose McGee: St. Jude Children’s Research Hospital
Giles W. Robinson: St. Jude Children’s Research Hospital
Jeffery M. Klco: St. Jude Children’s Research Hospital
Tanja A. Gruber: St. Jude Children’s Research Hospital
David W. Ellison: St. Jude Children’s Research Hospital
James R Downing: St. Jude Children’s Research Hospital
Jinghui Zhang: St. Jude Children’s Research Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract To evaluate the potential of an integrated clinical test to detect diverse classes of somatic and germline mutations relevant to pediatric oncology, we performed three-platform whole-genome (WGS), whole exome (WES) and transcriptome (RNA-Seq) sequencing of tumors and normal tissue from 78 pediatric cancer patients in a CLIA-certified, CAP-accredited laboratory. Our analysis pipeline achieves high accuracy by cross-validating variants between sequencing types, thereby removing the need for confirmatory testing, and facilitates comprehensive reporting in a clinically-relevant timeframe. Three-platform sequencing has a positive predictive value of 97–99, 99, and 91% for somatic SNVs, indels and structural variations, respectively, based on independent experimental verification of 15,225 variants. We report 240 pathogenic variants across all cases, including 84 of 86 known from previous diagnostic testing (98% sensitivity). Combined WES and RNA-Seq, the current standard for precision oncology, achieved only 78% sensitivity. These results emphasize the critical need for incorporating WGS in pediatric oncology testing.

Date: 2018
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DOI: 10.1038/s41467-018-06485-7

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