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Precision Diagnostics in Myeloid Malignancies : Development and Validation of a National Capture-Based Gene Panel

Orsmark-Pietras, Christina LU ; Lyander, Anna ; Ladenvall, Claes LU ; Hallström, Björn LU ; Staffas, Anna ; Awier, Hero ; Krstic, Aleksandra ; Baliakas, Panagiotis ; Barbany, Gisela and Håkansson, Cecilia Brunhoff , et al. (2024) In Genes Chromosomes and Cancer 63(7).
Abstract

Gene panel sequencing has become a common diagnostic tool for detecting somatically acquired mutations in myeloid neoplasms. However, many panels have restricted content, provide insufficient sensitivity levels, or lack clinically validated workflows. We here describe the development and validation of the Genomic Medicine Sweden myeloid gene panel (GMS-MGP), a capture-based 191 gene panel including mandatory genes in contemporary guidelines as well as emerging candidates. The GMS-MGP displayed uniform coverage across all targets, including recognized difficult GC-rich areas. The validation of 117 previously described somatic variants showed a 100% concordance with a limit-of-detection of a 0.5% variant allele frequency (VAF), achieved... (More)

Gene panel sequencing has become a common diagnostic tool for detecting somatically acquired mutations in myeloid neoplasms. However, many panels have restricted content, provide insufficient sensitivity levels, or lack clinically validated workflows. We here describe the development and validation of the Genomic Medicine Sweden myeloid gene panel (GMS-MGP), a capture-based 191 gene panel including mandatory genes in contemporary guidelines as well as emerging candidates. The GMS-MGP displayed uniform coverage across all targets, including recognized difficult GC-rich areas. The validation of 117 previously described somatic variants showed a 100% concordance with a limit-of-detection of a 0.5% variant allele frequency (VAF), achieved by utilizing error correction and filtering against a panel-of-normals. A national interlaboratory comparison investigating 56 somatic variants demonstrated highly concordant results in both detection rate and reported VAFs. In addition, prospective analysis of 323 patients analyzed with the GMS-MGP as part of standard-of-care identified clinically significant genes as well as recurrent mutations in less well-studied genes. In conclusion, the GMS-MGP workflow supports sensitive detection of all clinically relevant genes, facilitates novel findings, and is, based on the capture-based design, easy to update once new guidelines become available. The GMS-MGP provides an important step toward nationally harmonized precision diagnostics of myeloid malignancies.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
capture-based gene panel, interlaboratory comparison, myeloid malignancies, paired tumor-normal analysis, precision diagnostics, somatic variant detection
in
Genes Chromosomes and Cancer
volume
63
issue
7
article number
e23257
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:85199204439
  • pmid:39031442
ISSN
1045-2257
DOI
10.1002/gcc.23257
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2024 The Author(s). Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.
id
b83cdc66-cb32-4263-a07c-385677286868
date added to LUP
2024-07-31 16:32:40
date last changed
2024-08-01 08:53:20
@article{b83cdc66-cb32-4263-a07c-385677286868,
  abstract     = {{<p>Gene panel sequencing has become a common diagnostic tool for detecting somatically acquired mutations in myeloid neoplasms. However, many panels have restricted content, provide insufficient sensitivity levels, or lack clinically validated workflows. We here describe the development and validation of the Genomic Medicine Sweden myeloid gene panel (GMS-MGP), a capture-based 191 gene panel including mandatory genes in contemporary guidelines as well as emerging candidates. The GMS-MGP displayed uniform coverage across all targets, including recognized difficult GC-rich areas. The validation of 117 previously described somatic variants showed a 100% concordance with a limit-of-detection of a 0.5% variant allele frequency (VAF), achieved by utilizing error correction and filtering against a panel-of-normals. A national interlaboratory comparison investigating 56 somatic variants demonstrated highly concordant results in both detection rate and reported VAFs. In addition, prospective analysis of 323 patients analyzed with the GMS-MGP as part of standard-of-care identified clinically significant genes as well as recurrent mutations in less well-studied genes. In conclusion, the GMS-MGP workflow supports sensitive detection of all clinically relevant genes, facilitates novel findings, and is, based on the capture-based design, easy to update once new guidelines become available. The GMS-MGP provides an important step toward nationally harmonized precision diagnostics of myeloid malignancies.</p>}},
  author       = {{Orsmark-Pietras, Christina and Lyander, Anna and Ladenvall, Claes and Hallström, Björn and Staffas, Anna and Awier, Hero and Krstic, Aleksandra and Baliakas, Panagiotis and Barbany, Gisela and Håkansson, Cecilia Brunhoff and Gellerbring, Anna and Hagström, Anna and Hellström-Lindberg, Eva and Juliusson, Gunnar and Lazarevic, Vladimir and Munters, Arielle and Pandzic, Tatjana and Wadelius, Mia and Ås, Joel and Fogelstrand, Linda and Wirta, Valtteri and Rosenquist, Richard and Cavelier, Lucia and Fioretos, Thoas}},
  issn         = {{1045-2257}},
  keywords     = {{capture-based gene panel; interlaboratory comparison; myeloid malignancies; paired tumor-normal analysis; precision diagnostics; somatic variant detection}},
  language     = {{eng}},
  number       = {{7}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Genes Chromosomes and Cancer}},
  title        = {{Precision Diagnostics in Myeloid Malignancies : Development and Validation of a National Capture-Based Gene Panel}},
  url          = {{http://dx.doi.org/10.1002/gcc.23257}},
  doi          = {{10.1002/gcc.23257}},
  volume       = {{63}},
  year         = {{2024}},
}