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

• Published in: Genes chromosomes & cancer Vol. 63; no. 7; pp. e23257 - n/a
• Main Authors: Orsmark‐Pietras, Christina, Lyander, Anna, Ladenvall, Claes, Hallström, Björn, Staffas, Anna, Awier, Hero, Krstic, Aleksandra, Baliakas, Panagiotis, Barbany, Gisela, Håkansson, Cecilia Brunhoff, Gellerbring, Anna, Hagström, Anna, Hellström‐Lindberg, Eva, Juliusson, Gunnar, Lazarevic, Vladimir, Munters, Arielle, Pandzic, Tatjana, Wadelius, Mia, Ås, Joel, Fogelstrand, Linda, Wirta, Valtteri, Rosenquist, Richard, Cavelier, Lucia, Fioretos, Thoas
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2024; Wiley Subscription Services, Inc
• Subjects: Basic Medicine; Cancer and Oncology; Cancer och onkologi; capture-based gene panel; Clinical Genetics; Clinical Medicine; Gene Frequency; Genes; Genetic Testing - methods; Genetic Testing - standards; High-Throughput Nucleotide Sequencing - methods; Humans; interlaboratory comparison; Klinisk genetik; Klinisk medicin; Malignancy; Medical and Health Sciences; Medical Genetics; Medical Science; Medicin och hälsovetenskap; Medicinsk genetik; Medicinsk vetenskap; Medicinska och farmaceutiska grundvetenskaper; Mutation; myeloid malignancies; Myeloproliferative Disorders - diagnosis; Myeloproliferative Disorders - genetics; paired tumor-normal analysis; precision diagnostics; Precision Medicine - methods; somatic variant detection; Sweden; Sweden; paired tumor‐normal analysis; precision diagnostics; somatic variant detection; myeloid malignancies; capture‐based gene panel; interlaboratory comparison
• ISSN: 1045-2257; 1098-2264; 1098-2264
• DOI: 10.1002/gcc.23257

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 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.