Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F‐ and MPLW515 L‐positive myelofibrosis. Issue 11 (14th June 2019)

• Record Type: Journal Article
• Authors: Schulze, Susann; Stengel, Rayk; Jaekel, Nadja; Wang, Song‐Yau; Franke, Georg–Nikolaus; Roskos, Martin; Schneider, Melanie; Niederwieser, Dietger; Al‐Ali, Haifa Kathrin
• Is Part Of: Genes, chromosomes & cancer. Volume 58:Issue 11(2019)
• Page Start: 747
• Page End: 755
• Publication Date: 2019-06-14
• Subjects: germline mutations -- JAK2 mutation -- MPL mutation -- myelofibrosis -- noncanonical mutations -- somatic mutations; Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22781
• Languages: English
• ISSNs: 1045-2257

Abstract

Abstract: Sequential genotyping for phenotype‐driver mutations in JAK2 (exon 14), CALR (exon 9), and MPL (exon 10) is recommended in patients with myeloproliferative neoplasms. Yet, atypical JAK2‐ and MPL‐ mutations were described in some triple‐negative patients. Whether noncanonical and/or concomitant JAK2‐ and MPL‐ mutations exist in myelofibrosis (MF) regardless of phenotype‐driver mutations is not yet elucidated. For this, next‐generation sequencing (NGS) was performed using blood genomic DNA from 128 MF patients (primary MF, n = 93; post‐ET–MF, n = 18; post‐PV–MF, n = 17). While no atypical JAK2‐ or MPL‐ mutations were seen in 24 CALR‐ positive samples, two JAK2‐ mutations [c.3323A > G, p.N1108S; c.3188G > A, p.R1063H] were detected in two of the 21 (9.5%) triple‐negative patients. Twelve of the 82 (14.6%) JAK2 V617F‐positive cases had coexisting germline JAK2‐ mutations [ JAK2 R1063H, n = 6; JAK2 R893T, n = 1; JAK2 T525A, n = 1] or at least one somatic MPL‐ mutation [ MPL Y591D, n = 3; MPL W515 L, n = 2; MPL E335K, n = 1]. Overall, MPL‐ mutations always coexisted with JAK2 V617F and/or other MPL‐ mutations. None of the JAK2 V617F plus a second JAK2‐ mutation carried a TET2‐ mutation but all patients with JAK2 V617F plus an MPL‐ mutation harbored a somatic TET2‐ mutation. Four genomic clusters could be identified in the JAK2 V617F‐positive cohort. Cluster‐I (10%) (noncanonical JAK2 mutated (mut) + TET2 wildtype (wt) ) were younger and had less proliferative disease compared with cluster‐IV (5%) ( TET2 mut + MPL mut ). In conclusion, recurrent concomitant classical and/or noncanonical JAK2‐ and MPL‐ mutations could be detected by NGS in 15.7% of JAK2 V617F‐ and MPL W515‐positive MF patients with genotype‐phenotype associations. Many of the germline and/or somatic mutations might act as "Significantly Mutated Genes" contributing to the pathogenesis and phenotypic heterogeneity. A cost‐effective NGS‐based approach might be an important step towards patient‐tailored medicine.