Targeted next-generation sequencing identified novel mutations in triple-negative myeloproliferative neoplasms

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%) JAK2V617Fpositive cases had coexisting germline JAK2-mutations [JAK2R1063H, n = 6; JAK2R893T, n = 1; JAK2T525A, n = 1] or at least one somatic MPL-mutation [MPLY591D, n = 3; MPLW515 L, n = 2; MPLE335K, n = 1]. Overall, MPL-mutations always coexisted with JAK2V617F and/or other MPL-mutations. None of the JAK2V617F plus a second JAK2-mutation carried a TET2-mutation but all patients with JAK2V617F plus an MPL-mutation harbored a somatic TET2-mutation. Four genomic clusters could be identified in the JAK2V617F-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 JAK2V617F-and MPLW515-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. K E Y W O R D S germline mutations, JAK2 mutation, MPL mutation, myelofibrosis, noncanonical mutations, somatic mutations

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“…Chang Y-Can et al, 45 described an MPLM602T mutation in such a patient. Chang Y-Can et al, 45 described an MPLM602T mutation in such a patient.…”

Section: Discussionmentioning

confidence: 94%

“…Interesting is also the fact that MPL mutations could be found in patients with PV. Chang Y-Can et al, 45 described an MPLM602T mutation in such a patient. In our cohort, an MPLY591D mutation was found in one JAK2V617F positive patient with post-PV-MF (#13, Table 2).…”

Section: Discussionmentioning

confidence: 94%

Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F‐ and MPLW515 L‐positive myelofibrosis

Schulze

Stengel²,

Jaekel

et al. 2019

Genes Chromosomes & Cancer

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“…The most frequently affected genes were PDE4DIP , MAP3K1 , CDCEP1 and AFF3 . The PDE4DIP mutation was previously found in myeloproliferative neoplasms and medullary thyroid cancer 42,43 . MAP3K1 encodes a mitogen‐activated protein kinase kinase kinase that is involved in cell survival and apoptosis and was recently found to be related to breast and colorectal cancer 44‐47 .…”

Section: Discussionmentioning

confidence: 80%

The genomic profile of parathyroid carcinoma based on whole‐genome sequencing

Zhang

Wang

et al. 2020

Intl Journal of Cancer

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Parathyroid carcinoma (PC) is a rare endocrine malignancy with poor outcomes. Although some mutations such as CDC73 have been found in patients, the molecular mechanism of PC still needs extensive data to clarify. Whole‐genome sequencing (WGS) was performed with frozen samples from 23 PC patients. Peripheral leukocytes were collected from 14 patients and served as controls. Somatic and germline gene alterations, copy number abnormalities and structural variants were detected. Inactivating CDC73 mutations were identified in 39.1% of patients, but only one germline inactivating mutation was found. Other cancer‐related mutations identified in more than one case were MAF (2/23), NEB (6/23), NCOR1 (2/23), TTK (2/23), GRIN3A (4/23), TRIO (2/23), MAP1B (2/23), TJP2 (2/23) and FAM20A (2/23). In the seven wild‐type CDC73 samples, the mutated genes were enriched in pathways involving antigen presentation, allograft rejection or autoimmune disease. More copy number variants were found in patients with cancer recurrence (P = .006) and CDC73 mutations (P = .022) than in those without these characteristics. PIK3CA loss was found in one sample, which also harboured a CDC73 mutation. Gene alterations in the PI3K/AKT/mTOR pathway were found in 78.3% (18/23) of tumours. The most prominent cancer‐predisposing mutations were PDE4DIP (15/23), MAP3K1 (13/23) and CDC42EP1 (10/23). In conclusion, the PI3K/AKT/mTOR pathway may be pivotal in PC. CDC73 mutation correlated with an increased mutational burden and tumour relapse. PC patients with wild‐type CDC73 harboured mutations relevant to antigen presentation and autoimmune diseases. A molecular classification based on the CDC73 mutation may help to manage follow‐up and therapy for PC patients.

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“…13 IRS2 mutations were described in triple-negative MPN patients. 19 Osorio et al 20 demonstrated that IGFIR deregulation promotes MPN, incorporating new evidence that the IGF1R/IRS axis is potentially involved in the MPN phenotype and may represent a therapeutic target for these diseases.…”

Section: Introductionmentioning

confidence: 99%

NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells

Fenerich

Fernandes

Alves

et al. 2020

Sig Transduct Target Ther

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Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms (MPN); in this pathway, IRS2 is involved in the malignant transformation induced by JAK2 V617F , and upregulation of IGF1R signaling induces the MPN phenotype. NT157, a synthetic compound designed as an IGF1R-IRS1/2 inhibitor, has been shown to induce antineoplastic effects in solid tumors. Herein, we aimed to characterize the molecular and cellular effects of NT157 in JAK2 V617Fpositive MPN cell lines (HEL and SET2) and primary patient hematopoietic cells. In JAK2 V617F cell lines, NT157 decreased cell viability, clonogenicity, and cell proliferation, resulting in increases in apoptosis and cell cycle arrest in the G 2 /M phase (p < 0.05). NT157 treatment inhibited IRS1/2, JAK2/STAT, and NFκB signaling, and it activated the AP-1 complex, downregulated four oncogenes (CCND1, MYB, WT1, and NFKB1), and upregulated three apoptotic-related genes (CDKN1A, FOS, and JUN) (p < 0.05). NT157 induced genotoxic stress in a JAK2/STAT-independent manner. NT157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients (p < 0.05). These findings further elucidate the mechanism of NT157 action in a MPN context and suggest that targeting IRS1/2 proteins may represent a promising therapeutic strategy for MPN.

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Targeted next-generation sequencing identified novel mutations in triple-negative myeloproliferative neoplasms

Cited by 37 publications

References 19 publications

Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F‐ and MPLW515 L‐positive myelofibrosis

Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F‐ and MPLW515 L‐positive myelofibrosis

The genomic profile of parathyroid carcinoma based on whole‐genome sequencing

NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in JAK2V617F-positive myeloproliferative neoplasm cells

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