Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses

Skov, Vibe

doi:10.3390/cancers12082194

Cited by 32 publications

(29 citation statements)

References 283 publications

(504 reference statements)

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“…As to the interpretation of molecular findings, we deal with the limitations of an in silico approach for assessment of pathogenicity or protein function damage, as we relied on databases for clinical prediction of current use in molecular diagnostics. In absence of functional studies to prove the real biological impact of such variants, their finding may be helpful to determine the clonal nature of disease in triple-negative MPNs and complement the morphological criteria ( 47 ). This stands also in accordance with the revised 2017 WHO criteria.…”

Section: Discussionmentioning

confidence: 99%

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study

et al. 2021

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Lack of demonstrable mutations affecting JAK2, CALR, or MPL driver genes within the spectrum of BCR-ABL1-negative myeloproliferative neoplasms (MPNs) is currently referred to as a triple-negative genotype, which is found in about 10% of patients with essential thrombocythemia (ET) and 5–10% of those with primary myelofibrosis (PMF). Very few papers are presently available on triple-negative ET, which is basically described as an indolent disease, differently from triple-negative PMF, which is an aggressive myeloid neoplasm, with a significantly higher risk of leukemic evolution. The aim of the present study was to evaluate the bone marrow morphology and the clinical-laboratory parameters of triple-negative ET patients, as well as to determine their molecular profile using next-generation sequencing (NGS) to identify any potential clonal biomarkers. We evaluated a single-center series of 40 triple-negative ET patients, diagnosed according to the 2017 WHO classification criteria and regularly followed up at the Hematology Unit of our Institution, between January 1983 and January 2019. In all patients, NGS was performed using the Illumina Ampliseq Myeloid Panel; morphological and immunohistochemical features of the bone marrow trephine biopsies were also thoroughly reviewed. Nucleotide variants were detected in 35 out of 40 patients. In detail, 29 subjects harbored one or two variants and six cases showed three or more concomitant nucleotide changes. The most frequent sequence variants involved the TET2 gene (55.0%), followed by KIT (27.5%). Histologically, most of the cases displayed a classical ET morphology. Interestingly, prevalent megakaryocytes morphology was more frequently polymorphic with a mixture of giant megakaryocytes with hyperlobulated nuclei, normal and small sized maturing elements, and naked nuclei. Finally, in five cases a mild degree of reticulin fibrosis (MF-1) was evident together with an increase in the micro-vessel density. By means of NGS we were able to identify nucleotide variants in most cases, thus we suggest that a sizeable proportion of triple-negative ET patients do have a clonal disease. In analogy with driver genes-mutated MPNs, these observations may prevent issues arising concerning triple-negative ET treatment, especially when a cytoreductive therapy may be warranted.

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Section: Discussionmentioning

confidence: 99%

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study

et al. 2021

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“…13,14 The emergence of next-generation sequencing (NGS) has expanded insights into the molecular complexity of MPN, and more than 50 genes have been reported to be recurrently mutated. 15 Mutations outside of JAK2, CALR, and MPL (ie concomitant somatic mutations) are observed in >50% of patients with MPN, and increasing numbers are observed with disease progression. 16,17 The most common classes of concomitant mutations consist of genes involved in DNA methylation (TET2, DNMT3A, IDH1, IDH2), chromatin modification (ASXL1, EZH2), RNA splicing (SRSF2, U2AF1, SF3B1, ZRSR2), signaling pathways (LNK/SH2B3, CBL, NRAS, KRAS, PTPN1), transcription factors (RUNX1, NFE2), and DNA damage response/stress signaling (TP53, PPM1D).…”

Section: Introductionmentioning

confidence: 99%

“…16 Concomitant mutations may contribute to phenotype and are often associated with disease progression and inferior survival. 15,[18][19][20] Furthermore, the presence of specific concomitant mutations 18 , as well as the total number 19 and order of acquisition, influence prognosis. 21 Internationally, the most widely used first-line cytoreductive therapy in patients with high-risk ET or PV is hydroxyurea (HU).…”

Section: Introductionmentioning

confidence: 99%

Genomic profiling of a randomized trial of interferon-α vs hydroxyurea in MPN reveals mutation-specific responses

et al. 2022

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Background Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPN), little is known about their impact on molecular response to cytoreductive treatment. Methods We performed targeted next-generation sequencing (NGS) on 202 pre-treatment samples obtained from patients with MPN enrolled in the DALIAH trial (randomized controlled phase III clinical trial, NCT01387763) and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea (HU). The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Results Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (VAF) (median 0.29 to 0.07; p<0.0001) compared with those not achieving CHR (median 0.27 to 0.14; p<0.0001). In contrast, the CALR VAF did not significantly decline in neither those achieving CHR nor those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with HU, p=0.04. Furthermore, treatment-emergent DNMT3A-mutations were significantly enriched in IFNα treated patients not attaining CHR, p=0.02. A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted OR=5.29 [95% CI, 1.59-17.54]; p=0.007) as was a mutation in TET2 alone (age-adjusted OR=3.03 [95% CI, 1.03-9.01]; p=0.044). Conclusion At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN demonstrated distinct molecular responses and (2) DNMT3A-mutated clones/subclones emerged on treatment.

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“…While molecular testing is pivotal to guide MPN diagnosis [67], in rare instances it may yield puzzling results, which need to be interpreted after integration with clinical, laboratory, and histological data. This is specifically the case of genes rarely mutated in MPNs and associated with an aggressive clinical course.…”

Section: Mpn With "High Risk" Molecular Featuresmentioning

confidence: 99%

The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases

Pizzi

Croci

Ruggeri

et al. 2021

Cancers

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Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by increased proliferation of one or more myeloid lineages in the bone marrow. The classification and diagnostic criteria of MPNs have undergone relevant changes over the years, reflecting the increased awareness on these conditions and a better understanding of their biological and clinical-pathological features. The current World Health Organization (WHO) Classification acknowledges four main sub-groups of MPNs: (i) Chronic Myeloid Leukemia; (ii) classical Philadelphia-negative MPNs (Polycythemia Vera; Essential Thrombocythemia; Primary Myelofibrosis); (iii) non-classical Philadelphia-negative MPNs (Chronic Neutrophilic Leukemia; Chronic Eosinophilic Leukemia); and (iv) MPNs, unclassifiable (MPN-U). The latter are currently defined as MPNs with clinical-pathological findings not fulfilling the diagnostic criteria for any other entity. The MPN-U spectrum traditionally encompasses early phase MPNs, terminal (i.e., advanced fibrotic) MPNs, and cases associated with inflammatory or neoplastic disorders that obscure the clinical-histological picture. Several lines of evidence and clinical practice suggest the existence of additional myeloid neoplasms that may expand the spectrum of MPN-U. To gain insight into such disorders, this review addresses the history of MPN classification, the evolution of their diagnostic criteria and the complex clinical-pathological and biological features of MPN-U.

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Next Generation Sequencing in MPNs. Lessons from the Past and Prospects for Use as Predictors of Prognosis and Treatment Responses

Cited by 32 publications

References 283 publications

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study

Triple-Negative Essential Thrombocythemia: Clinical-Pathological and Molecular Features. A Single-Center Cohort Study

Genomic profiling of a randomized trial of interferon-α vs hydroxyurea in MPN reveals mutation-specific responses

The Classification of Myeloproliferative Neoplasms: Rationale, Historical Background and Future Perspectives with Focus on Unclassifiable Cases

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