Clinical impacts of the mutational spectrum in Japanese patients with primary myelofibrosis

Morishita, Soji; Ochiai, Tomonori; Misawa, Kyohei; Osaga, Satoshi; Inano, Tadaaki; Fukuda, Yasutaka; Edahiro, Yoko; Ohsaka, Akimichi; Araki, Marito; Komatsu, Norio

doi:10.1007/s12185-020-03054-x

Cited by 6 publications

(15 citation statements)

References 33 publications

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“…The mutations were detected from raw fastq data generated by the MiniSeq System as previously described. 3 The detected mutations obtained from a study that we previously reported. 3 All statistical analyses were performed using the R program.…”

Section: Discussionmentioning

confidence: 99%

“…Pooled sequencing libraries were prepared as previously described 3 . Briefly, gDNA fragmentation and subsequent indices ligation was performed using the QIAseq® FX DNA Library Core Kit and QIAseq® CDI Y‐Adapter Kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

“…10 We utilized genomic DNAs (gDNAs) collected from April 2010 to December 2020 which were stored at À80 C until use. The gDNAs were extracted from peripheral blood (2 ml) as previously described 3 on the first visit. This study was conducted in accordance with the 1975 Declaration of Helsinki and written informed consent was obtained from all participants before sample collection.…”

Section: Patient Sample Collectionmentioning

confidence: 99%

“…In contrast, non‐driver gene mutations whose normal counterparts function as epigenetic modifiers and splicing factors are frequently detected in primary myelofibrosis (PMF), a subgroup of Ph‐MPNs, 2,3 and some of these non‐driver mutations have been defined as high molecular risk (HMR) mutations ( ASXL1 , EZH2 , SRSF2 , U2AF1 , and IDH2 ) that strongly correlate with poor prognosis in PMF patients. Regarding the prognoses of PV and ET, elderly age, leukocytosis, and history of thrombosis have been identified as the common adverse factors 4,5 .…”

Section: Introductionmentioning

confidence: 99%

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Non‐driver gene mutation analysis in a large cohort of polycythemia vera and essential thrombocythemia

Morishita

Hashimoto

Furuya³

et al. 2022

European J of Haematology

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Objectives: A proportion of patients with polycythemia vera (PV) and essential thrombocythemia (ET) harbor non-driver mutations associated with poor prognosis.In this study, we analyzed the frequency of non-driver mutations in a large Japanese PV and ET cohort. Furthermore, we studied the relationship of these mutations and prognosis in Japanese patients.Methods: We enrolled 843 Japanese patients with PV or ET. Non-driver mutations were analyzed by target resequencing using next-generation sequencing. The association of the mutations with the prognosis was estimated using multivariable logistic regression analysis and log-rank test.Results: Non-driver mutations were detected in 31.1% and 24.5% patients with PV and ET, respectively. Among them, ASXL1 mutations were identified as a risk factor for leukemic/myelofibrotic transformation in PV and ET patients (hazard ratio: 4.68, p = .006). The higher-risk groups of the mutation-enhanced international prognostic system (MIPSS)-PV and MIPSS-ET incorporating non-driver mutations exhibited significantly shorter overall survival compared with the low-risk group (p < .001).Conclusions: These results implicate the importance of studying non-driver mutations for predicting the prognosis and survival of Japanese PV and ET patients.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Patient Sample Collectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Non‐driver gene mutation analysis in a large cohort of polycythemia vera and essential thrombocythemia

Morishita

Hashimoto

Furuya³

et al. 2022

European J of Haematology

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“…The ASXL1 mutation was associated with leukocytosis, systemic symptoms, and >1% peripheral primitive cells; the SRSF2 mutation was associated with older age and >1% peripheral primitive cells; and the EZH2 mutation was associated with >1% peripheral primitive cells. The frequency of >1 HMR mutation was increased in the high-risk group in several studies [25] [26], while the 5-year survival (OS) was significantly lower in the group of patients with HMR mutations compared to the group without HMR mutations, 47.5% and 85%, respectively [25]. In a previous long-term prognostic study of 1282 PMF patients, early mortality in PMF was found to be associated with genetic risk factors, while survival beyond 20 years could be predicted by clinical variables including age, sex, blood count, and symptoms [27].…”

Section: Impact Of Hmr Mutations On the Prognosis Of Pmfmentioning

confidence: 97%

Advances in the Study of High-Risk Gene Mutations for Primary Myelofibrosis

Xu¹,

Zhang²,

Tan³

et al. 2022

JBM

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Primary myelofibrosis is a kind of MPNs due to clonal appreciation of hematopoietic stem cells. With the development of second-generation sequencing, high-risk mutation (HMR) genes such as ASXL1, EZH2, SRSF2, and IDH1/2 have been shown to be associated with disease prognosis and progression, and although allo-HSCT remains the only possible treatment for PMF, with the development of JAK inhibitors, there is an increasing interest in the study of inhibitors of these mutant loci.

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Analysis of somatic mutations in the JAK2, CALR, MPL and ASXL1 genes and evaluation of their impact on the survival of patients with myelofibrosis

et al. 2023

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Background. The development of myelofibrosis (MF) is driven by complex molecular genetic events that include driver somatic mutations responsible for the constitutive activation of the JAK/STAT signaling pathway (JAK2, CALR, and MPL), additional mutations affecting epigenetic regulators (TET2, ASXL1, IDH1/2, etc.) and RNA splicing (SRSF2, U2AF1, SF3B1, etc.), as well as genetic aberrations that contribute to genomic instability and disease progression.Aim. To analyze driver (JAK2, CALR, MPL) and prognostic (ASXL1) somatic mutations in patients with MF and evaluate their impact on survival.Materials and methods. The study included 29 patients diagnosed with MF, selected by hematologists from the City Clinical Hospital No. 7 and Regional Clinical Hospital (Krasnoyarsk).Results. 26 (89.6 %) out of 29 examined patients had some driver mutations in JAK2, CALR, MPL genes. The p.V617F mutation in the JAK2 gene was found in 20 (68.9 %) patients. Mutations in the CALR gene were detected in 4 (13.8 %) patients, mutations in the MPL gene were found in 3 patients (10.3 %). In 1 of 26 patients, 2 driver mutations were present simultaneously. 3 (10.3 %) patients were triple negative. Mutations in the ASXL1 gene were detected in 12 (41.4 %) out of 29 examined patients. Conducted targeted NGS (next generation sequencing) for 13 out of 29 patients revealed additional genetic variants that contribute to the understanding of the development mechanism and disease course. When evaluating the overall survival in the groups of patients diagnosed with MF examined by us, depending on the combination of driver (JAK2, CALR, MPL) and prognostic (ASXL1) mutations, no statistically significant differences were found (p = 0.12). This appears to be due to the small sample size. At the same time, assessment of patient survival depending on ASXL1 status showed that in the presence of mutations in the ASXL1 gene, the median survival was 45 months (range 7–120 months), while in the absence of mutations it was 48 months (range 21–359 months) (p = 0.03).Conclusion. The results obtained allow us to assume that the presence of mutations in the ASXL1 gene is an unfavorable factor in the course of the disease.

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Clinical impacts of the mutational spectrum in Japanese patients with primary myelofibrosis

Cited by 6 publications

References 33 publications

Non‐driver gene mutation analysis in a large cohort of polycythemia vera and essential thrombocythemia

Non‐driver gene mutation analysis in a large cohort of polycythemia vera and essential thrombocythemia

Advances in the Study of High-Risk Gene Mutations for Primary Myelofibrosis

Analysis of somatic mutations in the <i>JAK2</i>, <i>CALR</i>, <i>MPL</i> and <i>ASXL1</i> genes and evaluation of their impact on the survival of patients with myelofibrosis

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