nach oben

Journal of Cancer Research and Clinical Oncology

Erschienen in:

10.01.2022 | Original Article – Cancer Research

Predictive values of mutational variant allele frequency in overall survival and leukemic progression of myelodysplastic syndromes

verfasst von: Lingxu Jiang, Li Ye, Liya Ma, Yanling Ren, Xinping Zhou, Chen Mei, Gaixiang Xu, Haiyang Yang, Chenxi Lu, Yingwan Luo, Shuanghong Zhu, Lu Wang, Chuying Shen, Wenli Yang, Qi Zhang, Yuxia Wang, Wei Lang, Yueyuan Han, Jie Jin, Hongyan Tong

Erschienen in: Journal of Cancer Research and Clinical Oncology | Ausgabe 4/2022

Einloggen, um Zugang zu erhalten

Abstract

Background

The implication of mutational variant allelic frequency (VAF) has been increasingly considered in the prognostic interpretation of molecular data in myeloid malignancies. However, the impact of VAF on outcomes of myelodysplastic syndromes (MDS) has not been extensively explored.

Methods

Targeted next-generation sequencing was performed in 350 newly diagnosed MDS cases. The associations of mutational VAF of each gene with overall survival (OS) and leukemia-free survival (LFS) were examined by multivariate Cox regression after univariate analysis.

Results

Shorter OS was independently associated with DNMT3A VAF (HR 1.020 per 1% VAF increase; 95% CI 1.005–1.035; p = 0.011) and TP53 VAF (HR 1.014 per 1% VAF increase; 95% CI 1.006–1.022; p = 0.001). LFS analyses revealed that TET2 VAF (HR 1.013 per 1% VAF increase; 95% CI 1.005–1.022; p = 0.003) and TP53 VAF (HR 1.012 per 1% VAF increase; 95% CI 1.004–1.021; p = 0.005) were independently associated with faster leukemic transformation. Furthermore, we established nomograms to predict OS and LFS, respectively, by integrating independent mutational predictors into the revised International Prognostic Scoring System.

Conclusion

Our study highlights that VAF of certain genes should be incorporated into routine clinical prognostication of survival and leukemic transformation of MDS.

Nur mit Berechtigung zugänglich

Arber DA et al (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127:2391–2405. https://doi.org/10.1182/blood-2016-03-643544CrossRefPubMed

Bacher U, Kohlmann A, Haferlach T (2015) Mutational profiling in patients with MDS: ready for every-day use in the clinic? Best Pract Res Clin Haematol 28:32–42. https://doi.org/10.1016/j.beha.2014.11.005CrossRefPubMed

Bejar R (2017) Implications of molecular genetic diversity in myelodysplastic syndromes. Curr Opin Hematol 24:73–78. https://doi.org/10.1097/Moh.0000000000000313CrossRefPubMedPubMedCentral

Bejar R et al (2015) Somatic mutations in MDS patients are associated with clinical features and predict prognosis independent of the IPSS-R: analysis of combined datasets from the International Working Group for Prognosis in MDS-Molecular Committee. Blood 126:907CrossRef

Belickova M et al (2016) TP53 mutation variant allele frequency is a potential predictor for clinical outcome of patients with lower-risk myelodysplastic syndromes. Oncotarget 7:36266–36279. https://doi.org/10.18632/oncotarget.9200CrossRefPubMedPubMedCentral

Greenberg P et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088CrossRefPubMed

Greenberg PL et al (2012) Revised international prognostic scoring system for myelodysplastic syndromes. Blood 120:2454–2465. https://doi.org/10.1182/blood-2012-03-420489CrossRefPubMedPubMedCentral

Haferlach T et al (2014) Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia 28:241–247. https://doi.org/10.1038/leu.2013.336CrossRefPubMed

Hirsch CM et al (2018) Consequences of mutant TET2 on clonality and subclonal hierarchy. Leukemia 32:1751–1761. https://doi.org/10.1038/s41375-018-0150-9CrossRefPubMedPubMedCentral

Hou HA et al (2018) Incorporation of mutations in five genes in the revised International Prognostic Scoring System can improve risk stratification in the patients with myelodysplastic syndrome Blood. Cancer J 8:39. https://doi.org/10.1038/s41408-018-0074-7CrossRef

Iasonos A, Schrag D, Raj GV, Panageas KS (2008) How to build and interpret a nomogram for cancer prognosis. J Clin Oncol 26:1364–1370. https://doi.org/10.1200/Jco.2007.12.9791CrossRefPubMed

Jiang L et al (2020a) Impact of mutational variant allele frequency on prognosis in myelodysplastic syndromes. Am J Cancer Res 10:4476–4487PubMedPubMedCentral

Jiang LX et al (2020b) Mutation status and burden can improve prognostic prediction of patients with lower-risk myelodysplastic syndromes. Cancer Sci 111:580–591. https://doi.org/10.1111/cas.14270CrossRefPubMed

Kim T et al (2017) The clonal origins of leukemic progression of myelodysplasia. Leukemia 31:1928–1935. https://doi.org/10.1038/leu.2017.17CrossRefPubMed

Kohlmann A, Grossmann V, Nadarajah N, Haferlach T (2013) Next-generation sequencing—feasibility and practicality in haematology. Brit J Haematol 160:736–753. https://doi.org/10.1111/bjh.12194CrossRef

Kulasekararaj AG et al (2013) TP53 mutations in myelodysplastic syndrome are strongly correlated with aberrations of chromosome 5, and correlate with adverse prognosis. Brit J Haematol 160:660–672. https://doi.org/10.1111/bjh.12203CrossRef

Lin ME et al (2018) Dynamics of DNMT3A mutation and prognostic relevance in patients with primary myelodysplastic syndrome. Clin Epigenetics. https://doi.org/10.1186/s13148-018-0476-1CrossRefPubMedPubMedCentral

Makishima H et al (2016) Dynamics of clonal evolution in myelodysplastic syndromes. Haematologica 101:157–157CrossRef

Makishima H et al (2017) Dynamics of clonal evolution in myelodysplastic syndromes. Nat Genet 49:204–212. https://doi.org/10.1038/ng.3742CrossRefPubMed

Montalban-Bravo G et al (2020) Genomic context and TP53 allele frequency define clinical outcomes in TP53-mutated myelodysplastic syndromes. Blood Adv 4:482–495. https://doi.org/10.1182/bloodadvances.2019001101CrossRefPubMedPubMedCentral

Nazha A, Bejar R (2017) Molecular data and the IPSS-R: how mutational burden can affect prognostication in MDS. Curr Hematol Malig Rep 12:461–467. https://doi.org/10.1007/s11899-017-0407-9CrossRefPubMed

Nazha A et al (2016) Incorporation of molecular data into the Revised International Prognostic Scoring System in treated patients with myelodysplastic syndromes. Leukemia 30:2214–2220. https://doi.org/10.1038/leu.2016.138CrossRefPubMed

Nazha A et al (2017) Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes. Leukemia 31:2848–2850. https://doi.org/10.1038/leu.2017.266CrossRefPubMed

Papaemmanuil E et al (2013) Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood 122:3616–3627. https://doi.org/10.1182/blood-2013-08-518886CrossRefPubMedPubMedCentral

Pellagatti A et al (2016) Targeted resequencing analysis of 31 genes commonly mutated in myeloid disorders in serial samples from myelodysplastic syndrome patients showing disease progression. Leukemia 30:247–250. https://doi.org/10.1038/leu.2015.129CrossRefPubMed

Raza A, Galili N (2012) The genetic basis of phenotypic heterogeneity in myelodysplastic syndromes. Nat Rev Cancer 12:849–859. https://doi.org/10.1038/nrc3321CrossRefPubMed

Sallman DA et al (2016) Impact of TP53 mutation variant allele frequency on phenotype and outcomes in myelodysplastic syndromes. Leukemia 30:666–673. https://doi.org/10.1038/leu.2015.304CrossRefPubMed

Shaffer LG, Slovak ML, Campbell LJ (2013) ISCN 2013: an international system for human cytogenetic nomenclature. S Karger, Basel

Walter MJ et al (2011) Recurrent DNMT3A mutations in patients with myelodysplastic syndromes. Leukemia 25:1153–1158. https://doi.org/10.1038/leu.2011.44CrossRefPubMedPubMedCentral

Wang W et al (2017) Characterization of TP53 mutations in low-grade myelodysplastic syndromes and myelodysplastic syndromes with a non-complex karyotype. Eur J Haematol 99:536–543. https://doi.org/10.1111/ejh.12971CrossRefPubMed

Wang HQ et al (2020) Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome. Sci Rep. https://doi.org/10.1038/s41598-020-74744-zCrossRefPubMedPubMedCentral

Yanling Ren CM, Ye Li, Luo Y, Zhou X, Yang H, Lin P, Weilai Xu, Ma L, Jin J, Tong H (2019) Analysis of clinical and molecular features of MDS patients with complex T karyotype in China. Blood Cells Mol Dis 75:13–19. https://doi.org/10.1016/j.bcmd.2018.11.006CrossRefPubMed

Titel: Predictive values of mutational variant allele frequency in overall survival and leukemic progression of myelodysplastic syndromes
verfasst von: Lingxu Jiang
Li Ye
Liya Ma
Yanling Ren
Xinping Zhou
Chen Mei
Gaixiang Xu
Haiyang Yang
Chenxi Lu
Yingwan Luo
Shuanghong Zhu
Lu Wang
Chuying Shen
Wenli Yang
Qi Zhang
Yuxia Wang
Wei Lang
Yueyuan Han
Jie Jin
Hongyan Tong
Publikationsdatum: 10.01.2022
Verlag: Springer Berlin Heidelberg
Erschienen in: Journal of Cancer Research and Clinical Oncology / Ausgabe 4/2022
Print ISSN: 0171-5216
Elektronische ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-021-03905-y

Targeting CCR2+ macrophages with BET inhibitor overcomes adaptive resistance to anti-VEGF therapy in ovarian cancer

Open Access
Original Article – Cancer Research

HER2 positivity as a biomarker for poor prognosis and unresponsiveness to anti-EGFR therapy in colorectal cancer

Original Article – Clinical Oncology

Three-dimensional models: a novel approach for lymphoma research

Review – Cancer Research

CXCL12/CXCR4 axis gene variants contribute to an increased vulnerability to HPV infection and cervical oncogenesis

Original Article – Cancer Research

Thromboembolic events and thromboprophylaxis associated with immunomodulators in multiple myeloma patients: a real-life study

Original Article – Clinical Oncology

Assessment of sorafenib induced changes in tumor perfusion of uveal melanoma metastases with dynamic contrast-enhanced ultrasound (DCE-US)

Open Access
Original Article – Clinical Oncology

Neu im Fachgebiet Onkologie

Polypen bei nahen Verwandten – erhöhtes Darmkrebsrisiko

20.01.2025
Risikofaktoren für Krebserkrankungen
Nachrichten

Werden bei erstgradigen Verwandten gutartige Darmpolypen identifiziert, ist das Risiko, selbst an einem Kolorektalkarzinom zu erkranken, deutlich erhöht – vor allem das für eine früh beginnende Erkrankung. Hier könnte sich eine frühe Koloskopie besonders lohnen.

KI-gestütztes Mammografiescreening überzeugt im Praxistest

16.01.2025
Künstliche Intelligenz im Gesundheitswesen
Nachrichten

Mit dem Einsatz künstlicher Intelligenz lässt sich die Detektionsrate im Mammografiescreening offenbar deutlich steigern. Mehr unnötige Zusatzuntersuchungen sind laut der Studie aus Deutschland nicht zu befürchten.

Welche Krebserkrankungen bei Zöliakie häufiger auftreten

16.01.2025
Zöliakie
Nachrichten

Eine große Kohortenstudie hat den Zusammenhang zwischen Zöliakie und gastrointestinalen Krebserkrankungen und inflammatorischen Krankheiten untersucht. Neben gastrointestinalen Tumoren ist auch ein nicht solider Krebs häufiger.

Adjuvanter PD-L1-Hemmer verhindert Rezidive bei Hochrisiko-Urothelkarzinom

15.01.2025
Urothelkarzinom
Nachrichten

Sind Menschen mit muskelinvasivem Urothelkarzinom für die neoadjuvante platinbasierte Therapie nicht geeignet oder sprechen sie darauf nicht gut an, ist Pembrolizumab eine adjuvante Alternative: Die krankheitsfreie Lebenszeit wird dadurch mehr als verdoppelt.

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Predictive values of mutational variant allele frequency in overall survival and leukemic progression of myelodysplastic syndromes