<i>TP53</i> mutation variant allele frequency is a potential predictor for clinical outcome of patients with lower-risk myelodysplastic syndromes

Beličková, Monika; Veselá, Jitka; Jonášová, Anna; Pejsova, Barbora; Votavová, Hana; Merkerová, Michaela Dostálová; Zemanová, Zuzana; Březinová, Jana; Mikulenková, Dana; Lauermannova, Marie; J, Válka; Michalova, Kyra; Neuwírtová, R; Čermák, Jaroslav

doi:10.18632/oncotarget.9200

Cited by 52 publications

(41 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Several investigators, who studied cancer and diseases with cutaneous manifestations, proposed that the VAF correlates with time of mutation acquisition and disease burden {Belickova 2016; Sallman 2016; Happle 1986}. In this study, we used VAF as a proxy for cellular percentage and mutational timing, with increasing VAF corresponding to events occurring earlier in development.…”

Section: Discussionmentioning

confidence: 99%

Early post-zygotic mutations contribute to congenital heart disease

Hsieh

et al. 2019

Preprint

View full text Add to dashboard Cite

53Background 54The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital 55 heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and 56 cardiovascular tissue has not been determined. 58Results 59We developed a computational method, Expectation-Maximization-based detection of Mosaicism (EM-60 mosaic), to analyze mosaicism in exome sequences of 2530 CHD proband-parent trios. EM-mosaic 61 detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 62 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac 63 tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 64 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic 65 variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were 66 confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, 67 suggesting a role in CHD. The frequency of mosaic variants above 10% mosaicism was 0.13/person in 68 blood and 0.14/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available 69 revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele 70 fraction. 72 Conclusions 73We estimate that ~1% of CHD probands have a mosaic variant detectable in blood that could contribute 74 to cardiac malformations, particularly those damaging variants expressed at higher allele fraction 75 compared to benign variants. Although blood is a readily-available DNA source, cardiac tissues analyzed 76 contributed ~5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses. 77 78 Keywords 79 Mosaic, Somatic, Congenital Heart Disease, Exome Sequencing 80 2 Background 81 Mosaicism results from somatic mutations that arise post-zygotically in an early embryonic cell, 82 resulting in two or more cell populations with distinct genotypes in the developing embryo {Biesecker 83 2013}. The developmental status of the early embryonic cell at the time of mutagenesis determines the 84 proportion of variant-carrying cells and the tissue distribution of these cells in the post-natal child {Acuna-85 Hidalgo 2015}. While germline variants have a variant allele frequency (VAF) of 0.5, somatic mosaic 86 variants have a significantly lower VAF. 87 Post-zygotic mosaic mutations have been implicated in several diseases including non-malignant 88 developmental disorders such as overgrowth syndromes {Poduri 2013; Lindhurst 2012; Kurek 2016}, 89 structural brain malformations {Poduri 2012; Jamuar 2014; Riviere 2012; Lee 2012}, epilepsy {Stosser 90 2018}, and autism spectrum disorder {Lim 2017; Krupp 2017; Freed 2016; Dou 2017}. Recent analyses 91 also identified mosaic variants in a cohort of patients with congenital heart disease (CHD) {Manheimer 92 2018}, but the prev...

show abstract

Section: Discussionmentioning

confidence: 99%

Early post-zygotic mutations contribute to congenital heart disease

Hsieh

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…There is evidence that TP53 VAF may inform distinct risk subgroups, which have been validated independent of current prognostic scoring systems (Sallman et al , ). In a study of lower‐risk patients with TP53 mutations at the time of diagnosis, >6% VAF was linked to shorter OS and progression‐free survival compared to patients with <6% VAF (Belickova et al , ). Though clone sizes may not change in complete remissions when MDS patients are treated with current therapy, (Merlevede et al , ) the consideration of VAF could offer further insight into the clinical trajectory of disease, especially by utilizing NGS before and after treatment for treatment of the future, and allogeneic haematopoietic stem cell transplantation (allo‐HSCT).…”

Section: Ngs and Prognostic Scoring Systemsmentioning

confidence: 99%

The evolving role of next generation sequencing in myelodysplastic syndromes

2019

View full text Add to dashboard Cite

Summary Myelodysplastic syndromes (MDS) are clonal haematological disorders characterized by haematopoietic cell dysplasia, peripheral blood cytopenias, and a predisposition for developing acute myeloid leukaemia (AML). Cytogenetics have historically been important in diagnosis and prognosis in MDS, but the growing accessibility of next generation sequencing (NGS) has led to growing research in the roles of molecular genetic variation on clinical decision‐making in these disorders. Multiple genes have been previously studied and found to be associated with specific outcomes or disease types within MDS and knowledge of mutations in these genes provides insight into previously defined MDS subtypes. Knowledge of these mutations also informs development of novel therapies in the treatment of MDS. The precise role of NGS in the diagnosis, prognosis and monitoring of MDS remains unclear but the improvements in NGS technology and accessibility affords clinicians an additional practice tool to provide the best care for patients.

show abstract

“…In general, increasing number of mutations is associated with progressively poorer prognosis . For mutations of a specific gene, higher TP53 mutation allelic burden was negatively associated with OS in both unselected MDS and LR‐MDS; higher TET2 clonal burden predicted an increased response to decitabine in MDS . In addition to MDS, variant allele frequency (VAF) has been associated with prognosis in patients with AML …”

Section: Introductionmentioning

confidence: 99%

Mutation status and burden can improve prognostic prediction of patients with lower‐risk myelodysplastic syndromes

et al. 2019

View full text Add to dashboard Cite

Patients with lower-risk myelodysplastic syndromes (LR-MDS) as defined by the International Prognostic Scoring System (IPSS) have more favorable prognosis in general, but significant inter-individual heterogeneity exists. In this study, we examined the molecular profile of 15 MDS-relevant genes in 159 patients with LR-MDS using nextgeneration sequencing. In univariate COX regression, shorter overall survival (OS) was associated with mutation status of ASXL1 (P = .001), RUNX1 (P = .031), EZH2 (P = .049), TP53 (P = .016), SRSF2 (P = .046), JAK2 (P = .040), and IDH2 (P = .035). We also found significantly shorter OS in patients with an adjusted TET2 variant allele frequency (VAF) ≥18% versus those with either an adjusted TET2 VAF <18% or without TET2 mutations (median: 20.4 vs 47.8 months; P = .020; HR = 2.183, 95%CI: 1.129-4.224). After adjustment for IPSS, shorter OS was associated with mutation status of ASXL1 (P < .001; HR = 4.306, 95% CI: 2.144-8.650), TP53 (P = .004; HR = 4.863, 95% CI: 1.662-14.230)and JAK2 (P = .002; HR = 5.466, 95%CI: 1.848-16.169), as well as adjusted TET2 VAF ≥18% (P = .008; HR = 2.492, 95% CI: 1.273-4.876). Also, OS was increasingly shorter as the number of mutational factors increased (P < .001). A novel prognostic scoring system incorporating the presence/absence of the four independent mutational factors into the IPSS further stratified LR-MDS patients into three prognostically different groups (P < .001). The newly developed scoring system redefined 10.1% (16/159) of patients as a higher-risk group, who could not be predicted by the currently prognostic models. In conclusion, integration of the IPSS with mutation status/burden of certain MDS-relevant genes may improve the prognostication of patients with LR-MDS and could help identify those with worse-than-expected prognosis for more aggressive treatment. K E Y W O R D Slower-risk myelodysplastic syndromes, mutation burden, mutation status, prognosis, variant allele frequency | 581 JIANG et Al.

show abstract

TP53 mutation variant allele frequency is a potential predictor for clinical outcome of patients with lower-risk myelodysplastic syndromes

Cited by 52 publications

References 26 publications

Early post-zygotic mutations contribute to congenital heart disease

Early post-zygotic mutations contribute to congenital heart disease

The evolving role of next generation sequencing in myelodysplastic syndromes

Mutation status and burden can improve prognostic prediction of patients with lower‐risk myelodysplastic syndromes

Contact Info

Product

Resources

About