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. 2022 Feb 28:12:849376.
doi: 10.3389/fonc.2022.849376. eCollection 2022.

DNMT3A R882 Mutations Confer Unique Clinicopathologic Features in MDS Including a High Risk of AML Transformation

Majd Jawad  1 , Michelle Afkhami  2   3 , Yi Ding  4 , Xiaohui Zhang  5 , Peng Li  6 , Kim Young  3 , Mina Luqing Xu  7 , Wei Cui  8 , Yiqing Zhao  9 , Stephanie Halene  10 , Aref Al-Kali  11 , David Viswanatha  1 , Dong Chen  1 , Rong He  1 , Gang Zheng  1   12
Affiliations

DNMT3A R882 Mutations Confer Unique Clinicopathologic Features in MDS Including a High Risk of AML Transformation

Majd Jawad et al. Front Oncol. .

Abstract

DNMT3A mutations play a prominent role in clonal hematopoiesis and myeloid neoplasms with arginine (R)882 as a hotspot, however the clinical implications of R882 vs. non-R882 mutations in myeloid neoplasms like myelodysplastic syndrome (MDS) is unclear. By data mining with publicly accessible cancer genomics databases and a clinical genomic database from a tertiary medical institution, DNMT3A R882 mutations were found to be enriched in AML (53% of all DNMT3A mutations) but decreased in frequency in clonal hematopoiesis of indeterminate potential (CHIP) (10.6%) or other myeloid neoplasms including MDS (27%) (p<.001). Next with the largest cohort of patients with DNMT3A R882 mutant MDS known to date from multiple institutions, DNMT3A R882 mutant MDS cases were shown to have more severe leukopenia, enriched SRSF2 and IDH2 mutations, increased cases with excess blasts (47% vs 22.5%, p=.004), markedly increased risk of AML transformation (25.8%, vs. 1.7%, p=.0001) and a worse progression-free survival (PFS) (median 20.3, vs. >50 months, p=.009) than non-R882 mutant MDS cases. DNMT3A R882 mutation is an independent risk factor for worse PFS, and importantly the differences in the risk of AML transformation between R882 vs. non-R882 mutant patients cannot be explained by different treatment approaches. Interestingly the higher risk of AML transformation and the worse PFS in DNMT3A R882 mutant MDS cases are mitigated by coexisting SF3B1 or SRSF2 mutations. The unique clinicopathologic features of DNMT3A R882 mutant MDS shed light on the prognostic and therapeutic implications of DNMT3A R882 mutations.

Keywords: DNMT3A; R882 mutations; acute myeloid leukemia; genetics; myelodysplastic syndromes.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Frequency and distribution of DNMT3A mutations (R882 versus non-R882) in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and clonal hematopoiesis of indeterminate potential (CHIP). GENIE database and myeloid studies available in cBioPortal were used for to retrieve DNMT3A mutations in patients with myeloid neoplasms. Two studies (7, 30) on clonal hematopoiesis of indeterminate potential (CHIP) were used to retrieve DNMT3A mutations in healthy individuals without hematologic malignancies.
Figure 2
Figure 2
Forrest plots of odds ratio with 95% confidence internal of co-existing mutations between DNMT3A R882 vs. non-R882 mutant cases. (A) Acute myeloid leukemia (AML) and (B) myelodysplastic syndrome (MDS). GENIE database and myeloid studies available in cBioPortal were extracted and used for the analysis. Statistically significant co-existing mutation are highlighted with black lines.
Figure 3
Figure 3
Distribution of coexisting mutations of genes commonly mutated in AML and MDS ordered by gene function. Each column represents a patient.
Figure 4
Figure 4
DNMT3A R882 mutations confer increased risk of AML transformation and worse progression free survival in MDS, which are masked by the coexisting SF3B1 or SRSF2 mutations. (A) Cumulative incidence of AML transformation in DNMT3A (R882 vs. Non-R882) mutant MDS. (B) Progression free survival analysis in patients with DNMT3A (R882 vs. Non-R882) mutant myelodysplastic syndrome (MDS). (C) The distribution of IPSS-R scores in the R882 group and the other group. (D) Cox proportional hazards model analysis of risk factors for worse progression free survival. Statistically significant factors are highlighted with black lines. (E) Overall survival analysis in patients with DNMT3A (R882 vs. Non-R882) mutant myelodysplastic syndrome (MDS). (F) Progression free survival analysis in DNMT3A (R882 vs. Non-R882) mutant MDS with mutant and wildtype SF3B1/SRSF2.
Figure 5
Figure 5
MDS treatment approaches and AML transformation. Treatment information was collected for 53 out of 62 MDS patients with DNMT3A R882 mutations, and 38 out of 62 patients with DNMT3A non-R882 mutations. Different treatment approaches were listed together with the occurrence AML transformation.
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