Jawad Majd, Afkhami Michelle, Ding Yi, Zhang Xiaohui, Li Peng, Young Kim, Xu Mina Luqing, Cui Wei, Zhao Yiqing, Halene Stephanie, Al-Kali Aref, Viswanatha David, Chen Dong, He Rong, Zheng Gang
Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.
Division of Molecular Pathology and Therapy Biomarkers, Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
Front Oncol. 2022 Feb 28;12:849376. doi: 10.3389/fonc.2022.849376. eCollection 2022.
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, 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 R882 mutant MDS known to date from multiple institutions, R882 mutant MDS cases were shown to have more severe leukopenia, enriched and 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. 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 R882 mutant MDS cases are mitigated by coexisting or mutations. The unique clinicopathologic features of R882 mutant MDS shed light on the prognostic and therapeutic implications of R882 mutations.
突变在克隆性造血和以精氨酸（R）882为热点的髓系肿瘤中起重要作用，然而，R882突变与非R882突变在骨髓增生异常综合征（MDS）等髓系肿瘤中的临床意义尚不清楚。通过挖掘公开可用的癌症基因组数据库和一家三级医疗机构的临床基因组数据库，发现R882突变在急性髓系白血病（AML）中富集（占所有DNMT3A突变的53%），但在意义未明的克隆性造血（CHIP）（10.6%）或包括MDS在内的其他髓系肿瘤（27%）中的频率降低（p<0.001）。接下来，在来自多个机构的迄今为止已知的最大一组R882突变型MDS患者中，R882突变型MDS病例显示白细胞减少更严重， 和 突变富集，原始细胞增多的病例增加（47%对22.5%，p = 0.004），AML转化风险显著增加（25.8%对1.7%，p = 0.0001），无进展生存期（PFS）更差（中位数20.3个月对>50个月，p = 0.009），比非R882突变型MDS病例更差。 突变是PFS较差的独立危险因素，重要的是，R882与非R882突变患者之间AML转化风险的差异不能用不同的治疗方法来解释。有趣的是，共存的 或 突变可减轻R882突变型MDS病例中较高的AML转化风险和较差的PFS。R882突变型MDS独特的临床病理特征揭示了R882突变的预后和治疗意义。
