Rapid growth of acquired UBA1 mutations predisposes male patients to low-risk MDS

IF 12.8 1区 医学 Q1 HEMATOLOGY
Peng Li, F. N. U. Alnoor, Wei Xie, Margaret Williams, Julie Feusier, Yi Ding, Xiangrong Zhao, Gang Zheng, Chen Zhao, Arthur W. Zieske, Youli Zu, Philipp W. Raess, Srinivas Tantravahi, Afaf Osman, Ami B. Patel, Tsewang Tashi, Jay L. Patel, Anna P. Matynia, Madhu P. Menon, Rodney R. Miles, Jeffrey R. Jacobsen, Tracy I. George, Douglas W. Sborov, Philippe Szankasi, Paul Rindler, Devin Close, Robert S. Ohgami
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Abstract

Between June 2022 and November 2023, targeted next-generation sequencing (NGS) was performed on blood or bone marrow samples at four US medical centers. We identified 27 distinct presumably somatic UBA1 variants in 86 patients (1%, Fig. 1A). Sixty-six patients (0.7%) carried nine different pathogenic/likely pathogenic variants (PV, Fig. 1B above the protein sequence). Most were canonical loss-of-start-codon variants: p.M41T (N = 24), p.M41L (N = 21), and p.M41V (N = 14), followed by previously reported (c.118-1 G>C, N = 2) and two novel splice site variants (c.118-10_118-1 del and c.118-5_118-1 del) upstream of the p.M41 codon. Further, three VEXAS-causal missense variants p.Y55H (N = 1), p.G477A (N = 1), and p.A478S (N = 1) were also classified as PV [1, 2, 4]. An additional 18 distinct novel variants (below the protein sequence in Fig. 1B and in Supplementary Table 1), classified as variants of uncertain significance (VUS), including two recurrent variants (p.D506N and p.I890F), were identified in the remaining 20 patients (Fig. 1B, C, patients 67-86).

Thirty-one (47%) patients with UBA1 PV exhibited at least one concomitant variant, representing a significantly lower frequency compared to VUS patients (85%, p = 0.04, Fig. 1C, D and Table 1), accompanied by a lower somatic mutation burden, defined as the number of somatic variants per patient (Fig. 1E, mean ± SEM, 2.0 ± 0.2 in PV vs. 4.0 ± 0.5 in VUS, p = 0.0001). UBA1 clone sizes were notably larger in PV (Fig. 1F, mean ± SEM, 26.1% ± 1.5) than those in VUS (16.0% ± 3.3, p = 0.002). Fifty-five PV patients (83%) exhibited UBA1 variant VAFs higher than those of the leading concurrent variants, if any, indicating that UBA1 PV were the founding clones. In contrast, only 40% of VUS (Fig. 1G, p = 0.001) were the leading clones. In PV patients, DNMT3A was the most commonly mutated gene (23%), followed by TET2 (12%) and ASXL1 (6%, Fig. 1C). In VUS patients, the most prevalent concomitant variant was TET2 (Supplementary Fig. 1A, 35%, p = 0.03), followed by ASXL1 (25%, p = 0.02) and DNMT3A variants (10%, p = 0.03). Notably, variants involved in tyrosine kinase or RAS signaling pathways were significantly more prevalent in VUS patients (Supplementary Fig. 1A–C).

Table 1 The clinical diagnosis, molecular and cytogenetic profiles of 86 individuals with presumed somatic UBA1 variants.
Full size table

Abstract Image

获得性 UBA1 突变的快速增长使男性患者易患低风险 MDS
2022 年 6 月至 2023 年 11 月期间,美国四家医疗中心对血液或骨髓样本进行了有针对性的下一代测序(NGS)。我们在 86 名患者(1%,图 1A)中发现了 27 个不同的推测体细胞 UBA1 变异。66名患者(0.7%)携带九种不同的致病/可能致病变异体(PV,图 1B 蛋白序列上方)。大多数是典型的起始密码子缺失变异:p.M41T(24 例)、p.M41L(21 例)和 p.M41V(14 例),其次是之前报道的 p.M41 密码子上游的 c.118-1 G>C, 2 例)和两个新的剪接位点变异(c.118-10_118-1 del 和 c.118-5_118-1 del)。此外,三个导致 VEXAS 的错义变异 p.Y55H(N = 1)、p.G477A(N = 1)和 p.A478S(N = 1)也被归类为 PV [1、2、4]。其余 20 名患者(图 1B、C,患者 67-86)中还发现了 18 个不同的新型变异(图 1B 和补充表 1 中蛋白质序列下方),被归类为意义不确定的变异(VUS),其中包括两个复发性变异(p.D506N 和 p.I890F)。31 名 UBA1 PV 患者(47%)至少出现了一种伴随变异,与 VUS 患者(85%,p = 0.04,图 1C、D 和表 1)相比频率明显较低,同时体细胞突变负荷也较低,体细胞突变负荷定义为每名患者的体细胞变异数(图 1E,平均值 ± SEM,PV 患者为 2.0 ± 0.2,VUS 患者为 4.0 ± 0.5,p = 0.0001)。PV患者的UBA1克隆大小(图1F,平均值±SEM,26.1%±1.5)明显大于VUS患者(16.0%±3.3,p = 0.002)。55 例 PV 患者(83%)的 UBA1 变体 VAF 值高于主要并发变体(如果有的话)的 VAF 值,这表明 UBA1 PV 是创始克隆。相比之下,只有 40% 的 VUS(图 1G,p = 0.001)是主导克隆。在 PV 患者中,DNMT3A 是最常见的突变基因(23%),其次是 TET2(12%)和 ASXL1(6%,图 1C)。在 VUS 患者中,最常见的伴随变异是 TET2(补充图 1A,35%,p = 0.03),其次是 ASXL1(25%,p = 0.02)和 DNMT3A 变异(10%,p = 0.03)。值得注意的是,涉及酪氨酸激酶或RAS信号通路的变异在VUS患者中的发生率明显更高(补充图1A-C)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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