While Waldenström macroglobulinemia (WM) is characterized by an almost unifying mutation in MYD88, clinical presentation at diagnosis and response to therapy can be widely different among WM patients. Current prognostic tools only partially address this clinical heterogeneity. Limited data compiling both molecular and cytogenetic information have been used in risk prognostication in WM. To investigate the clinical impact of genetic alterations in WM, we evaluated cytogenetic and molecular abnormalities by chromosome banding analyses, FISH and targeted NGS in a retrospective cohort of 239 WM patients, including 187 patients treated by first-line chemotherapy or immunochemotherapy. Most frequent mutations were identified in MYD88 (93%), CXCR4 (29%), MLL2 (11%), ARID1A (8%), TP53 (8%), CD79A/B (6%), TBL1XR1 (4%) and SPI1 (4%). The median number of cytogenetic abnormalities was two (range, 0–22). Main cytogenetic abnormalities were 6q deletion (del6q) (27%), trisomy 4 (tri4) (12%), tri18 (11%), del13q (11%), tri12 (7.5%) and del17p (7%). Complex karyotype (CK) was observed in 15% (n = 31) of cases, including 5% (n = 12) of highly CK (high-CK). TP53 abnormalities (TP53abn) were present in 15% of evaluable patients. TP53abn and del6q were associated with CK/high-CK (p < .05). Fifty-three percent of patients with hyperviscosity harbored CXCR4 mutations. Cytogenetic and molecular abnormalities did not significantly impact time to first treatment and response to therapy. Prognostic factors associated with shorter PFS were del6q (p = .01), TP53abn (p = .002) and high-CK (p = .01). These same factors as well as IPSSWM, tri4, CXCR4 frameshift and SPI1 mutations were significantly associated with lower OS (p < .05). These results argue for integration of both cytogenetic and molecular screening in evaluation of first-line WM patients.

中文翻译：

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Waldenström 巨球蛋白血症患者的细胞遗传学和分子异常：相关性和预后影响

虽然 Waldenström 巨球蛋白血症 (WM) 的特征是MYD88 中几乎统一的突变，但 WM 患者的诊断时的临床表现和对治疗的反应可能大不相同。当前的预后工具仅部分解决了这种临床异质性。用于 WM 风险预测的有限数据汇集了分子和细胞遗传学信息。为了研究 WM 遗传改变的临床影响，我们通过染色体显带分析、FISH 和靶向 NGS 在 239 名 WM 患者的回顾性队列中评估了细胞遗传学和分子异常，其中 187 名患者接受了一线化疗或免疫化疗。在MYD88 (93%)、CXCR4 (29%)、MLL2 (11%)、ARID1A (8%)、TP53 (8%)、CD79A/B (6%)、TBL1XR1 (4%) 和SPI1 (4%)。细胞遗传学异常的中位数为 2（范围，0-22）。主要的细胞遗传学异常是 6q 缺失 (del6q) (27%)、三体 4 (tri4) (12%)、tri18 (11%)、del13q (11%)、tri12 (7.5%) 和 del17p (7%)。在 15% (n = 31) 的病例中观察到复杂核型 (CK)，包括 5% (n = 12) 的高 CK（高 CK）。15% 的可评估患者存在TP53异常 ( TP53 abn)。TP53 abn 和 del6q 与 CK/高 CK 相关 ( p  < .05)。53% 的高粘滞血症患者CXCR4突变。细胞遗传学和分子学异常对首次治疗的时间和对治疗的反应没有显着影响。与较短 PFS 相关的预后因素是 del6q ( p  = .01)、TP53 abn ( p  = .002) 和高 CK ( p  = .01)。这些相同的因素以及 IPSSWM、tri4、CXCR4移码和SPI1突变与较低的 OS 显着相关 ( p  < .05)。这些结果支持将细胞遗传学和分子筛查整合到一线 WM 患者的评估中。