中枢神经系统原发性弥漫性大 B 细胞淋巴瘤的基因组分析提示了新的潜在治疗靶点。
Genomic Profiling of Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System Suggests Novel Potential Therapeutic Targets.
机构信息
Haematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria of Bologna, Bologna, Italy; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Functional and Molecular Neuroimaging Unit, Bologna, Italy.
出版信息
Mod Pathol. 2023 Dec;36(12):100323. doi: 10.1016/j.modpat.2023.100323. Epub 2023 Sep 9.
Primary diffuse large B-cell lymphoma of the primary central nervous system (CNS-DLBCL) is an aggressive disease, with dismal prognosis despite the use of high-dose methotrexate-based polychemotherapy. Our study aimed to expand the biologic profiles of CNS-DLBCL and to correlate them with clinical/imaging findings to gain diagnostic insight and possibly identify new therapeutic targets. We selected 61 CNS-DLBCL whose formalin-fixed paraffin-embedded samples were available at first diagnosis. These were investigated by immunohistochemistry, cMYC rearrangements were explored by fluorescence in situ hybridization, and CNS-DLBCL mutated genes were evaluated by next-generation sequencing. CD10, BCL6, and IRF4 were observed in 16%, 83.6%, and 93% of cases, respectively. As typical of CNS lymphoma, 10 (16.4%) of 61 cases were classified as germinal center (GCB) type and 51 (83.6%) of 61 as non-germinal center (non-GCB) type according to the Hans algorithm. Double-expression status for BCL2 and cMYC was detected in 36 (59%) of 61 cases whereas 25 (41%) of 61 were non-DE. Rearrangement of the cMYC gene was detected in 2 cases, associated with BCL6 translocation only in 1 case MYD88, PIM1, CD79B, and TP53 were mutated in 54.5%, 53.5%, 30.2%, and 18.4% cases, respectively. Novel mutations not previously reported in CNS-DLBCL were found: AIP in 23.1%, PI3KCA in 15%, NOTCH1 in 11.4%, GNAS in 8.1%, CASP8 in 7.9%, EGFR in 6.4%, PTEN in 5.1, and KRAS in 2.6% of cases. Survival was significantly longer for patients with mutated MYD88 (8.7 months vs 1.7 months; log-rank test = 5.43; P = .020) and for patients with mutated CD79B (10.8 months vs 2.5 months; log-rank test = 4.64; P = .031). MYD88 and CD79B predicted a longer survival in patients affected by CNS-DLBCL. Notably, we identified novel mutations that enrich the mutational landscape of CNS-DLBCL, suggest a role of PTEN-PI3K-AKT and receptor tyrosine kinase-RAS-mitogen-activated protein kinase signaling in a subset of CNS-DLBCL, and provide new potential therapeutic targets.
原发性中枢神经系统弥漫性大 B 细胞淋巴瘤（CNS-DLBCL）是一种侵袭性疾病，尽管使用了大剂量甲氨蝶呤为基础的联合化疗，预后仍不佳。我们的研究旨在扩展 CNS-DLBCL 的生物学特征，并将其与临床/影像学表现相关联，以获得诊断见解，并可能确定新的治疗靶点。我们选择了 61 例 CNS-DLBCL 患者，其初次诊断时的福尔马林固定石蜡包埋样本可用。通过免疫组织化学进行检测，通过荧光原位杂交检测 cMYC 重排，通过下一代测序评估 CNS-DLBCL 突变基因。分别有 16%、83.6%和 93%的病例观察到 CD10、BCL6 和 IRF4。根据 Hans 算法，10（16.4%）例为生发中心（GCB）型，51（83.6%）例为非生发中心（非-GCB）型，10 例（16.4%）为典型的中枢神经系统淋巴瘤。61 例中 36 例（59%）检测到 BCL2 和 cMYC 的双重表达状态，25 例（41%）为非 DE。检测到 2 例 cMYC 基因重排，仅在 1 例中与 BCL6 易位相关。MYD88、PIM1、CD79B 和 TP53 突变分别在 54.5%、53.5%、30.2%和 18.4%的病例中检测到。发现了以前在 CNS-DLBCL 中未报道的新突变：AIP 在 23.1%的病例中，PI3KCA 在 15%的病例中，NOTCH1 在 11.4%的病例中，GNAS 在 8.1%的病例中，CASP8 在 7.9%的病例中，EGFR 在 6.4%的病例中，PTEN 在 5.1%的病例中，KRAS 在 2.6%的病例中。携带 MYD88 突变的患者（8.7 个月 vs 1.7 个月；对数秩检验 = 5.43；P =.020）和携带 CD79B 突变的患者（10.8 个月 vs 2.5 个月；对数秩检验 = 4.64；P =.031）的生存时间明显更长。在患有 CNS-DLBCL 的患者中，MYD88 和 CD79B 可预测更长的生存时间。值得注意的是，我们鉴定了新的突变，这些突变丰富了 CNS-DLBCL 的突变景观，提示 PTEN-PI3K-AKT 和受体酪氨酸激酶-RAS-丝裂原激活蛋白激酶信号通路在中枢神经系统弥漫性大 B 细胞淋巴瘤的亚群中发挥作用，并提供了新的潜在治疗靶点。
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