Department of Neurosurgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China.
Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi'an, China.
Clin Lymphoma Myeloma Leuk. 2023 Apr;23(4):291-302. doi: 10.1016/j.clml.2023.01.003. Epub 2023 Jan 12.
Primary central nervous system lymphoma (PCNSL) is a highly aggressive type of extranodal non-Hodgkin lymphoma, of which approximately 90% of the cases are diffuse large B-cell lymphoma (DLBCL). In recent years, the incidence of PCNSL has significantly increased in women and older men. Although advanced treatments such as high-dose methotrexate (HD-MTX) and targeted agents have been introduced, the prognosis of these patients remains poorer than those with other forms of non-Hodgkin's lymphoma.
Twelve cases of Chinese PCNSL were analyzed to detect their genetic alterations using whole-exome sequencing (WES). We identified 448 potential somatic single nucleotide variants (SNVs) with a median of 12 SNVs per PCNSL sample and 35 small indels with potentially protein-changing features in 9 PCNSL samples.
We found that myeloid differentiation factor 88 (MYD88) had the highest mutation frequency, which affected the activity of the nuclear factor-κB (NF-κB) pathway. PCNSL samples with low-density lipoprotein receptor-related protein 1B (LRP1B) mutations had a higher mutation rate than samples with wild-type LRP1B. Polycystic kidney and hepatic disease 1 (PKHD1), the causal gene of autosomal recessive polycystic kidney disease (ARPKD), was identified in 2 PCNSL cases and exhibited missense mutations. Pathway analysis revealed enrichment in pathways associated with central carbon metabolism in cancer, renal cell carcinoma, nicotine addiction, bladder cancer, and long-term depression.
WES revealed significantly mutated genes associated with the molecular mechanisms of PCNSL, which could serve as therapeutic targets to improve patient outcomes.
原发性中枢神经系统淋巴瘤（PCNSL）是一种侵袭性很强的结外非霍奇金淋巴瘤，其中约 90%的病例为弥漫性大 B 细胞淋巴瘤（DLBCL）。近年来，女性和老年男性 PCNSL 的发病率显著增加。尽管引入了大剂量甲氨蝶呤（HD-MTX）和靶向药物等先进治疗方法，但这些患者的预后仍不如其他类型的非霍奇金淋巴瘤患者。
对 12 例中国 PCNSL 患者进行全外显子组测序（WES）分析，以检测其遗传改变。我们在 9 例 PCNSL 样本中发现了 448 个潜在的体细胞单核苷酸变异（SNVs），中位数为每个 PCNSL 样本 12 个 SNVs，35 个具有潜在蛋白改变特征的小插入缺失。
我们发现髓样分化因子 88（MYD88）的突变频率最高，影响核因子-κB（NF-κB）通路的活性。低密度脂蛋白受体相关蛋白 1B（LRP1B）突变的 PCNSL 样本比野生型 LRP1B 样本的突变率更高。多囊肾病和肝疾病 1（PKHD1）是常染色体隐性多囊肾病（ARPKD）的致病基因，在 2 例 PCNSL 病例中被鉴定出存在错义突变。通路分析显示，癌症、肾细胞癌、尼古丁成瘾、膀胱癌和长期抑郁相关的中央碳代谢途径富集。
WES 揭示了与 PCNSL 分子机制相关的显著突变基因，这些基因可作为治疗靶点，改善患者预后。
