Ikoma Haruka, Carreras Joaquim, Kikuti Yara Yukie, Miyaoka Masashi, Nagase Shunsuke, Kondo Yusuke, Ito Atsushi, Orita Makoto, Tomita Sakura, Hiraiwa Shinichiro, Kawada Hiroshi, Garcia Juan F, Roncador Giovanna, Campo Elias, Nakamura Naoya
Department of Pathology, School of Medicine, Tokai University, Isehara, Japan.
Department of Pathology, School of Medicine, Tokai University, Isehara, Japan.
J Mol Diagn. 2025 Aug;27(8):796-807. doi: 10.1016/j.jmoldx.2025.05.002. Epub 2025 Jun 5.
It was recently reported that follicular lymphoma (FL) with BCL6 rearrangement (R) is associated with favorable progression-free survival, whereas BCL2-R and BCL2-6-R cases are associated with disease progression. However, the pathologic mechanism remained unexplored. This study analyzed the mutational landscape and immune microenvironment of 31 FL cases, including 16 BCL2-R, 11 BCL6-R, and 4 BCL2-6-R FL cases. The method included an in-house next-generation targeted sequencing panel of 168 genes associated with aggressive B-cell lymphoma and FL, whole genome copy number change microarray (OncoScan), and immunohistochemistry for the immune microenvironment focused on M2-like tumor-associated macrophages, regulatory T lymphocytes, and programmed cell death protein 1 (PDCD1; alias PD-1)-positive follicular T helper cells. The resulting mutational profile was compatible with a previously reported conventional FL series featuring frequent mutations in CREBBP, KMT2D, TNFRSF14, STAT6, and CD36. Moreover, BCL6-R cases had mutations in ARID1B, ARID5B, and RHOA; low frequency of mutations in other genes, such as OSBPL10, PTPRD, ATM, and HLA-B; 6q loss; and absence of disease progression. In comparison with BCL6-R cases, BCL2-R and BCL2-6-R cases had mutations in EZH2, chromosome 18 copy number gain, and disease progression in some cases. The immune microenvironment profile was heterogeneous; however, BCL6-R cases demonstrated higher infiltration of colony-stimulating factor 1 receptor- and leukocyte immunoglobulin like receptor B3 (LILRB3; alias CD85a)-positive cells. In conclusion, compared with BCL2-R, FL with BCL6-R exhibited some differences in mutational profiles and immune microenvironment.
最近有报道称，伴有BCL6重排（R）的滤泡性淋巴瘤（FL）与无进展生存期良好相关，而BCL2-R和BCL2-6-R病例则与疾病进展相关。然而，其病理机制仍未得到探索。本研究分析了31例FL病例的突变图谱和免疫微环境，其中包括16例BCL2-R、11例BCL6-R和4例BCL2-6-R FL病例。方法包括针对与侵袭性B细胞淋巴瘤和FL相关的168个基因的内部新一代靶向测序面板、全基因组拷贝数变化微阵列（OncoScan）以及针对免疫微环境的免疫组织化学，重点关注M2样肿瘤相关巨噬细胞、调节性T淋巴细胞和程序性细胞死亡蛋白1（PDCD1；别名PD-1）阳性滤泡辅助性T细胞。所得突变谱与先前报道的传统FL系列一致，其特征是CREBBP、KMT2D、TNFRSF14、STAT6和CD36频繁突变。此外BCL6-R病例在ARID1B、ARID5B和RHOA中有突变；其他基因如OSBPL10、PTPRD、ATM和HLA-B的突变频率较低；6号染色体缺失；且无疾病进展。与BCL6-R病例相比，BCL2-R和BCL2-6-R病例在EZH2中有突变、18号染色体拷贝数增加，且部分病例有疾病进展。免疫微环境图谱具有异质性；然而，BCL6-R病例显示集落刺激因子1受体和白细胞免疫球蛋白样受体B亚家族成员3（LILRB3；别名CD85a）阳性细胞的浸润更高。总之，与BCL2-R相比，伴有BCL6-R的FL在突变谱和免疫微环境方面表现出一些差异。
