Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA; Department of Pathology, Cooper University Hospital, Cooper Medical School of Rowan University, Camden, NJ, 08003, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA; Department of Pathology, Northwell Health, Great Neck, NY, 11021, USA.
Hum Pathol. 2020 Oct;104:73-83. doi: 10.1016/j.humpath.2020.07.002. Epub 2020 Aug 12.
Conventional chordoma is a rare slow-growing malignant tumor of notochordal origin primarily arising at the base of the skull and sacrococcygeal bones. Chordoma may arise from its benign counterpart, benign notochordal cell tumors, and can also undergo dedifferentiation progressing into dedifferentiated chordoma. No study has directly compared the genomic alterations among these tumors comprising a morphologic continuum. Our prior study identified frequent chromosome 3p loss of heterozygosity and minimal deleted regions on chromosome 3 encompassing SETD2, encoding a histone methyltransferase involved in histone H3 lysine 36 trimethylation (H3K36me3). In the present study, we expanded our study to include 65 sacral conventional chordoma cases, 3 benign notochordal cell tumor cases, and 2 dedifferentiated chordoma cases using single nucleotide polymorphism (SNP) array, targeted next-generation sequencing analysis, and immunohistochemistry. We performed immunohistochemical analysis of histone, H3K36me3, and investigated whether there is any association between the clinical behavior and recurrent chromosome or aneuploidy or H3K36me3 protein expression. We found that there is increased genomic instability from benign notochordal cell tumor to conventional chordoma to dedifferentiated chordoma. The highly recurrent genomic aberration, chromosome 3p loss of heterozygosity (occurred in 70% of conventional chordomas), is correlated with longer relapse-free survival, but not with overall survival or metastasis-free survival in sacral chordoma. Chordomas demonstrate variable patterns and levels of H3K36me3 expression, and reduced expression of H3K36me3 showed marginally significant correlation with longer relapse-free survival. Copy number alterations in the genes encoding the H3K36me3 methylation transferase complex and demethylase may account for the altered H3K36me3 expression levels.
传统脊索瘤是一种罕见的、生长缓慢的恶性肿瘤，主要起源于颅底和骶尾部骨骼。脊索瘤可能起源于其良性对应物——良性脊索瘤细胞肿瘤，也可能发生去分化，进展为去分化脊索瘤。目前尚无研究直接比较这些形态连续体肿瘤中的基因组改变。我们之前的研究确定了频繁的染色体 3p 杂合性缺失和染色体 3 上包含 SETD2 的最小缺失区域，SETD2 编码一种组蛋白甲基转移酶，参与组蛋白 H3 赖氨酸 36 三甲基化（H3K36me3）。在本研究中，我们使用单核苷酸多态性（SNP）阵列、靶向下一代测序分析和免疫组织化学，将研究范围扩大到 65 例骶骨传统脊索瘤病例、3 例良性脊索瘤细胞肿瘤病例和 2 例去分化脊索瘤病例。我们进行了组蛋白、H3K36me3 的免疫组织化学分析，并研究了临床行为与染色体或非整倍体的复发之间是否存在任何关联或 H3K36me3 蛋白表达。我们发现，从良性脊索瘤细胞肿瘤到传统脊索瘤再到去分化脊索瘤，基因组不稳定性增加。高度反复出现的基因组异常，即染色体 3p 杂合性缺失（发生在 70%的传统脊索瘤中），与骶骨脊索瘤的无复发生存时间延长相关，但与总生存时间或无转移生存时间无关。脊索瘤表现出不同的 H3K36me3 表达模式和水平，H3K36me3 表达降低与无复发生存时间延长具有边缘显著相关性。H3K36me3 甲基转移酶复合物和去甲基化酶编码基因的拷贝数改变可能解释了 H3K36me3 表达水平的改变。
