Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 59005, United States of America.
Department of Pathology, University of California-San Francisco, San Francisco, CA 94115, United States of America.
Ann Diagn Pathol. 2022 Aug;59:151967. doi: 10.1016/j.anndiagpath.2022.151967. Epub 2022 May 6.
Loss-of-function mutations in EED and SUZ12, core components of the polycomb repressive complex 2 (PRC2), occur in >90% of sporadic and radiation-associated malignant peripheral nerve sheath tumors (MPNST) and in roughly 70% of NF1-related tumors. PRC2 inactivation results in loss of H3K27me3 expression and aberrant downstream transcription. H3K27me3 expression is lost in 40-90% of spindle cell MPNST but is not specific. A single study has suggested that dimethylated H3K27 (H3K27me2) is a more specific marker of MPNST.
We compared the expression of H3K27me3 and H3K27me2 by immunohistochemistry in a series of MPNST (n = 26), neurofibroma (n = 11), conventional dermatofibrosarcoma protuberans (n = 8), fibrosarcomatous dermatofibrosarcoma protuberans (n = 7), spindle cell rhabdomyosarcoma (n = 6), high-risk solitary fibrous tumor (n = 9), dedifferentiated chondrosarcoma (n = 7), synovial sarcoma (n = 9), diffuse midline glioma, H3K27-altered (n = 13), conventional diffuse astrocytoma (n = 2), conventional cutaneous melanoma (n = 8), uveal melanoma (n = 8), cellular blue nevus (n = 17) and melanoma arising in blue nevus (n = 6).
H3K27me3 and H3K27me2 expression patterns were concordant in 115/137 (84%) with 85 cases (62%) expressing both markers and 30 cases (22%) showing loss of both. Discordant results were seen in 22 cases (H3K27me3 loss with retained H3K27me2, 10 cases (7%); H3K27me3 expression with H3K27me2 loss, 12 cases (9%)). H3K27me2 loss was not specific for MPNST and was also seen in certain other tumors, in particular those in the "blue nevus family".
We conclude that H3K27me2 loss is not specific for MPNST, and like H3K27me3, should be used in the appropriate clinicopathologic, immunohistochemical and molecular genetic context. Loss of H3K27me2 with retained H3K27me3 is a common feature of "blue nevus family" melanocytic tumors known to harbor GNAQ/GNA11 mutations.
EED 和 SUZ12 是多梳抑制复合物 2 (PRC2) 的核心组成部分，其功能丧失突变发生在超过 90%的散发和放射相关的恶性外周神经鞘瘤 (MPNST) 中，以及大约 70%的 NF1 相关肿瘤中。PRC2 的失活导致 H3K27me3 表达缺失和下游转录异常。40-90%的梭形细胞 MPNST 中丢失 H3K27me3 表达，但不具有特异性。一项研究表明，二甲基化 H3K27（H3K27me2）是 MPNST 的更特异性标志物。
我们通过免疫组化比较了一系列 MPNST（n=26）、神经纤维瘤（n=11）、常规隆突性皮肤纤维肉瘤（n=8）、纤维肉瘤样隆突性皮肤纤维肉瘤（n=7）、梭形细胞横纹肌肉瘤（n=6）、高危孤立性纤维性肿瘤（n=9）、去分化软骨肉瘤（n=7）、滑膜肉瘤（n=9）、弥漫性中线胶质瘤，H3K27 改变（n=13）、常规弥漫性星形细胞瘤（n=2）、常规皮肤黑色素瘤（n=8）、脉络膜黑色素瘤（n=8）、细胞性蓝色神经瘤（n=17）和蓝色神经瘤起源的黑色素瘤（n=6）中 H3K27me3 和 H3K27me2 的表达模式。
在 137 例中有 115 例（84%）H3K27me3 和 H3K27me2 的表达模式一致，其中 85 例（62%）同时表达两种标志物，30 例（22%）同时丢失两种标志物。22 例（H3K27me3 丢失而 H3K27me2 保留，10 例（7%）；H3K27me3 表达而 H3K27me2 丢失，12 例（9%））出现不一致的结果。H3K27me2 丢失并不特异于 MPNST，也可见于某些其他肿瘤，特别是那些“蓝色神经瘤家族”中的肿瘤。
我们的结论是，H3K27me2 的丢失并不特异于 MPNST，与 H3K27me3 一样，应在适当的临床病理、免疫组织化学和分子遗传学背景下使用。保留 H3K27me3 的 H3K27me2 丢失是已知携带 GNAQ/GNA11 突变的“蓝色神经瘤家族”黑色素瘤的共同特征。
