虽然报道了导致mTORC1过激活的TSC1或TSC2失活突变与肝血管平滑肌脂肪瘤（hAML）有关，但其他可能对hAML发展有贡献的体细胞遗传事件的作用尚不明确。关于hAML的肿瘤微环境（TME）的数据也很有限。本研究的目的是在基因组水平上识别其他体细胞事件和TME的变化，以了解hAML的肿瘤发生机制。 在本研究中，我们对九个散发性hAML肿瘤进行外显子测序，并对另外三个hAML进行TSC2的深覆盖靶向测序。采用免疫组织化学和多重免疫荧光技术，对15种蛋白质进行分析，以表征肿瘤微环境并评估免疫细胞的浸润情况。在12例中，发现10例（83%）存在TSC2失活体细胞变异，中位等位基因频率为13.6%。此外，还发现了5至18个与TSC1或TSC2无关的体细胞变异（中位数: 9个，中位等位基因频率为21%），其中大部分无明确的临床意义。拷贝数变化较少，但由于肿瘤纯度较低而无法检测到。免疫组织化学显示大量带有与库普弗细胞不同外观的CD68+巨噬细胞。多重免疫荧光显示，存在较低数量的耗竭的PD-1+/PD-L1+、FOXP3+和CD8+T细胞。 hAML肿瘤中的TSC2失活突变具有一致性，并且具有与其他与TSC相关的肿瘤相似的体细胞突变率较低。通过仔细的组织学评估、标准的免疫组织化学和多重免疫荧光技术，证实了非肿瘤炎性细胞（主要为巨噬细胞）的显著浸润。© 2023 约翰iley & Sons股份有限公司。

Although TSC1 or TSC2 inactivating mutations that lead to mTORC1 hyperactivation have been reported in hepatic angiomyolipomas (hAML), the role of other somatic genetic events that may contribute to hAML development is unknown. There are also limited data regarding the tumour microenvironment (TME) of hAML. The aim of the present study was to identify other somatic events in genomic level and changes in TME that contribute to tumorigenesis in hAML.In this study, we performed exome sequencing in nine sporadic hAML tumours and deep-coverage targeted sequencing for TSC2 in three additional hAML. Immunohistochemistry and multiplex immunofluorescence were carried out for 15 proteins to characterise the tumour microenvironment and assess immune cell infiltration. Inactivating somatic variants in TSC2 were identified in 10 of 12 (83%) cases, with a median allele frequency of 13.6%. Five to 18 somatic variants (median number: nine, median allele frequency 21%) not in TSC1 or TSC2 were also identified, mostly of uncertain clinical significance. Copy number changes were rare, but detection was impaired by low tumour purity. Immunohistochemistry demonstrated numerous CD68+ macrophages of distinct appearance from Küpffer cells. Multiplex immunofluorescence revealed low numbers of exhausted PD-1+/PD-L1+, FOXP3+ and CD8+ T cells.hAML tumours have consistent inactivating mutations in TSC2 and have a low somatic mutation rate, similar to other TSC-associated tumours. Careful histological review, standard IHC and multiplex immunofluorescence demonstrated marked infiltration by non-neoplastic inflammatory cells, mostly macrophages.© 2023 John Wiley & Sons Ltd.