Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
Lab Invest. 2018 Apr;98(4):414-426. doi: 10.1038/s41374-017-0003-6. Epub 2018 Jan 16.
The discovery of mutations in genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH) has expanded our understanding not only of altered metabolic pathways but also epigenetic dysregulation in cancer. IDH1/2 mutations occur in enchondromas and chondrosarcomas in patients with the non-hereditary enchondromatosis syndromes Ollier disease and Maffucci syndrome and in sporadic tumors. IDH1/2 mutations result in excess production of the oncometabolite (D)-2-hydroxyglutarate. In contrast, SDH and FH act as tumor suppressors and genomic inactivation results in succinate and fumarate accumulation, respectively. SDH deficiency may result from germline SDHA, SDHB, SDHC, or SDHD mutations and is found in autosomal-dominant familial paraganglioma/pheochromocytoma and Carney-Stratakis syndrome, describing the combination of paraganglioma and gastrointestinal stromal tumor (GIST). In contrast, patients with the non-hereditary Carney triad, including paraganglioma, GIST, and pulmonary chondroma, usually lack germline SDH mutations and instead show epigenetic SDH complex inactivation through SDHC promoter methylation. Inactivating FH germline mutations are found in patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome comprising benign cutaneous/uterine leiomyomas and renal cell carcinoma. Mutant IDH, SDH, and FH share common inhibition of α-ketoglutarate-dependent oxygenases such as the TET family of 5-methylcytosine hydroxylases preventing DNA demethylation, and Jumonji domain histone demethylases increasing histone methylation, which together inhibit cell differentiation. Ongoing studies aim to better characterize these complex alterations in cancer, the different clinical phenotypes, and variable penetrance of inherited and sporadic cancer predisposition syndromes. A better understanding of the roles of metabolic enzymes in cancer may foster the development of therapies that specifically target functional alterations in tumor cells in the future. Here, the physiologic functions of these metabolic enzymes, the mutational spectrum, and associated functional alterations will be discussed, with a focus on mesenchymal tumor predisposition syndromes.
基因突变的发现编码代谢酶异柠檬酸脱氢酶（IDH）、琥珀酸脱氢酶（SDH）和富马酸水合酶（FH）不仅扩展了我们对代谢途径改变的认识，而且扩展了对癌症表观遗传失调的认识。IDH1/2 突变发生在非遗传性软骨瘤病综合征 Ollier 病和 Maffucci 综合征患者的软骨瘤和软骨肉瘤以及散发性肿瘤中。IDH1/2 突变导致致癌代谢物（D）-2-羟基戊二酸的过量产生。相比之下，SDH 和 FH 作为肿瘤抑制因子，基因组失活导致琥珀酸和富马酸的积累。SDH 缺陷可能是由于种系 SDHA、SDHB、SDHC 或 SDHD 突变引起的，存在于常染色体显性家族性副神经节瘤/嗜铬细胞瘤和 Carney-Stratakis 综合征中，描述了副神经节瘤和胃肠道间质瘤（GIST）的组合。相比之下，非遗传性 Carney 三联征患者，包括副神经节瘤、GIST 和肺软骨瘤，通常缺乏种系 SDH 突变，而是通过 SDHC 启动子甲基化显示表观遗传 SDH 复合物失活。遗传性平滑肌瘤病和肾细胞癌（HLRCC）综合征患者中发现了 FH 种系失活突变，该综合征包括良性皮肤/子宫平滑肌瘤和肾细胞癌。突变 IDH、SDH 和 FH 具有共同的抑制作用α-酮戊二酸依赖性加氧酶，如 5-甲基胞嘧啶羟化酶的 TET 家族，防止 DNA 去甲基化，和 Jumonji 结构域组蛋白去甲基化酶增加组蛋白甲基化，共同抑制细胞分化。正在进行的研究旨在更好地描述这些癌症中的复杂改变，不同的临床表型和遗传性和散发性癌症易感性综合征的可变外显率。更好地了解代谢酶在癌症中的作用可能会促进未来针对肿瘤细胞功能改变的治疗方法的发展。在这里，将讨论这些代谢酶的生理功能、突变谱和相关的功能改变，重点是间充质肿瘤易感性综合征。
