异柠檬酸脱氢酶基因突变在软骨肉瘤中的研究进展及展望

doi:10.12114/j.issn.1007-9572.2023.0284

摘要/Abstract

摘要： 人类代谢基因中异柠檬酸脱氢酶（IDH）是较易发生突变的基因。在烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的作用下，突变的IDH可与α-酮戊二酸（α-KG）结合并将其还原为2-羟基戊二酸（2-HG），参与肿瘤发生的多种生物过程。IDH在脑胶质瘤及急性髓系白血病中研究较多，在软骨肉瘤中的研究甚少。软骨肉瘤中存在IDH基因高频突变，易出现复发和转移，复发或转移后治疗方案有限，患者预后较差，临床迫切需要寻找新的治疗方案。本文就IDH基因突变在软骨肉瘤发生、预后、鉴别诊断及治疗中的作用予以综述，通过进一步阐述IDH基因突变在软骨肉瘤发生、发展中的生物学作用，并对强效的IDH抑制剂及抗癌药物研发进行展望，为临床治疗方案的制订及预后判断提供参考依据。

关键词: 软骨肉瘤, 异柠檬酸脱氢酶, 突变, 肿瘤治疗, 综述

Abstract:

Isocitrate dehydrogenase (IDH) is the more mutation-prone human metabolic gene. In the presence of nicotinamide adenine dinucleotide phosphate (NADPH), mutant IDH can bind to α-ketoglutaric acid (α-KG) and reduce it to 2-hydroxyglutaric acid (2-HG), participating in various biological processes of tumorigenesis. IDH has been widely studied in glioma and acute myeloid leukemia, and rarely in chondrosarcoma. Chondrosarcoma is prone to recurrence and metastasis due to the presence of high-frequency mutations in the IDH gene, and treatment options are limited after recurrence or metastasis, resulting in a poor prognosis for patients and an urgent clinical need to find new treatment options. This article reviews the role of IDH mutations in the development, prognosis, differential diagnosis and treatment of chondrosarcoma, further elaborates the biological role of IDH gene mutation in the occurrence and development of chondrosarcoma, and provides an outlook on the development of powerful IDH inhibitors and anti-cancer drugs, in order to provide a reference for the establishment of therapeutic regimen and prognostic evaluation.

Key words: Chondrosarcoma, Isocitrate dehydrogenase, Mutation, Tumor treatment, Review

赵静静,张志红,甄俊平. 异柠檬酸脱氢酶基因突变在软骨肉瘤中的研究进展及展望[J]. 中国全科医学, 2024, 27(11): 1400-1404. DOI: 10.12114/j.issn.1007-9572.2023.0284.
ZHAO Jingjing,ZHANG Zhihong,ZHEN Junping. Research Progress and Prospects of Isocitrate Dehydrogenase Gene Mutation in Chondrosarcoma[J]. Chinese General Practice, 2024, 27(11): 1400-1404. DOI: 10.12114/j.issn.1007-9572.2023.0284.

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参考文献 30

[1]	YANG H，YE D，GUAN K L，et al. IDH1 and IDH2 mutations in tumorigenesis：mechanistic insights and clinical perspectives[J]. Clin Cancer Res，2012，18（20）：5562-5571. DOI：10.1158/1078-0432.CCR-12-1773.
[2]	PATHMANAPAN S，ILKAYEVA O，MARTIN J T，et al. Mutant IDH and non-mutant chondrosarcomas display distinct cellular metabolomes[J]. Cancer Metab，2021，9（1）：13. DOI：10.1186/s40170-021-00247-8.
[3]	AMARY M F，BACSI K，MAGGIANI F，et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours[J]. J Pathol，2011，224（3）：334-343. DOI：10.1002/path.2913.
[4]	LUGOWSKA I，TETERYCZ P，MIKULA M，et al. IDH1/2 mutations predict shorter survival in chondrosarcoma[J]. J Cancer，2018，9（6）：998-1005. DOI：10.7150/jca.22915.
[5]	VUONG H G，NGO T N M，DUNN I F. Prognostic importance of IDH mutations in chondrosarcoma：an individual patient data meta-analysis[J]. Cancer Med，2021，10（13）：4415-4423. DOI：10.1002/cam4.4019.
[6]	王睿峰，郭卫. 软骨肿瘤异柠檬酸脱氢酶基因突变的研究进展[J]. 中华骨与关节外科杂志，2021，14（2）：155-160. DOI：10.3969/j.issn.2095-9958.2021.02.16.
[7]	CHOW W A. Chondrosarcoma：biology，genetics，and epigenetics[J]. F1000Res，2018，7：F1000FacultyRev-F1000Faculty1826. DOI：10.12688/f1000research.15953.1.
[8]	GUO J X，ZHANG R Y，YANG Z，et al. Biological roles and therapeutic applications of IDH2 mutations in human cancer[J]. Front Oncol，2021，11：644857. DOI：10.3389/fonc.2021.644857.
[9]	YE D，XIONG Y，GUAN K L. The mechanisms of IDH mutations in tumorigenesis[J]. Cell Res，2012，22（7）：1102-1104. DOI：10.1038/cr.2012.51.
[10]	EVANS B，GRINER E. Registered report：Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases[J]. Elife，2015，4：e07420. DOI：10.7554/eLife.07420.
[11]	XU Y Q，LIU L W，NAKAMURA A，et al. Studies on the regulatory mechanism of isocitrate dehydrogenase 2 using acetylation mimics[J]. Sci Rep，2017，7（1）：9785. DOI：10.1038/s41598-017-10337-7.
[12]	CHEN C B，ZHOU H，WEI F，et al. Increased levels of hypoxia-inducible factor-1α are associated with Bcl-xL expression，tumor apoptosis，and clinical outcome in chondrosarcoma[J]. J Orthop Res，2011，29（1）：143-151. DOI：10.1002/jor.21193.
[13]	KOIVUNEN P，LEE S，DUNCAN C G，et al. Transformation by the（R）-enantiomer of 2-hydroxyglutarate linked to EGLN activation[J]. Nature，2012，483（7390）：484-488. DOI：10.1038/nature10898.
[14]	HU X Y，LI L Y，EID J E，et al. IDH1 mutation induces HIF-1α and confers angiogenic properties in chondrosarcoma JJ012 cells[J]. Dis Markers，2022，2022：7729968. DOI：10.1155/2022/7729968.
[15]	CHAN S M，THOMAS D，CORCES-ZIMMERMAN M R，et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia[J]. Nat Med，2015，21（2）：178-184. DOI：10.1038/nm.3788.
[16]	ZHANG L J，SORENSEN M D，KRISTENSEN B W，et al. D-2-hydroxyglutarate is an intercellular mediator in IDH-mutant gliomas inhibiting complement and T cells[J]. Clin Cancer Res，2018，24（21）：5381-5391. DOI：10.1158/1078-0432.CCR-17-3855.
[17]	AMER K M，MUNN M，CONGIUSTA D，et al. Survival and prognosis of chondrosarcoma subtypes：seer database analysis[J]. J Orthop Res，2020，38（2）：311-319. DOI：10.1002/jor.24463.
[18]	ZHU G G，NAFA K，AGARAM N，et al. Genomic profiling identifies association of IDH1/IDH2 mutation with longer relapse-free and metastasis-free survival in high-grade chondrosarcoma[J]. Clin Cancer Res，2020，26（2）：419-427. DOI：10.1158/1078-0432.CCR-18-4212.
[19]	KERR D A，LOPEZ H U，DESHPANDE V，et al. Molecular distinction of chondrosarcoma from chondroblastic osteosarcoma through IDH1/2 mutations[J]. Am J Surg Pathol，2013，37（6）：787-795. DOI：10.1097/PAS.0b013e31827ab703.
[20]	BHARTI J N，ELHENCE P，BHASKAR S，et al. Chondrosarcoma skull base：a case report[J]. Curr Med Imaging，2023，19（11）：1346-1350. DOI：10.2174/1573405619666230207144546.
[21]	YOU Z，ZHANG J，ZHANG H，et al. Status of IDH mutations in chondrosarcoma of the jaws[J]. Int J Oral Maxillofac Surg，2023，52（1）：26-31. DOI：10.1016/j.ijom.2022.03.003.
[22]	JEONG W，KIM H J. Biomarkers of chondrosarcoma[J]. J Clin Pathol，2018，71（7）：579-583. DOI：10.1136/jclinpath-2018-205071.
[23]	BJÖRNSSON J，MCLEOD R A，UNNI K K，et al. Primary chondrosarcoma of long bones and limb girdles[J]. Cancer，1998，83（10）：2105-2119. DOI：10.1002/(sici)1097-0142(19981115)83:10<2105:aid-cncr9>3.0.co;2-u.
[24]	SUIJKER J，OOSTING J，KOORNNEEF A，et al. Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines[J]. Oncotarget，2015，6（14）：12505-12519. DOI：10.18632/oncotarget.3723.
[25]	LI L Y，PAZ A C，WILKY B A，et al. Treatment with a small molecule mutant IDH1 inhibitor suppresses tumorigenic activity and decreases production of the oncometabolite 2-hydroxyglutarate in human chondrosarcoma cells[J]. PLoS One，2015，10（9）：e0133813. DOI：10.1371/journal.pone.0133813.
[26]	NAKAGAWA M，NAKATANI F，MATSUNAGA H，et al. Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma[J]. Oncogene，2019，38（42）：6835-6849. DOI：10.1038/s41388-019-0929-9.
[27]	Agios制药白血病药物AG-221探索试验传来佳音[J]. 临床合理用药杂志，2015，8（2）：179.
[28]	SHAH F H，KIM S J. Identification of medicinal compounds as potential inhibitors for mutated isocitrate dehydrogenases against chondrosarcoma[J]. Saudi J Biol Sci，2022，29（1）：161-167. DOI：10.1016/j.sjbs.2021.08.077.
[29]	VENNEKER S，KRUISSELBRINK A B，BARANSKI Z，et al. Beyond the influence of IDH mutations：exploring epigenetic vulnerabilities in chondrosarcoma[J]. Cancers，2020，12（12）：3589. DOI：10.3390/cancers12123589.
[30]	ROY D M，WALSH L A，CHAN T A. Driver mutations of cancer epigenomes[J]. Protein Cell，2014，5（4）：265-296. DOI：10.1007/s13238-014-0031-6.

突变位点	常见突变形式
IDH1
R132	R132H（组氨酸）	R132C（半胱氨酸）	R132S（丝氨酸）	R132G（甘氨酸）	R132L（亮氨酸）	R132H（异亮氨酸）
IDH2
R172	R172W（色氨酸）	R172G（甘氨酸）	R172S（丝氨酸）
R140	R140L（亮氨酸）	R140Q（谷氨酰胺）	R140W（色氨酸）

突变位点	常见突变形式
IDH1
R132	R132H（组氨酸）	R132C（半胱氨酸）	R132S（丝氨酸）	R132G（甘氨酸）	R132L（亮氨酸）	R132H（异亮氨酸）
IDH2
R172	R172W（色氨酸）	R172G（甘氨酸）	R172S（丝氨酸）
R140	R140L（亮氨酸）	R140Q（谷氨酰胺）	R140W（色氨酸）