CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
Institute of Intelligent Medical Research (IIMR), BGI Genomics, 518083, Shenzhen, China.
Nat Commun. 2024 Nov 3;15(1):9495. doi: 10.1038/s41467-024-53821-1.
Gastrointestinal stromal tumor (GISTs) are clinically heterogenous exhibiting varying degrees of disease aggressiveness in individual patients. We comprehensively describe the genomic and transcriptomic landscape of a cohort of 117 GISTs including 31 low-risk, 18 intermediate-risk, 29 high-risk, 34 metastatic and 5 neoadjuvant GISTs from 105 patients. GISTs have notably low tumor mutation burden but widespread copy number variations. Aggressive GISTs harbor remarkably more genomic aberrations than low-/intermediate-risk GISTs. Complex genomic alterations, chromothripsis and kataegis, occur selectively in aggressive GISTs. Despite the paucity of mutations, recurrent inactivating YLPM1 mutations are identified (10.3%, 7 of 68 patients), enriched in high-risk/metastatic GIST and functional study further demonstrates YLPM1 inactivation promotes GIST proliferation, growth and oxidative phosphorylation. Spatially and temporally separated GISTs from individual patients demonstrate complex tumor heterogeneity in metastatic GISTs. Finally, four prominent subtypes are proposed with different genomic features, expression profiles, immune characteristics, clinical characteristics and subtype-specific treatment strategies. This large-scale analysis depicts the landscape and provides further insights into GIST pathogenesis and precise treatment.
胃肠道间质瘤（GISTs）在临床上表现出异质性，在个体患者中表现出不同程度的疾病侵袭性。我们全面描述了 117 例 GIST 患者的基因组和转录组图谱，其中包括 31 例低危、18 例中危、29 例高危、34 例转移性和 5 例新辅助 GISTs，来自 105 例患者。GISTs 的肿瘤突变负担明显较低，但存在广泛的拷贝数变异。侵袭性 GISTs 比低/中危 GISTs 具有更多的基因组异常。复杂的基因组改变、染色体碎裂和kataegis 选择性地发生在侵袭性 GISTs 中。尽管突变很少，但在高危/转移性 GIST 中鉴定到了反复出现的 YLPM1 失活突变（10.3%，68 例患者中的 7 例），功能研究进一步表明 YLPM1 失活促进了 GIST 的增殖、生长和氧化磷酸化。来自个体患者的空间和时间分离的 GISTs 在转移性 GIST 中表现出复杂的肿瘤异质性。最后，提出了四个突出的亚型，具有不同的基因组特征、表达谱、免疫特征、临床特征和亚型特异性治疗策略。这项大规模分析描绘了景观，并进一步深入了解 GIST 的发病机制和精确治疗。
