PO.MD01.01 · 分子诊断与数据
跨多中心队列的软骨肉瘤突变分析
Mutational profiling of chondrosarcoma across multicenter cohorts
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：软骨肉瘤的分子疗法仍然有限，部分原因在于这些癌症的罕见性，这阻碍了广泛的基因组表征工作。大型、标准化、多中心数据库（如AACR Project GENIE）以及后续的独立研究的建立，已开始汇集该疾病广泛的突变谱。本摘要对这些研究的突变数据进行了初步分析。
方法：通过cBioPortal访问GENIE队列v18.0、MSK Nature Communications Sarcoma 2022和UCLA Cell 2024肉瘤数据集，进行整理和分析。这些数据集包括常规软骨肉瘤（CS）、去分化软骨肉瘤（DDCS）和间叶性软骨肉瘤（MCS）的患者信息。可用数据包括患者年龄、性别、种族、突变谱，以及CS和DDCS的生存结局。
结果：这些数据集共涵盖518例软骨肉瘤患者：428例CS、38例DDCS和52例MCS。活检时的平均年龄，CS患者为52岁，DDCS患者为63岁，MCS患者为33岁。女性分别占CS、DDCS和MCS患者的40.4%、54.1%和55.8%。在有种族记录的患者中，CS的种族分布为74%白人、5%黑人、10%亚裔和12%其他；DDCS为89%白人、5%黑人、3%亚裔和3%其他；MCS为83%白人、13%黑人和4%其他。每个患者样本的平均突变计数，CS为10.1，DDCS为5.4，MCS为2.6。各疾病中突变最频繁的前五个基因如下——CS：TP53（124/439）、IDH1（113/437）、IDH2（35/423）、KMT2D（15/186）和TERT（14/179）；DDCS：TP53（24/40）、IDH1（18/40）、TERT（13/38）、IDH2（12/40）、FLT4（8/40）；MCS：MAP3K13（5/18）、INSR（4/17）、SDHA（5/23）、KMT2D（4/24）和KMT5A（2/13）。中位总生存期，CS患者为58个月，DDCS患者为25个月。值得注意的是，除TP53、IDH1和IDH2之外许多突变最频繁的基因都参与染色质调控和基因组稳定性（KMT2A、KMT2D、TERT等），且这些突变在DDCS中更为常见。
结论：这项多中心突变分析证实，在TP53之后，CS和DDCS中突变最频繁的基因是IDH1和IDH2。参与染色质调控和基因组稳定性的基因突变在DDCS中更为普遍，这可能促成其更强的侵袭性。这些发现支持了在软骨肉瘤中靶向这些通路的持续努力。
查看英文原文 English abstract
Background: Molecular therapies for chondrosarcomas remain limited, in part due to the rarity of these cancers, which hampers efforts at broad genomic characterization. The establishment of large, standardized, multicenter databases, such as the AACR Project GENIE, along with subsequent individual studies, has begun to assemble an extensive mutational profile of this disease. This abstract provides a preliminary analysis of the mutational data from these studies.
Methods: The GENIE Cohort v18.0, MSK Nature Communications Sarcoma 2022, and UCLA Cell 2024 sarcoma datasets, accessed via cBioPortal, were collated and analyzed. These datasets included patient information for conventional chondrosarcoma (CS), dedifferentiated chondrosarcoma (DDCS), and mesenchymal chondrosarcoma (MCS). Available data included patient age, sex, race, mutational profiles, and, for CS and DDCS, survival outcomes.
Results: In total, the datasets encompassed 518 patients with chondrosarcoma: 428 CS, 38 DDCS, and 52 MCS. The average age at biopsy was 52 for CS patients, 63 for DDCS patients, and 33 for MCS patients. Women comprised 40.4%, 54.1%, and 55.8% of CS, DDCS, and MCS patients, respectively. Among patients with recorded race, the racial distribution was 74% White, 5% Black, 10% Asian, and 12% Other for CS; 89% White, 5% Black, 3% Asian, and 3% Other for DDCS; and 83% White, 13% Black, and 4% Other for MCS. The average mutation count per patient sample was 10.1 for CS, 5.4 for DDCS, and 2.6 for MCS. The top five most frequently mutated genes for each disease were as follows - CS: TP53 (124/439), IDH1 (113/437), IDH2 (35/423), KMT2D (15/186), and TERT (14/179); DDCS: TP53 (24/40), IDH1 (18/40), TERT (13/38), IDH2 (12/40), FLT4 (8/40); MCS: MAP3K13 (5/18), INSR (4/17), SDHA (5/23), KMT2D (4/24), and KMT5A (2/13). Median overall survival was 58 months for CS patients versus 25 months for DDCS patients. Notably, many of the most frequently mutated genes beyond TP53 , IDH1 , and IDH2 are involved in chromatin regulation and genomic stability ( KMT2A , KMT2D , TERT , etc.), and these mutations are more common in DDCS.
Conclusion: This multicenter mutational analysis confirms that, after TP53 , the most frequently mutated genes in CS and DDCS are IDH1 and IDH2 . Mutations in genes involved in chromatin regulation and genomic stability are more prevalent in DDCS, which may contribute to its increased aggressiveness. These findings support ongoing efforts to target these pathways in chondrosarcoma.
利益披露 Disclosure
L. Li, None..
W. Tao, None..
R. L. Walker, None..
M. Kc, None..
D. Gundala, None..
J. E. Eid, None..
Z. Duan, None..
J. C. Trent, None.