PO.CL07.01 · 临床研究
全面基因组分析推动精准肿瘤学发展并扩大乌兹别克人群对靶向治疗的可及性
Comprehensive genomic profiling drives precision oncology and expands accessibility to targeted therapies in Uzbek populations
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：目前67%的死亡率与发病率比值表明，乌兹别克斯坦大多数癌症在晚期才被发现。此外，症状往往只有在肿瘤较大或已发生转移时才出现，而晚期癌症治疗费用高昂、难度大且常常致命。精密的基础设施需要大量资金、训练有素的专业人员以及昂贵的筛查程序。在若干情况下，治疗方案的实施甚至缺乏关于肿瘤敏感性和疗效的信息。最终，患者因多次检测和治疗而遭受严重毒性。为应对这些问题，个体化分子检测和治疗监测方法十分必要。本研究展示了全面基因组分析（CGP）在补充乌兹别克斯坦癌症患者分子谱方面的效能。这可能以非侵入性的规模开辟多种治疗和监测可能性。
方法：对124例经我们的CGP检测进行基因组分析的患者进行回顾性研究，考察其突变谱。所有患者均为乌兹别克族，年龄介于25至85岁之间。采用下一代测序（NGS）技术，使用OncoIndx®检测组合对这些患者进行CGP。
结果：在124例进行基因组分析的患者中，共检测到331个致病性/可能致病性变异，其中TP53占所有变异的20.2%（67个）。鉴定出若干移码和截短型TP53变异，提示TP53蛋白功能受损，从而可能导致致癌应激、DNA损伤及多条主要通路功能障碍。此外，PIK3CA、APC、KRAS、EGFR、PTEN和BRCA1/2变异在该患者队列中也以较高频率出现，分别为8.5%（28个）、6.3%（21个）、6%（20个）、4.5%（15个）、2.7%（9个）和1.8%（6个）。这些变异合起来可能提示细胞增殖和DNA修复通路存在重大损伤。错配修复（MMR）基因，包括MSH6、MSH3、MLH1、PMS2、MUTYH和MSH2，也被发现发生突变，频率分别为1.2%（4个）、0.9%（3个）、0.9%（3个）、0.3%（1个）、0.3%（1个）和0.3%（1个），显示MMR通路受损。队列中3例结肠癌和肺癌患者表现出高微卫星不稳定性（MSI），同时基因组结果显示细胞增殖、MMR和DNA修复通路存在损伤。
结论：总之，本研究凸显了我们的CGP检测在识别跨多条通路的多样致癌驱动因素方面的益处，并且在乌兹别克族研究人群中，它在扩大靶向治疗机会以应对关键通路损伤方面增添了价值。
查看英文原文 English abstract
Background: The current, mortality-to-incidence ratio of 67% indicates most cancers are detected at advanced stages in Uzbekistan. In addition, symptoms appear only when the cancer is large or metastatic and advanced cancer is expensive, difficult to treat, and often fatal. Sophisticated infrastructure requires large funding, trained professional and expensive screening procedures. In several instances, treatment regimen is also administered without information on tumor sensitivity and efficacy. Eventually, patients suffer severe toxicity from multiple tests and treatments. To address these events, personalized molecular tests and treatment monitoring approaches are necessary. This study shows the efficacy of comprehensive genomic profiling (CGP) to append the molecular spectrum of cancer patients from Uzbekistan. This may open several treatment and monitoring possibilities in non-invasive scale.
Methods: A total of 124 genomically profiled patients by our CGP assay were retrospectively investigated for mutational spectrum. All patients belonged to Uzbek ethnicity with ages between 25 to 85 years. CGP was performed on these patients using next-generation sequencing (NGS) with the OncoIndx® panel.
Results: Of the 124 patients profiled genomically, 331 pathogenic/likely pathogenic variants were detected with TP53 constituting 20.2% (67) of all variants. Several frameshift and truncated TP53 variants were identified suggesting an impairment of TP53 protein thereby potentially leading to oncogenic stress, DNA damage, and several major pathway malfunctioning. Further, variants in PIK3CA, APC, KRAS, EGFR, PTEN , and BRCA1/2 were also present with high frequencies in the patient cohort at 8.5% (28), 6.3% (21), 6% (20), 4.5% (15), 2.7% (9), and 1.8% (6) respectively. Together, these variants may suggest major impairments in cell proliferation, and DNA repair pathways. Mismatch Repair (MMR) genes including MSH6, MSH3, MLH1, PMS2, MUTYH , and MSH2 were also found to be mutated at frequencies of 1.2% (4), 0.9% (3), 0.9% (3), 0.3% (1), 0.3% (1), and 0.3% (1) respectively showing damages in MMR pathway. Three patients in the cohort with colon and lung cancers exhibited high microsatellite instability (MSI) whilst genomic findings showed impairments in cell proliferation, MMR, and DNA repair pathways.
Conclusion: To conclude, this study highlights the benefit of our CGP assay in identifying diverse oncogenic drivers across multiple pathways and in the study population of the Uzbek ethnicity, it added value in expanding targeted therapeutic opportunities to manage critical pathway impairments.
利益披露 Disclosure
Z. Olimova, None..
G. Shafi, None..
D. Farrukh, None..
Y. Bhattacharya, None..
M. Basavalingegowda, None..
K. Hariramani, None.