Genomic and epigenomic evolution of acquired resistance to combination therapy in esophageal squamous cell carcinoma.
Genomic and epigenomic evolution of acquired resistance to combination therapy in esophageal squamous cell carcinoma.
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DOI：
10.1172/jci.insight.150203
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发表时间：
2021-09-08
期刊：
影响因子：
8
通讯作者：
Zhan Q
中科院分区：
文献类型：
--
作者：
Min Q;Wang Y;Wu Q;Li X;Teng H;Fan J;Cao Y;Fan P;Zhan Q
靶向动脉灌注维拉帕米联合化疗（TVCC）是食管鳞状细胞癌（ESCC）有效的临床介入治疗，但多药耐药（MDR）仍然是复发或不良预后的主要原因，且MDR的潜在分子机制、时间瘤内异质性和耐药的克隆进化过程尚未确定。为了阐明治疗过程中遗传和表观遗传改变在获得性耐药进化中的作用，我们对 3 组（完全缓解、部分缓解和疾病进展）的每个治疗干预周期的 7 名食管鳞癌患者的 16 份连续标本进行了全外显子组测序，并对这 7 名患者中的 3 名（每组 1 名患者）进行了全基因组亚硫酸氢盐测序。患有进行性疾病的患者表现出显着更高的基因组和表观基因组时间异质性。在联合治疗期间观察到由有益的新突变驱动的亚克隆扩增，这解释了耐多药的出现。值得注意的是，SLC7A8 被鉴定为潜在的新型 MDR 基因，功能分析表明突变型 SLC7A8 促进 ESCC 细胞系的耐药表型。治疗期间启动子甲基化动态揭示了 8 个耐药蛋白编码基因，其特征是启动子区域甲基化程度低。有趣的是，SLC8A3 和突变体 SLC7A8 的启动子低甲基化在相同的途径、蛋白质消化和吸收中富集，表明治疗过程中存在潜在的新型 MDR 机制。我们的综合多组学研究揭示了时间遗传和表观遗传肿瘤间和肿瘤内异质性、克隆进化过程和表观基因组变化的动态，为联合治疗期间食管鳞癌难治性患者提供了潜在的 MDR 治疗靶点。国家自然科学基金、北京大学肿瘤医院科学基金、中国医学科学院医学科学创新基金、深圳湾实验室重大项目、广东省基础与应用基础研究基金、北京市医学研究院第三轮公益性发展改革试点项目等。
Targeted arterial infusion of verapamil combined with chemotherapy (TVCC) is an effective clinical interventional therapy for esophageal squamous cell carcinoma (ESCC), but multidrug resistance (MDR) remains the major cause of relapse or poor prognosis, and the underlying molecular mechanisms of MDR, temporal intratumoral heterogeneity, and clonal evolutionary processes of resistance have not been determined. To elucidate the roles of genetic and epigenetic alterations in the evolution of acquired resistance during therapies, we performed whole-exome sequencing on 16 serial specimens from 7 patients with ESCC at every cycle of therapeutic intervention from 3 groups, complete response, partial response, and progressive disease, and we performed whole-genome bisulfite sequencing for 3 of these 7 patients, 1 patient from each group. Patients with progressive disease exhibited a substantially higher genomic and epigenomic temporal heterogeneity. Subclonal expansions driven by the beneficial new mutations were observed during combined therapies, which explained the emergence of MDR. Notably, SLC7A8 was identified as a potentially novel MDR gene, and functional assays demonstrated that mutant SLC7A8 promoted the resistance phenotypes of ESCC cell lines. Promoter methylation dynamics during treatments revealed 8 drug resistance protein-coding genes characterized by hypomethylation in promoter regions. Intriguingly, promoter hypomethylation of SLC8A3 and mutant SLC7A8 were enriched in an identical pathway, protein digestion and absorption, indicating a potentially novel MDR mechanism during treatments. Our integrated multiomics investigations revealed the dynamics of temporal genetic and epigenetic inter- and intratumoral heterogeneity, clonal evolutionary processes, and epigenomic changes, providing potential MDR therapeutic targets in treatment-resistant patients with ESCC during combined therapies. National Natural Science Foundation of China, Science Foundation of Peking University Cancer Hospital, CAMS Innovation Fund for Medical Sciences, Major Program of Shenzhen Bay Laboratory, Guangdong Basic and Applied Basic Research Foundation, and the third round of public welfare development and reform pilot projects of Beijing Municipal Medical Research Institutes.
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DOI：
10.1073/pnas.090013497
发表时间：
2000-05-09
影响因子：
11.1
作者：
Gisselsson, D;Pettersson, L;Mandahl, N
通讯作者：
Mandahl, N
影响因子：
12.3
作者：
Blokzijl F;Janssen R;van Boxtel R;Cuppen E
通讯作者：
Cuppen E
食管鳞状细胞癌的空间瘤内异质性和时间克隆进化
影响因子：
30.8
作者：
Hao, Jia-Jie;Lin, De-Chen;Dinh, Huy Q.;Mayakonda, Anand;Jiang, Yan-Yi;Chang, Chen;Jiang, Ye;Lu, Chen-Chen;Shi, Zhi-Zhou;Xu, Xin;Zhang, Yu;Cai, Yan;Wang, Jin-Wu;Zhan, Qi-Min;Wei, Wen-Qiang;Berrnan, Benjamin P.;Wang, Ming-Rong;Koeffler, H. Phillip
通讯作者：
Koeffler, H. Phillip
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
DOI：
10.1093/bioinformatics/btr670
发表时间：
2012-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Boeva V;Popova T;Bleakley K;Chiche P;Cappo J;Schleiermacher G;Janoueix-Lerosey I;Delattre O;Barillot E
通讯作者：
Barillot E