Integrated DNA and RNA sequencing reveals early drivers involved in metastasis of gastric cancer.
Integrated DNA and RNA sequencing reveals early drivers involved in metastasis of gastric cancer.
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整合 DNA 和 RNA 测序揭示了胃癌转移的早期驱动因素
DOI：
10.1038/s41419-022-04838-1
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发表时间：
2022-04-21
影响因子：
9
通讯作者：
Guo, Weijian
中科院分区：
文献类型：
--
作者：
Zhang, Jieyun;Liu, Fatao;Yang, Yanan;Yu, Nuoya;Weng, Xiaoling;Yang, Yue;Gong, Zhe;Huang, Shenglin;Gan, Lu;Sun, Sijie;Zhang, Xiaowei;Gong, Yiwei;Liu, Yun;Guo, Weijian
胃癌（GC）是第二大恶性肿瘤死亡原因，转移是胃癌死亡的重要原因。考虑到寻找转移性驱动突变的困难，我们在这里尝试了一种新的策略。我们对GC进行了综合基因组分析，并确定了导致转移的早期驱动因素。对432例中国胃癌患者的肿瘤组织及相应的正常组织进行了全外显子组测序（WES）、转录组测序和靶向外显子组测序（TES），特别是对有T1期及淋巴结转移的高转移潜能组（HMP）和无淋巴结及远处转移的低转移潜能组（LMP）进行了比较分析。与LMP组相比，HMP组的突变负荷和异质性更高，免疫抑制信号更丰富，免疫细胞浸润更多。构建了基于差异表达基因的整合mRNA-lncRNA标签，其预后价值优于传统的TNM分期。我们通过WES鉴定了176个候选的促转移突变，并选择了8个基因用于后续TES。突变的TP 53和MADCAM 1与低无转移生存率显著相关。我们进一步证明了突变的MADCAM 1不仅可以直接促进癌细胞迁移，还可以通过建立免疫抑制微环境来触发肿瘤转移，包括通过Akt/mTOR轴调节CCL 2来促进PD-L1介导的免疫逃逸和重编程肿瘤相关巨噬细胞。总之，具有不同转移潜力的GC在遗传水平上是可区分的，并且我们揭示了许多潜在的转移驱动突变。早发转移性胃癌中的驱动突变可通过建立免疫抑制微环境促进转移。本研究为胃癌的靶向治疗提供了可能。
Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy here. We conducted an integrative genomic analysis on GC and identified early drivers lead to metastasis. Whole-exome sequencing (WES), transcriptomes sequencing and targeted-exome sequencing (TES) were performed on tumors and matched normal tissues from 432 Chinese GC patients, especially the comparative analysis between higher metastatic-potential (HMP) group with T1 stage and lymph-node metastasis, and lower metastatic-potential (LMP) group without lymph-nodes or distant metastasis. HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, more immune cell infiltration than LMP group. An integrated mRNA-lncRNA signature based on differentially expressed genes was constructed and its prognostic value was better than traditional TNM stage. We identified 176 candidate prometastatic mutations by WES and selected 8 genes for following TES. Mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. We further demonstrated that mutated MADCAM1 could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages by regulating CCL2 through Akt/mTOR axis. In conclusion, GCs with different metastatic-potential are distinguishable at the genetic level and we revealed a number of potential metastatic driver mutations. Driver mutations in early-onset metastatic GC could promote metastasis by establishing an immunosuppressive microenvironment. This study provided possibility for future target therapy of GC.
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染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
28.5
作者：
Ni SJ;Zhao LQ;Wang XF;Wu ZH;Hua RX;Wan CH;Zhang JY;Zhang XW;Huang MZ;Gan L;Sun HL;Dimri GP;Guo WJ
通讯作者：
Guo WJ
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
DOI：
10.1073/pnas.1618215113
发表时间：
2016-12-20
影响因子：
11.1
作者：
Gao, ChongFeng;Su, Yanli;Woude, George F. Vande
通讯作者：
Woude, George F. Vande
影响因子：
64.8
作者：
Berger, Michael F.;Hodis, Eran;Heffernan, Timothy P.;Deribe, Yonathan Lissanu;Lawrence, Michael S.;Protopopov, Alexei;Ivanova, Elena;Watson, Ian R.;Nickerson, Elizabeth;Ghosh, Papia;Zhang, Hailei;Zeid, Rhamy;Ren, Xiaojia;Cibulskis, Kristian;Sivachenko, Andrey Y.;Wagle, Nikhil;Sucker, Antje;Sougnez, Carrie;Onofrio, Robert;Ambrogio, Lauren;Auclair, Daniel;Fennell, Timothy;Carter, Scott L.;Drier, Yotam;Stojanov, Petar;Singer, Meredith A.;Voet, Douglas;Jing, Rui;Saksena, Gordon;Barretina, Jordi;Ramos, Alex H.;Pugh, Trevor J.;Stransky, Nicolas;Parkin, Melissa;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Wargo, Jennifer;Schadendorf, Dirk;Meyerson, Matthew;Gabriel, Stacey B.;Golub, Todd R.;Wagner, Stephan N.;Lander, Eric S.;Getz, Gad;Chin, Lynda;Garraway, Levi A.
通讯作者：
Garraway, Levi A.