Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer.
Whole genome sequencing puts forward hypotheses on metastasis evolution and therapy in colorectal cancer.
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DOI：
10.1038/s41467-018-07041-z
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发表时间：
2018-11-14
影响因子：
16.6
通讯作者：
Allgayer H
中科院分区：
文献类型：
--
作者：
Ishaque N;Abba ML;Hauser C;Patil N;Paramasivam N;Huebschmann D;Leupold JH;Balasubramanian GP;Kleinheinz K;Toprak UH;Hutter B;Benner A;Shavinskaya A;Zhou C;Gu Z;Kerssemakers J;Marx A;Moniuszko M;Kozlowski M;Reszec J;Niklinski J;Eils J;Schlesner M;Eils R;Brors B;Allgayer H
对转移过程的不完全理解阻碍了个性化治疗。在这里，我们报告了最全面的全基因组研究结直肠转移与匹配的原发性肿瘤。65%的体细胞突变起源于共同的祖先，15%是肿瘤特异性的，19%是转移特异性的，这意味着转移中的突变率更高。肿瘤和转移特异性突变携带BRCAness水平升高。我们证实了新组分ARHGEF 7/ARHGEF 33的多阶段进展。反复突变的非编码元件包括ncRNA RP 11 - 594 N15.3、AC 010091、SNHG 14、FOXP 2的3'UTR、DACH 2、TRPM 3、XKR 4、ANO 5、CBL、CBLB，后四种潜在的转移和巨噬细胞增多症-/PD-L1介导的免疫抑制中的双重主角。可操作的转移特异性病变包括FAT 1、FGF 1、BRCA 2、KDR和AKT 2-、AKT 3-和PDGFRA-3'UTR。转移特异性突变在PI 3 K-Akt信号传导、细胞粘附、ECM和肝星状细胞活化基因中富集，表明位点特异性定殖的遗传程序。我们的研究结果提出了关于肿瘤和转移演变的假设，以及与个性化治疗相关的转移特异性事件的证据。转移性病变的演变和遗传性质尚未完全确定。在本文中，作者对结直肠转移瘤与匹配的原发性肿瘤进行了全面的全基因组研究，并定义了一个多阶段进展模型和转移特异性变化，这些变化在一定程度上是治疗上可行的。
Incomplete understanding of the metastatic process hinders personalized therapy. Here we report the most comprehensive whole-genome study of colorectal metastases vs. matched primary tumors. 65% of somatic mutations originate from a common progenitor, with 15% being tumor- and 19% metastasis-specific, implicating a higher mutation rate in metastases. Tumor- and metastasis-specific mutations harbor elevated levels of BRCAness. We confirm multistage progression with new components ARHGEF7/ARHGEF33. Recurrently mutated non-coding elements include ncRNAs RP11-594N15.3, AC010091, SNHG14, 3’ UTRs of FOXP2, DACH2, TRPM3, XKR4, ANO5, CBL, CBLB, the latter four potentially dual protagonists in metastasis and efferocytosis-/PD-L1 mediated immunosuppression. Actionable metastasis-specific lesions include FAT1, FGF1, BRCA2, KDR, and AKT2-, AKT3-, and PDGFRA-3’ UTRs. Metastasis specific mutations are enriched in PI3K-Akt signaling, cell adhesion, ECM and hepatic stellate activation genes, suggesting genetic programs for site-specific colonization. Our results put forward hypotheses on tumor and metastasis evolution, and evidence for metastasis-specific events relevant for personalized therapy. The evolution and genetic nature of metastatic lesions is not completely characterized. Here the authors perform a comprehensive whole-genome study of colorectal metastases in comparison to matched primary tumors and define a multistage progression model and metastasis-specific changes that, in part, are therapeutically actionable.
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影响因子：
12.3
作者：
Brannon AR;Vakiani E;Sylvester BE;Scott SN;McDermott G;Shah RH;Kania K;Viale A;Oschwald DM;Vacic V;Emde AK;Cercek A;Yaeger R;Kemeny NE;Saltz LB;Shia J;D'Angelica MI;Weiser MR;Solit DB;Berger MF
通讯作者：
Berger MF
影响因子：
78.5
作者：
Klein, Christoph A.
通讯作者：
Klein, Christoph A.
影响因子：
5.2
作者：
Cascio S;Finn OJ
通讯作者：
Finn OJ
影响因子：
11.2
作者：
Gavert, Nancy;Shvab, Anna;Ben-Ze'ev, Avri
通讯作者：
Ben-Ze'ev, Avri
DOI：
10.1002/cyto.1131
发表时间：
2001-08-15
期刊：
CYTOMETRY
影响因子：
--
作者：
Balázs, M;Adám, Z;Adány, R
通讯作者：
Adány, R