Heidelberg Center for Personalized Oncology, DKFZ-HIPO, DKFZ, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
Division of Applied Bioinformatics, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), 69120 Heidelberg, Germany.
Nat Commun. 2018 Nov 14;9(1):4782. doi: 10.1038/s41467-018-07041-z.
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.
对转移过程的不完全理解阻碍了个体化治疗。在这里，我们报告了对结直肠转移瘤与匹配的原发性肿瘤进行的最全面的全基因组研究。65%的体细胞突变源自一个共同的祖细胞，其中 15%是肿瘤特异性的，19%是转移特异性的，这意味着转移瘤中的突变率更高。肿瘤特异性和转移特异性突变具有更高水平的 BRCAness。我们通过新的成分 ARHGEF7/ARHGEF33 证实了多步进展。经常发生突变的非编码元件包括 ncRNAs RP11-594N15.3、AC010091、SNHG14、FOXP2、DACH2、TRPM3、XKR4、ANO5、CBL、CBLB 的 3' UTR，后四个可能是转移和吞噬作用/PD-L1 介导的免疫抑制的双重主角。可操作的转移特异性病变包括 FAT1、FGF1、BRCA2、KDR 和 AKT2、AKT3 和 PDGFRA 的 3' UTR。转移特异性突变在 PI3K-Akt 信号转导、细胞黏附、细胞外基质和肝星状细胞激活基因中富集，提示存在针对特定部位定植的遗传程序。我们的研究结果提出了关于肿瘤和转移进化的假说，并为个性化治疗提供了转移特异性事件的证据。
