最新测序研究发现，4-10%结直肠癌具有Rspo2或Rspo3融合突变。机制研究认为该融合激活Wnt通路，并驱动依赖于该通路的肿瘤增殖。申请人采用Nanostring法在24例已知基因型人源性肿瘤移植瘤（PDX）中证实了该方法的可靠性；并在结直肠癌肝转移临床标本发现25%（7/28）出现融合，显著高于文献报道水平；药效研究发现Wnt抑制剂显著抑制具有该融合的PDX。因此，该融合突变可能与结直肠癌发生、转移相关，并可能是Wnt抑制剂的疗效预测标志。本研究拟采用Nanostring方法检测200例结直肠癌（肝转移/无肝转移）的RSPO2/3融合突变，明确中国人群发生该融合的频率、新的融合方式及与结肠癌肝转移的相关性。明确该融合突变能否导致NIH/3T3细胞发生恶性转化及其机制；研究该融合突变对结直肠癌发生、转移和耐药的影响及其分子机制；并扩大PDX样本明确其作为Wnt抑制剂疗效预测标志的可能。

Latest cancer genome study finds that 4-10% of colorectal cancer patients have fusion mutation of Rspo2 or Rspo3, which is known to activate Wnt signaling pathway and promote proliferation of CRC cells. We performed nanostring assay to screen Rspo2 and Rspo3 fusion in 24 CRC PDXs, of which 16 were known having such fusions. The reliability of the assay were verified by the results. Then 7 out of 28 samples of CRCLM were found Rspo2/Rspo3 fusions by nanostring assay, which was far more frequent than it was reported in common CRC population. Furthermore, we found Wnt inhibitor CGX1231 could strongly inhibit the tumor growth in two PDXs with Rspo2/Rspo3 fusion mutations. Therefore, We raise the hypothesis that Rspo2/Rspo3 fusion mutations could drive the tumorigenesis and liver metastasis of CRC, and could be a potential predict biomarker for Wnt inhibitor. In this study, we intend to test Rspo2 and Rspo3 fusion mutations in 200 colorectal cancer samples by nanostring assay and find its prevalence in Chinese population as well as its relation with the colorectal cancer liver metastasis.Secondly we will investigate whether RSPO2 and RSPO3 fusion mutations can cause the malignant transformation of NIH/3T3 cells. The effect of RSPO2 and RSPO3 fusion mutation on the tumorigenesis and metastasis of colorectal cancer and its mechanism will be investigated, as well as its relationship with drug resistance. Finally, the possibility of RSPO2 and RSPO3 fusion mutations as predict biomarkers for Wnt inhibitor and its mechanism will be further verified in more PDXs.