RSPO fusion transcripts in colorectal cancer in Japanese population

Abstract

R-spondin (RSPO) gene fusions have recently been discovered in a subset of human colorectal cancer (CRC) in the U.S. population; however, whether the fusion is recurrent in CRC arising in patients from the other demographic areas and whether it is specific for CRC remain uncertain. In this study, we examined 75 primary CRCs and 121 primary lung cancers in the Japanese population for EIF3E-RSPO2 and PTPRK-RSPO3 fusion transcripts using RT-PCR and subsequent sequencing analyses. Although the expression of EIF3E-RSPO2 and PTPRK-RSPO3 was not detected in any of the lung carcinomas, RSPO fusions were detected in three (4%) of the 75 CRCs. Two CRCs contained EIF3E-RSPO2 fusion transcripts, and another CRC contained PTPRK-RSPO3 fusion transcripts. Interestingly, in one of the two EIF3E-RSPO2 fusion-positive CRCs, a novel fusion variant form of EIF3E-RSPO2 was identified: exon 1 of EIF3E was connected to exon 2 of RSPO2 by a 351-bp insertion. A quantitative RT-PCR analysis revealed that RSPO mRNA expression was upregulated in the three CRCs containing RSPO fusion transcripts, while it was downregulated in nearly all of the other CRCs. An immunohistochemical analysis and a mutational analysis revealed that the RSPO fusion-containing CRC had a CDX2 cell lineage, was positive for mismatch repair protein expression, and had the wild-type APC allele. Finally, the forced expression of RSPO fusion proteins were shown to endow colorectal cells with an increased growth ability. These results suggest that the expression of RSPO fusion transcripts is related to a subset of CRCs arising in the Japanese population.

RSPO2 gene rearrangement: a powerful driver of β-catenin activation in liver tumours

“…Here, we identified a recurrent RSPO2 gene rearrangement due to a 46.4 kb microdeletion on chromosome 8q23.1 as the most prevalent cause of activated β-catenin signalling in HCA with wild-type CTNNB1 gene as demonstrated by targeted ultra-deep sequencing and independent validation using AMP-based NGS translocation detection. An identical microdeletion was previously described in colorectal cancer 34. Here, it was demonstrated that upstream of RSPO2 , a 351 bp SINE was fused to exon 1 of the eukaryotic translation initiation factor 3 subunit E ( EIF3E ) gene.…”

R-spondin 2 promotes proliferation and migration via the Wnt/β-catenin pathway in human hepatocellular carcinoma

“…However, the association between RSPO and cancer has not been extensively studied. Studies on the role of RSPO2 in cancer primarily focus on colon tumors (14,15). A recent study reported that high-copy amplifications of RSPO2 gene were observed in 231 HCC cases via whole exome sequencing (25).…”

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

“…1A and Supplementary Table S2), had not been identified by the in vitro functional assay, maybe due to the low sensitivity of the assay. It has been reported that RSPO2 and RSPO3 genes are targets of rearrangements in colon cancer and that resulting fusions increase gene expression (29,31). On the basis of these reports, we performed a PCR-based screen and also mRNAseq analysis.…”

“…Ectopic expression of Rspo2 was shown to increase tumorigenic and invasive properties of mouse breast cell lines (25). Genomic rearrangements and transcriptional activation in human tumors that result in elevated RSPO expression have been identified, suggesting that RSPO may be functionally important for tumor development (29)(30)(31)(32). However, no direct demonstration of a functional role for RSPO in cancer development and maintenance has been reported to date.…”