Recurrent R-spondin fusions in colon cancer

By S. Seshagiri, Eric W. Stawiski, S. Durinck, Z. Modrusan, E. Storm, C. Conboy, Subhra Chaudhuri, Y. Guan, V. Janakiraman, B. Jaiswal and 17 more. Nature, 2012

956 citations recorded by the source corpus.

Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.

Subfields: Molecular Biology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/522f8b5178de65f6bec151e33c4985b1b9c42cc3

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In Molecular Biology

1. Hans Clevers
2. Aviv Regev
3. R. Nusse
4. Eric S. Lander
5. W. de Lau
6. W. Peng
7. P. Gros
8. Alexander van Oudenaarden

In Pathology and Forensic Medicine

1. R. Nusse
2. Edward L. Giovannucci
3. Hans Clevers
4. C. Sawyers
5. V. Kuchroo
6. F. Janku

Citations in the corpus

• Wnt/β-catenin signaling in cancers and targeted therapies (2021, background): “In detail, Rspo fusions are regarded as important for tumorigenesis in CRC, by activating Wnt/β-catenin signaling.(119) Rspo2/3 chromosome rearrangements”
• Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974 (2013, background): “In addition, overexpression of Wnt ligands or costimulants, such as R-Spondin 2/3 (RSPO2/3), or silencing of Wnt inhibitor genes has been reported in various cancers (1, 4).”
• Phase 1 study of single-agent WNT974, a first-in-class Porcupine inhibitor, in patients with advanced solid tumours (2021, background): “In addition, RSPO fusions have been reported in ~10% of primary CRC tumour samples.(6) Downstream of the Wnt receptor complex, a number of additional factors are involved in the regulation of signalling.”
• Spatially organized multicellular immune hubs in human colorectal cancer (2021, background): “High expression of RSPO3 drives tumor growth and can arise from PTPRK-RSPO3 fusion events in a small fraction of human CRC (Hilkens et al., 2017; Seshagiri et al., 2012).”
• Lessons from the cancer genome. (2013, neutral): “, 2011) and R-spondin family members in 10% of colon cancers (Seshagiri et al., 2012).”
• Prospective derivation of a Living Organoid Biobank of colorectal cancer patients (2015, background): “Gene fusions involving the Wnt-agonistic RSPO2 and RSPO3 genes have been observed in 5%–10% of CRC (Seshagiri et al., 2012).”
• The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength (2014, positive): “Of interest, gene fusions that affect R-spondin-2 and R-spondin-3 and lead to higher expression levels of functional R-spondin have been reported in a subset of human colon cancers (Seshagiri et al. 2012).”
• Identification of Targetable FGFR Gene Fusions in Diverse Cancers (2013, neutral): “Subsequently, recurrent gene rearrangements have been identified in carcinomas of the lung, breast, colon, and thyroid, among other epithelial tissues (8-12).”
• Integrative clinical genomics of advanced prostate cancer (2015, positive): “Moreover, we also discovered R-spondin fusions involving RSPO2, as previously observed in colorectal carcinoma (Seshagiri et al., 2012) in association with RSPO2 overexpression in these cases (Figure 6C).”