Comprehensive analysis of R-spondin fusions and RNF43 mutations implicate novel therapeutic options in colorectal cancer.

Seeber, Andreas; Battaglin, Francesca; Zimmer, Kai; Kocher, Florian; Baca, Yasmine; Xiu, Joanne; Spizzo, Gilbert; Novotny-Diermayr, Veronica; Rieder, Dietmar; Puccini, Alberto; Swensen, Jeffrey; Ellis, Michelle; Goldberg, Richard M; Grothey, Axel; Shields, Anthony F; Marshall, John L; Weinberg, Benjamin A; Sackstein, Paul E; Hon Lim, Kiat; San Tan, Gek; ... (2022). Comprehensive analysis of R-spondin fusions and RNF43 mutations implicate novel therapeutic options in colorectal cancer. Clinical cancer research, 28(9), pp. 1863-1870. American Association for Cancer Research 10.1158/1078-0432.CCR-21-3018

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PURPOSE

Gene fusions involving R-spondin (RSPOfp) and RNF43 mutations have been shown to drive Wnt-dependent tumor initiation in colorectal cancer (CRC). Herein, we aimed to characterize the molecular features of RSPOfp/RNF43 mutated (mut) compared to wildtype CRCs to gain insights into potential rationales for therapeutic strategies.

EXPERIMENTAL DESIGN

A discovery cohort was classified for RSPOfp/RNF43 status using DNA/RNA sequencing and immunohistochemistry. An independent cohort was used to validate our findings.

RESULTS

The discovery cohort consisted of 7,245 CRC samples. RSPOfp and RNF43 mutations were detected in 1.3% (n=94) and 6.1% (n=443) of cases. We found 5 RSPO fusion events that had not previously been reported (e.g. IFNGR1-RSPO3). RNF43-mut tumors were associated with right-sided primary tumors. No RSPOfp tumors had RNF43 mutations. In comparison to wildtype CRCs, RSPOfp tumors were characterized by a higher frequency of BRAF, BMPR1A and SMAD4 mutations. APC mutations were observed in only a minority of RSPOfp-positive compared to wildtype cases (4.4 vs. 81.4%). Regarding RNF43 mutations, a higher rate of KMT2D and BRAF mutations were detectable compared to wildtype samples. While RNF43 mutations were associated with a microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) phenotype (64.3%), and a TMB {greater than or equal to}10 mt/Mb (65.8%), RSPOfp was not associated with MSI-H/dMMR. The validation cohort replicated our genetic findings.

CONCLUSIONS

This is the largest series of RSPOfp/RNF43-mut CRCs reported to date. Comprehensive molecular analyses asserted the unique molecular landscape associated with RSPO/RNF43 and suggested potential alternative strategies to overcome the low clinical impact of Wnt-targeted agents and immunotherapy.

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