05/26/2023

Characterizing the Landscape of RING-Type E3 Ubiquitin Transferase-Altered (RNF43 Alt) Colorectal Cancer (CRC) and Defining Unique Subsets With Potential Therapeutic Vulnerabilities in Microsatellite Instability-High (MSI-H) CRC

ASCO 2023 PRESENTATION
Authors Abdul Rafeh Naqash, Amin Nassar, Lisa Macera, Elizabeth Mauer, Justin Guinney, Calvin Y. Chao, Elio Adib, Emanuel Petricoin, Arjun Mittra, Naoko Takebe, Timothy Lewis Cannon

Background:RNF43 is a tumor suppressor gene that represses the WNT/β-catenin pathway. Emerging data show that RNF43 alt are commonly present in MSI-H CRC with improved outcomes to immune checkpoint inhibitors (ICI). We evaluated whether genomic and transcriptomic analysis of MSI-H RNF43 alt CRC defines distinct subsets with potential therapeutic vulnerabilities.

Methods:We analyzed CRC tumors (any stage/ subtype) sequenced with Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq). RNF43 alt were defined as pathogenic/likely pathogenic per OncoKB, or copy number aberrations (CNA); deep deletions, or amplifications (>8x). RNF43 alt vs. wildtype (wt) were compared using Chi-squared/Fisher’s Exact tests or Wilcoxon rank-sum tests to evaluate differences in biomarkers. Gene Set Variation Analysis (GSVA) was applied to gene expression data to derive single-sample pathway enrichment scores. ICI-treated MSI-H CRC from the MSKCC cohort (n = 74), publicly available in AACR GENIE v13, was used to assess the overall survival (OS) using the Kaplan-Meier method.

Results:RNF43 alt was identified in 5.2% (635 of 12,243) CRC tumors. CNA accounted for 6% of RNF43 alt CRC. RNF43 alt vs. RNF43 wt CRC was associated with older age (median 69 vs. 59 years, p < 0.001), more prevalent in females (56% vs 43%; p < 0.001). A detailed comparison of RNF43 alt vs. RNF43 wt CRC with p < 0.001 are shown (Table). Of MSI-H CRC (n = 714), 51% were RNF43 alt, with 80% being RNF43 p.GLY659fs. Among MSI-H RNF43 alt CRC, BRAF alt was co-mutated in 59%, with BRAFV600E constituting 99%. Median TMB was higher for MSI-H RNF43 alt vs. MSI-H RNF43 wt (40 vs. 31 mut/MB, p < 0.001). Among MSI-H CRC, GSVA identified significant downregulation of Cetuximab_benefit pathway and upregulation of IGF1R and PI3K/AKT pathways in RNF43 alt vs RNF43 wt. Among ICI-treated MSI-H CRC (n = 74) from the MSKCC cohort, no significant OS difference (HR 0.81 [95%CI: 0.34 – 1.97]; p = 0.65) was noted for RNF43 alt (n = 42) vs. wt (n = 32).

Conclusions:RNF43 alt are common in MSI-H CRC and associated with potentially actionable genomic and transcriptomic signatures. Functional characterization of interplay between the WNT signaling and therapeutically relevant pathways (PI3K/AKT, BRAF, IGF1R, Cetuximab benefit) to better define optimal ICI combination approaches in MSI-H RNF43 alt CRC is ongoing.

RNF43 altered, Total = 635 RNF43 WT, Total = 11608
Sidedness*

Left

Transverse

Right

77/230 (33%)

35/230 (15%)

118/230 (51%)

3474/4381 (79%)

189/4381 (4%)

718/4381 (16%)

TMB Median (mut/MB) 27 3
TMB > 10 MB 375/632 (59%) 441/10740 (4%)
PDL1 positivity (IHC)+ 21/187 (11%) 180/4169 (4%)
MSI-H and/or dMMR 364/633 (58%) 350/11345 (3%)

*Of tumors with known sidedness, +of tumors with internal IHC. Bold denominators reflect non-missing data.

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