Validation of SNHG11 as a prognostic and predictive biomarker for anti-EGFR benefit in colorectal cancer using real-world data.

Abstract

3138 Background: Long non-coding RNAs (lncRNAs) regulate colorectal cancer (CRC) initiation, progression, and therapeutic response through interactions with oncogenic and microenvironmental pathways. SNHG11 has been implicated in CRC through epigenetic and c-Myc–driven transcriptional programs. In CALGB/SWOG 80405, higher tumor SNHG11 expression correlated with improved outcomes, particularly anti-EGFR therapy (Bartolini 2025, ASCO 43; 16_suppl). We comprehensively evaluated molecular correlates with SNHG11 and validated the prognostic and predictive value in an independent real-world CRC cohort. Methods: In total, 15,456 CRC underwent DNA (592-gene or whole exome) and RNA (whole transcriptome) sequencing at Caris Life Sciences. Tumors were stratified by SNHG11 expression quartiles, comparing low (Q1) vs high (Q4). CMS classification was assessed using RNAseq. Associations were assessed using X 2 /Fisher’s exact with p-values adjusted for multiple comparisons (q<0.05). Clinical outcome was obtained from insurance claims. Overall survival (OS) was calculated from tissue collection to last contact and time-on-treatment (ToT) from treatment start to end. Cox proportional hazards model generated hazard ratio (HR) and log-rank p-values. Results: SNHG11 Q1 tumors were associated with higher right-sided prevalence (28% vs 18%, p<0.001), lower left-sided prevalence (50% vs 62%, p<0.001), and older age than Q4 (64 vs 62, p<0.001). Consistent with the findings in CALGB/SWOG 80405, Q4 were associated with CMS2 (53% vs 19%, p<0.001) while Q1 with CMS4 (49% vs 21%, p<0.001). Q1 tumors showed increased MSI-H/dMMR, TMB-H and PD-L1 expression (10% vs 3%, 15% vs 5% and 5% vs 2%, respectively, all p<0.001). TP53 and APC mutations were enriched in Q4 vs Q1 (84% vs 69% and 85% vs 72%, p<0.001) whereas KRAS (49% vs 41%), BRAF (13% vs 7%), ARID1A (12% vs 8%), RNF43 (6% vs 2%) and CTNNB1 (3% vs 2%) mutations were higher in Q1 vs Q4 (p<0.001). Q4 was associated with longer OS vs Q1 (mOS 30.8 vs 27.8 months; HR 0.93; 95% CI 0.89–0.97, p<0.001). After adjusting for MSI status, tumor sidedness, age, race, and anti-EGFR therapy, Q4 remained a significant independent predictor of improved OS compared to Q1 (adjusted HR=0.93; 95% CI: 0.89-0.96; p<0.001). Q4 was significantly associated with longer ToT in patients receiving anti-EGFR therapy vs Q1 (7.4 vs 5.8 months, HR 0.86; 95% CI 0.79–0.93, p<0.001) with no association observed with bevacizumab ToT. Conclusions: In this large independent real-world cohort, we provided additional molecular insight into a key lncRNA SNHG11 in CRC. Consistent with previous findings in a large randomized controlled trial, we confirm that elevated SNHG11 expression was associated with CMS2, left-sided tumors, longer OS and longer TOT of anti-EGFR therapy, supporting SNHG11 as a promising prognostic biomarker and a candidate predictive biomarker for anti-EGFR benefit in CRC.