Small nucleolar RNAs (snoRNAs) expression and effects on patient (pt) outcomes in metastatic colorectal cancer (mCRC): Data from CALGB (Alliance)/SWOG 80405.

Abstract

3145 Background: SnoRNAs are non-coding RNAs that primarily guide the chemical modification of ribosomal RNA. Emerging evidence suggests snoRNAs play critical roles in cancer, including CRC, by regulating cell proliferation, apoptosis and tumor progression. Aberrant snoRNA expression has been linked to CRC development and poor prognosis, offering potential as diagnostic biomarkers and therapeutic targets. We investigated whether the tumor expression levels of 3 types of snoRNAs (SCARNA, SNORA, SNORD) affect treatment response in pts enrolled in CALGB/SWOG 80405 (NCT00265850). Methods: 433 mCRC pts treated with bevacizumab (bev, n = 226) or cetuximab (cet, n = 207) in combination with first-line chemotherapy were analyzed. RNA was isolated from FFPE tumor samples and sequenced on the HiSeq 2500 (Illumina). 422 snoRNAs were evaluated (23 SCARNA, 140 SNORA, 259 SNORD). Overall survival (OS) and progression-free survival (PFS) were compared across tertiles of gene expression (high [H], medium [M], low [L]) by multivariable Cox proportional hazards models adjusted for age, sex, ECOG performance status, tumor side, number of metastatic sites, KRAS , CMS subtypes, and treatment. Interaction tests for the predictive effect (bev vs cet) were performed. P -values were corrected for multiple testing using the Benjamini-Hochberg approach ( q < 0.05). Results: Only SCARNA21 achieved statistical significance for OS after false discovery rate (FDR) adjustment. Tumors with H levels of SCARNA21 had shorter survival compared to tumors with M or L expression (median OS 24.4 vs 32.4 vs 33.9 months, respectively; P = 0.0015, q = 0.033), independent of treatment. No snoRNAs achieved FDR significance for PFS. However, several snoRNAs showed significant treatment interactions with biologic agents. SCARNA6-H and SCARNA5-H tumors had longer PFS and OS when treated with cet, but shorter PFS and OS when treated with bev, compared to the M and L expression groups (PFS interaction q = 0.0067 and 0.045, respectively; OS interaction q = 0.022 and 0.034, respectively). SCARNA7 also showed significant treatment interaction for OS, favoring cet in the H expression group ( q = 0.018); the opposite was observed for SNORA63B, SNORA63D, SNORA35B, and SNORA36C ( q = 0.027, 0.027, 0.027 and 0.047, respectively). No significant results were observed for any of the tested SNORDs. Conclusions: SnoRNAs dysregulation affects key pathways such as cell cycle control and immune evasion, making them promising players in CRC biology. Our study highlights the prognostic and predictive potential of specific snoRNAs in mCRC. Notably, high SCARNA21 expression was linked to shorter OS, while SCARNA5 and 6 showed predictive value for treatment response, indicating their potential for guiding treatment decisions. Further validation is needed to confirm these findings, and mechanistic studies are warranted.