Clinicogenomic characterization of MUC16 and MUC17 in small cell lung cancer.

Abstract

e20165 Background: Small cell lung cancer (SCLC) is an aggressive malignancy with limited therapies and poor survival. Transmembrane mucins, like MUC16 (CA125) and MUC17, regulate tumor progression, immune evasion, and treatment response. MUC16 mutations are associated with poor prognosis in non–small cell lung cancer but favorable outcomes in gastric cancer, highlighting the need for disease-specific evaluation. The combined role of MUC16 and MUC17 has not been systematically examined. We investigated the clinicogenomic context and prognostic relevance of MUC16 and MUC17 in SCLC. Methods: Clinicogenomic data from four publicly available SCLC cohorts in cBioPortal (n = 239) were analyzed. MUC16 and MUC17 were assessed for mutational patterns, tumor mutational burden (TMB), overall survival (OS), and progression-free survival (PFS). Results: MUC16 was identified in 64 patients (26.8%), MUC17 in 54 (22.5%), and both in 25 (10.5%), ranking seventh and tenth most common mutations. Mutational characteristics of MUC16 and MUC17 are summarized in Table 1. Patients with MUC16/MUC17 had higher rates of TP53 (93.1% vs. 58.5%) and RB1 (66.7% vs. 47.6%) mutations (both p < 0.01) and a significantly higher median TMB (11.2 vs. 3.7 mutations/Mb, p < 0.01) compared with unaltered patients. Median OS was shorter in patients with MUC16 (22.0 vs. 27.0 months; HR 1.18, 95% CI 0.74–1.89), MUC17 (22.0 vs. 27.0 months; HR 1.17, 95% CI 0.64–2.11), or both alterations (23.0 vs. 27.0 months; HR 1.21, 95% CI 0.71–1.65) compared with unaltered group. Median PFS was also shorter in patients with MUC16 (10 vs. 18 months, p = 0.21), MUC17 (7 vs. 10.5 months, p = 0.02), or both alterations (10 vs. 18 months, p = 0.18). Conclusions: MUC16 / MUC17 alterations are relatively common in SCLC and are associated with high TMB and frequent TP53/RB1 co-mutations, warranting further mechanistic investigation. These mutations are predominantly missense and extracellular, consistent with long-gene passenger mutagenesis rather than oncogenic drivers, suggesting a potential role as immunogenic subset biomarkers. Although survival differences were not statistically significance, differences may be noted with comparison to wild type mutations. The association with worse survival trends with elevated TMB prognostic relevance may evolve with increasing immunotherapy use. While mutation and expression are distinct yet correlated, emerging targeted and personalized therapies may hold future relevance. Study limitations include cohort heterogeneity and lack of expression-level data. Prospective studies integrating genomics and treatment response are needed to determine the therapeutic potential of MUC16 / MUC17 in SCLC. Mutational profile of MUC16 and MUC17 . MUC16 MUC17 Mutation Type Missense 180 61 Nonsense 5 4 Frameshift 2 4 Splice 5 0 In Frame 0 0 Fusion 0 0 Mutation Location Extracellular (non-SEA) 178 64 Extracellular (SEA) 14 4 Transmembrane 0 0 Cytoplasmic 0 1