SCG3 and YAP1 define molecular subtypes of small cell carcinoma of the cervix with divergent multi-omics features and prognostic outcomes

Small cell carcinoma of the cervix (SCCC) is a rare and highly aggressive neuroendocrine malignancy with poor prognosis and limited therapeutic options. Its clinical management is hampered by a poor understanding of the molecular mechanisms underlying its heterogeneity. This study aimed to define the molecular subtypes of SCCC and delineate their distinct genomic, immune and clinical characteristics through an integrated multi-omics analysis. RNA-sequencing data from 19 SCCC tumors were subjected to non-negative matrix factorization (NMF) to identify molecular subtypes. Pathway activation and drug sensitivity profiles were inferred using bioinformatics analyses. Whole-genome sequencing, viral capture sequencing, and OncoScan SNP array profiling were used to uncover subtype-specific genomic alterations. Immunohistochemistry on formalin-fixed paraffin-embedded tissues validated key markers and characterized subgroup-related biology. Survival analyses were performed to assess prognostic relevance. NMF revealed two robust molecular subtypes distinguished by reciprocal expression of SCG3 and YAP1 . The SCG3 High / YAP1 Low subtype exhibited pronounced neuroendocrine differentiation, an immune-desert microenvironment with scarce CD8 + T-cell infiltration, preferential HPV18 integration at chromosome 8q24.21 leading to MYC amplification, and inferior survival outcomes. In contrast, the SCG3 Low / YAP1 High subtype showed attenuated neuroendocrine features, enrichment of immune-related pathways, higher CD8 + T cell density, and absence of the preferential HPV18 integration pattern. Cross-cancer analyses revealed a conserved neuroendocrine–immune polarization between SCCC and small cell lung cancer (SCLC), suggesting shared subtype-specific therapeutic vulnerabilities. SCCC can be molecularly classified into two distinct subtypes defined by opposing SCG3 and YAP1 expression patterns, each characterized by unique genomic, immunologic, and clinical profiles. This molecular framework provides a basis for subtype-guided precision oncology in SCCC.