SCG3 and YAP1 define molecular subtypes of small cell carcinoma of the cervix with divergent multi-omics features and prognostic outcomes
7 affiliations
- 1Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- 2Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei China
- 3University of Chinese Academy of Sciences, Beijing, China
- 4Department of Gynecologic Oncology, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang China
- 5Desert Research Centre, Cairo, Egypt
- 6Department of Obstetrics and Gynecology, Peking University People’s Hospital, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044 China
- 7City University of Hongkong, Hongkong, China
Abstract
Background: 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.
Purpose: 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.
Methods: 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.
Results: NMF revealed two robust molecular subtypes distinguished by reciprocal expression of SCG3 and YAP1. The SCG3High/YAP1Low 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 SCG3Low/YAP1High 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.
Conclusion: 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.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08723-9.
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BibTeX
@article{fan2026scg3,
title = {{SCG3 and YAP1 define molecular subtypes of small cell carcinoma of the cervix with divergent multi-omics features and prognostic outcomes}},
author = {Xinran Fan and Yao Jia and Xiangqin Li and Mengjia Huang and Changzheng Wang and Silu Meng and Ahmed H. Ghonaim and Bing Xiao and Junlan Li and Hongqi Dai and Ruoqi Ning and Haiying Sun and Shuaicheng Li and Ding Ma and Shuang Li},
journal = {Journal of Translational Medicine},
year = {2026},
month = aug,
doi = {10.1186/s12967-026-08723-9},
url = {https://doi.org/10.1186/s12967-026-08723-9},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - SCG3 and YAP1 define molecular subtypes of small cell carcinoma of the cervix with divergent multi-omics features and prognostic outcomes
AU - Xinran Fan
AU - Yao Jia
AU - Xiangqin Li
AU - Mengjia Huang
AU - Changzheng Wang
AU - Silu Meng
AU - Ahmed H. Ghonaim
AU - Bing Xiao
AU - Junlan Li
AU - Hongqi Dai
AU - Ruoqi Ning
AU - Haiying Sun
AU - Shuaicheng Li
AU - Ding Ma
AU - Shuang Li
PY - 2026
DA - 2026/08/05
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-08723-9
UR - https://doi.org/10.1186/s12967-026-08723-9
AB - Background: 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. Purpose: 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. Methods: 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. Results: NMF revealed two robust molecular subtypes distinguished by reciprocal expression of SCG3 and YAP1. The SCG3High/YAP1Low 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 SCG3Low/YAP1High 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. Conclusion: 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. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12967-026-08723-9.
SN - 1479-5876
ER -