Cervical Squamous Cell Carcinoma (CESC)

Overview

Cervical squamous cell carcinoma (CESC) is a malignant epithelial tumor of the uterine cervix, predominantly driven by high-risk HPV infection. On OncoTree it is a subtype of CERVIX. Other histologic subtypes of cervical cancer include endocervical adenocarcinoma and adenosquamous carcinoma.

Cohorts in the corpus

  • 177 cervical cancer patients (CESC) prospectively sequenced at Memorial Sloan Kettering Cancer Center (Feb 2014 – May 2019) using MSK-IMPACT (341/410/468 genes). Histologic subtypes: squamous cell carcinoma (39%), usual endocervical adenocarcinoma (28%), gastric-type adenocarcinoma (12%), adenosquamous (12%). Dataset: cervix_msk_2023; compared against cesc_tcga_pan_can_atlas_2018. PMID:37643132

Recurrent alterations

  • PIK3CA — most frequent alteration; mutations/amplifications in 25% of cases; enriched in squamous (38%) vs. gastric type (5%). Most common OncoKB level 3B actionable alteration. PMID:37643132
  • ERBB2 — alterations in 12% (4% amplifications, 9% oncogenic mutations); enriched in usual endocervical adenocarcinoma (28%). One patient with D769N mutation had exceptional response to HER kinase inhibitor (>5 years). PMID:37643132
  • KRAS — mutations in 12%; enriched in gastric type (27%) and UEA (20%); includes KRAS G12C hotspot. Significantly enriched vs. TCGA (P=0.019). PMID:37643132
  • TP53 — mutations in 11%; predominant in gastric type (55%). Mutually exclusive with HPV positivity (3.5% of HPV+ vs. 53.8% of HPV-negative gastric-type cases, P=0.00007). PMID:37643132
  • KMT2C — altered in 10%; enriched in squamous (14%). PMID:37643132
  • KMT2D — altered in 9%; enriched in squamous (14%). PMID:37643132
  • STK11 — altered in 14% of gastric type and 33% of adenosquamous carcinoma. PMID:37643132
  • TERT — promoter mutations in 12% of squamous cases. PMID:37643132
  • CDKN2A, SMAD4 — genomic drivers in gastric-type adenocarcinoma resembling pancreatobiliary tumors. PMID:37643132
  • In 16 recurrent/metastatic cervical SCC profiled by MSK-IMPACT (Morris et al.): TP53 mutation frequency 25% (4/16) versus 3% (5/170) in TCGA primary cervix tumors (OR 8.3, P=.008); paralleling the pattern in advanced HPV-positive HNSC where TP53 mutations accumulate with disease progression PMID:27442865.
  • Cervical cancer showed responses to neratinib in the SUMMIT basket trial for HER2-mutant solid tumors, including HER2 S310 (extracellular hotspot) mutants, in contrast to bladder cancer which showed lineage-based resistance despite the same allele PMID:29420467
  • TCGA CESC mutational signatures were compared with vulvar SCC (the first WES landscape of that tumor type); open question remains whether PIK3CA and FAT1 prevalences align across gynecologic SCCs including CESC and vulvar SCC PMID:29422544
  • Pan-cancer fusion study (9,624 TCGA samples) identified FGFR3–TACC3 in 1.7% of CESC samples; CESC was part of the squamous cluster with chr_3p loss and chr_3q gain in the aneuploidy analysis; ERBB2 fusions with HPV-integration proximity were also detected in cervical tumors PMID:29617662
  • Pan-cancer aneuploidy study placed CESC in the squamous arm-level cluster (chr_3p loss + chr_3q gain) alongside HPV+ and HPV− HNSC, ESCC, and LUSC; HPV-positive status stratifies samples within this cluster PMID:29622463

Subtypes

  • Squamous cell carcinoma (39%): enriched for PIK3CA (38%), APOBEC signature (46%), KMT2C/D, TERT promoter mutations. PMID:37643132
  • Usual endocervical adenocarcinoma (UEA, 28%): enriched for ERBB2 (28%), KRAS (20%). PMID:37643132
  • Gastric-type endocervical adenocarcinoma (12%): enriched for KRAS (27%), TP53 (55%), STK11 (14%), SMAD4/CDKN2A; genomic drivers resemble pancreatobiliary tumors. PMID:37643132
  • Adenosquamous carcinoma (12%): enriched for STK11 (33%), PTEN (14%). PMID:37643132
  • TMB-high (>10 mut/Mb): 13% of cases; 3 also MSI-H. PMID:37643132

Therapeutic landscape

  • 37% of cases had at least one actionable alteration (OncoKB level 3B); 17% enrolled on therapeutic clinical trials (10% matched to trial based on MSK-IMPACT). PMID:37643132
  • ERBB2 is a likely important therapeutic target, especially in UEA (28% altered); neratinib showed 25% ORR and 7.0-month median PFS in HER2-mutant cervical cancer. PMID:37643132
  • TMB-H/MSI-H tumors (13%) are eligible for pembrolizumab; 2 exceptional responders to dual checkpoint blockade had TMB-low/MSS but PD-L1-positive, HPV-positive tumors. PMID:37643132
  • KRAS G12C inhibitors (adagrasib, sotorasib) relevant for ~12% of patients with KRAS mutations. PMID:37643132
  • ROBIN METEOR center (U54 CA274318; Washington University) METEOR-CRATR MCT (NCT05975593) has enrolled 26 cervical cancer patients with 65 tumor samples (22 with serial biopsies) and 126 DICOM-RT plans archived. Preliminary findings: CRT consistently induced myeloid-derived-cell infiltration and upregulation of p53/MDM2 in cervix tumor cells without significant upregulation of the PD-L1/PD-1 axis. HPV genotype and gene expression, rather than histology, drove cervical tumor biology; myeloid-derived immunosuppressive pathways are flagged as promising therapeutic targets. PMID:41941260

Sources

  • PMID:37643132 — Assessing the Genomic Landscape of Cervical Cancers: Clinical Opportunities and Therapeutic Targets (Clinical Cancer Research, 2023)
  • PMID:41941260

This page was processed by crosslinker on 2026-05-04.

This page was processed by crosslinker on 2026-05-04. - PMID:27442865 — Morris et al. 2017 (JAMA Oncol). TP53 mutation rate 25% in recurrent/metastatic CESC vs 3% in TCGA primary cervix (OR 8.3, P=.008).

This page was processed by entity-page-writer on 2026-05-15. - PMID:29420467 - PMID:29422544

This page was processed by entity-page-writer on 2026-05-15. - PMID:29617662

This page was processed by wiki-cli on 2026-05-15. - PMID:29622463

This page was processed by wiki-cli on 2026-05-15.