Cutaneous Squamous Cell Carcinoma (CSCC)

Overview

Cutaneous squamous cell carcinoma (CSCC) is a keratinocyte-derived malignancy of the skin, predominantly driven by UV-induced mutagenesis. It sits under the SKIN category in OncoTree. It typically evolves from normal skin through clonal field expansion, actinic keratosis (AK), and invasive carcinoma.

Cohorts in the corpus

  • 16 archival tissue cases with cSCC immediately adjacent to actinic keratosis, sequenced with a cancer gene panel at ~380X depth. 137 normal keratinocytes, 131 melanocytes, and 23 fibroblasts from 15 donors profiled at single-cell resolution via clonal expansion and whole-exome sequencing. Dataset: normal_skin_melanocytes_2024. PMID:39091884

Recurrent alterations

  • TP53 — dominant-negative missense mutations in normal keratinocytes associated with hypermutation (up to 49.71 mut/Mb); trunk events in AK-cSCC phylogenies; less common than NOTCH1 in normal skin but more common in cSCC. PMID:39091884
  • NOTCH1 — loss-of-function mutations frequent in normal keratinocyte clones; typically early/trunk events in cSCC evolution. PMID:39091884
  • CDKN2A — loss-of-function mutations emerging in actinic keratosis (AK) as trunk events. PMID:39091884
  • TERT — promoter gain-of-function mutations emerging in AK (trunk events), upregulating telomerase. PMID:39091884
  • ARID2 — loss-of-function mutations enriched specifically at the AK-to-cSCC transition; SWI/SNF chromatin remodeling complex disruption. PMID:39091884
  • NOTCH2 — loss-of-function in AK; secondary hits to Notch pathway on phylogenetic branches. PMID:39091884
  • WES of 39 aggressive head-and-neck cSCCs revealed an extreme UV-driven mutation burden (median 61.2 mutations/Mb); 23 candidate drivers identified including TP53 (95%), NOTCH1 (59%), NOTCH2 (51%), FAT1 (44%), CDKN2A (44%), KMT2C (39%); KMT2C mutation associated with bone invasion and shorter recurrence-free survival (HR 5.16) PMID:25303977
  • Targeted sequencing of 504 cancer-associated genes on 29 lymph-node metastases from HPV-negative CSCC identified high UV mutational burden (~33 mut/Mb), recurrent TP53 (79%), CDKN2A (48%), NOTCH1/2/4 inactivation, and activating RAS/RTK/PI3K events (38%); RAS/RTK/PI3K + chromatin-remodeling co-mutation was the strongest predictor of shorter PFS. PMID:25589618
  • NanoSeq quantification of NB-UVB-induced somatic mutation burden in normal skin established UVR signature (SBS7a/SBS7b/DBS1) accumulation as a precursor risk model; cSCC mean mutation burden of 50 substitutions/Mb was used as the endpoint for surveillance-exposure modelling PMID:26950094
  • In 21 recurrent/metastatic CSCC profiled by MSK-IMPACT (Morris et al.): UV-light mutational signature in 86% (18/21) associated with higher mutation counts (37.9 vs 4.3, P=.008); TERT promoter mutations in 52%; 3p deletion + TP53 co-occurrence in 32% — the first report in cutaneous SCC PMID:27442865.
  • Published cutaneous squamous cell carcinoma mutational signature datasets were used as a reference comparison in the first WES landscape of vulvar SCC; HPV(-) vulvar SCC displayed higher mutational load than HPV(+) cases, consistent with patterns observed in CSCC PMID:29422544

Subtypes

  • Stepwise evolutionary model: TP53/NOTCH1 mutations in normal skin → CDKN2A/TERT mutations in AK → ARID2 loss-of-function and MAPK-pathway activation at the AK-to-cSCC transition. PMID:39091884
  • In 6/16 cases, AK and adjacent cSCC shared no somatic alterations, indicating clonal independence (“collisions”). PMID:39091884

Therapeutic landscape

  • High expression of immune checkpoint ligands (PVR, NECTIN2, CD274/PD-L1, CD80, CD86) and checkpoint receptors (CTLA4, TIGIT, PD-1) at the invasive front of cSCC supports rationale for immune checkpoint inhibitor therapy. PMID:39091884
  • ARID2 loss-of-function mutations at the AK-to-cSCC transition may link SWI/SNF disruption to immune evasion, potentially informing immunotherapy strategies. PMID:39091884

Sources

  • PMID:39091884 — Genetic evolution of keratinocytes to cutaneous squamous cell carcinoma (bioRxiv, 2024)

  • PMID:25303977

  • PMID:25589618

  • PMID:26950094 — Fowler et al., NanoSeq NB-UVB mutation-burden study; cSCC mean burden of 50 substitutions/Mb used as endpoint for surveillance-exposure modelling

This page was processed by entity-page-writer on 2026-05-15. - PMID:27442865 — Morris et al. 2017 (JAMA Oncol). UV signature in 86% of 21 advanced CSCC; TERT promoter mutations 52%; first report of 3p deletion + TP53 in cutaneous SCC.

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

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