Transcriptomic analysis of cutaneous squamous cell carcinoma reveals a multigene prognostic signature associated with metastasis

Wang, Jun; Harwood, Catherine A.; Bailey, Emma; Bewicke-Copley, Findlay; Anene, Chinedu Anthony; Thomson, J.; Qamar, Muhammad Fiaz; Laban, Rhiannon; Nourse, Craig; Schoenherr, Christina; Healy, Eugene; Lai, Chester; Craig, Paul; Moyes, Colin; Rickaby, William; Martin, Joanne; Proby, Charlotte M.; Inman, Gareth J.; Leigh, Irene M.

doi:10.1016/j.jaad.2023.08.012

Cited by 2 publications

(2 citation statements)

References 29 publications

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“…Previous work has identified GEP signatures that may predict metastatic risk, but these have not been able to predict both metastasis and survival [17,18,55]. Other GEP derivations were inclusive of large numbers of low-risk tumors unlikely to metastasize, only controlling for age, sex, and tumor location, neglecting to control for stage [18]. Intermediate to high-risk tumors (BWH T2a & T2b) are known to have more outcome variability, making prediction and risk-stratification increasingly difficult [5].…”

Section: Discussionmentioning

confidence: 99%

“…However, understanding of the transcriptional changes with respect to high-risk clinical/histopathological features and outcome is poor. Multi-gene prognostic modeling in high-risk cSCC has demonstrated promise in early reports [17,18]. To date, there have been no prognostic models integrating WES and whole transcriptomic sequencing on matched samples.…”

Section: Introductionmentioning

confidence: 99%

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Whole Exome and Transcriptome Sequencing of Stage-Matched, Outcome-Differentiated Cutaneous Squamous Cell Carcinoma Identifies Gene Expression Patterns Associated with Metastasis and Poor Outcomes

Nassir,

Yousif,

et al. 2024

Preprint

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Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in humans and kills as many people annually as melanoma. The mutational and transcriptional landscape of cSCC has identified driver mutations associated with disease progression as well as key pathway activation in the progression of pre-cancerous lesions. The understanding of the transcriptional changes with respect to high-risk clinical/histopathological features and outcome is poor. Here, we examine stage-matched, outcome-differentiated cSCC and associated clinicopathologic risk factors using whole exome and transcriptome sequencing on matched samples. Exome analysis identified key driver mutations includingTP53,CDKN2A,NOTCH1,SHC4,MIIP,CNOT1,C17orf66,LPHN22, andTTC16and pathway enrichment of driver mutations in replicative senescence, cellular response to UV, cell-cell adhesion, and cell cycle. Transcriptomic analysis identified pathway enrichment of immune signaling/inflammation, cell-cycle pathways, extracellular matrix function, and chromatin function. Our integrative analysis identified 183 critical genes in carcinogenesis and were used to develop a gene expression panel (GEP) model for cSCC. Three outcome-related gene clusters included those involved in keratinization, cell division, and metabolism. We found 16 genes were predictive of metastasis (Risk score ≥ 9 Met & Risk score < 9 NoMet). The Risk score has an AUC of 97.1% (95% CI: 93.5% - 100%), sensitivity 95.5%, specificity 85.7%, and overall accuracy of 90%. Eleven genes were chosen to generate the risk score for Overall Survival (OS). The Harrell’s C-statistic to predict OS is 80.8%. With each risk score increase, the risk of death increases by 2.47 (HR: 2.47, 95% CI: 1.64-3.74; p<0.001) after adjusting for age, immunosuppressant use, and metastasis status.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Whole Exome and Transcriptome Sequencing of Stage-Matched, Outcome-Differentiated Cutaneous Squamous Cell Carcinoma Identifies Gene Expression Patterns Associated with Metastasis and Poor Outcomes

Nassir,

Yousif,

et al. 2024

Preprint

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Gene expression landscape of cutaneous squamous cell carcinoma progression

Bencomo,

Lee

2023

Preprint

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BackgroundCutaneous squamous cell carcinomas (SCC) are the second most common human cancer and have been characterized by RNA sequencing (RNA-Seq); however, the transferability of findings from individual studies may be limited by small sample sizes and diverse analysis protocols.ObjectivesTo define the transcriptome landscape at different stages in the progression of normal skin to SCC through a meta-analysis of publicly available RNA-Seq samplesMethodsWhole-transcriptome data from 73 normal skin samples, 46 actinic keratoses (AK), 16 in situ SCC, 13 keratoacanthomas (KA), and 147 SCC (including 30 SCC from immunocompromised patients and 8 SCC from individuals with recessive dystrophic epidermolysis bullosa [RDEB]) was uniformly processed to harmonize gene expression. Differential expression, fusion detection, and cell-type deconvolution analyses were performed.ResultsIndividual RNA-Seq studies of SCC demonstrated study-specific clustering and varied widely in their differential gene expression detection. Following batch correction, we defined a consensus set of differentially expressed genes (DEGs), including those altered in the preinvasive stages of SCC development, and used single-cell RNA-Seq data to demonstrate that DEGs are often, but not always, expressed by tumor-specific keratinocytes (TSKs). Analysis of the cellular composition of SCC, KA, and RDEB-SCC identified an increase in differentiated keratinocytes in KA, while RDEB-SCC contained the most TSKs. Compared to SCC arising in immunocompetent patients, SCC from immunosuppressed individuals demonstrated fewer memory B cells and CD8 T cells. A comprehensive and unbiased search for fusion transcripts in SCC and intermediate disease stages identified few candidates that recur in >1% of all specimens, suggesting most SCC are not driven by oncogenic gene fusions. Finally, using GTEx data, we distilled a novel 300-gene signature of chronic sun exposure that affirms greater cumulative ultraviolet (UV) exposure in later stages of SCC development.ConclusionsOur results define the gene expression landscape of SCC progression, characterize cell subpopulation heterogeneity in SCC subtypes that contribute to their distinct clinical phenotypes, demonstrate that gene fusions are not a common cause of SCC, and identify UV-responsive genes associated with SCC development.What is already known about this topic?Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers worldwide.Several studies have examined gene expression changes in SCC using RNA sequencing (RNA-Seq) but comparison of their results is difficult due to inter-study variation and diverse bioinformatic pipelines and protocols.A few gene fusions have been described in SCC, but a comprehensive characterization of fusion transcripts in patient samples has not been performed.What does this study add?We re-analyzed RNA-Seq data from 11 studies of SCC and its preinvasive stages to create a list of consensus differentially expressed genes and identify those that are UV-responsive.Clinically aggressive SCC displayed more tumor-specific keratinocytes, while keratoacanthomas contained more differentiated keratinocytes. SCC in immunocompetent persons had more memory B cells and CD8 T cells than those arising in immunosuppressed individuals.Previously reported gene fusions were not detected and most fusion candidates did not demonstrate pathogenic features.What is the translational message?Our analysis harmonizes differing results from previous studies to provide a robust list of genes implicated in SCC development.Our findings suggest gene fusions are not a common driver event in SCC.

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Transcriptomic analysis of cutaneous squamous cell carcinoma reveals a multigene prognostic signature associated with metastasis

Cited by 2 publications

References 29 publications

Whole Exome and Transcriptome Sequencing of Stage-Matched, Outcome-Differentiated Cutaneous Squamous Cell Carcinoma Identifies Gene Expression Patterns Associated with Metastasis and Poor Outcomes

Whole Exome and Transcriptome Sequencing of Stage-Matched, Outcome-Differentiated Cutaneous Squamous Cell Carcinoma Identifies Gene Expression Patterns Associated with Metastasis and Poor Outcomes

Gene expression landscape of cutaneous squamous cell carcinoma progression

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