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1.
Br J Dermatol ; 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38867481

RESUMO

BACKGROUND: Cutaneous 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. OBJECTIVES: To define the transcriptome landscape at different stages in the progression of normal skin to SCC through a meta-analysis of publicly available RNA-Seq samples. METHODS: Whole-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. RESULTS: Individual 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. CONCLUSIONS: Our 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.

2.
Transl Oncol ; 27: 101557, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36257209

RESUMO

The human skin is a complex organ that forms the first line of defense against pathogens and external injury. It is composed of a wide variety of cells that work together to maintain homeostasis and prevent disease, such as skin cancer. The exponentially rising incidence of skin malignancies poses a growing public health challenge, particularly when the disease course is complicated by metastasis and therapeutic resistance. Recent advances in single-cell transcriptomics have provided a high-resolution view of gene expression heterogeneity that can be applied to skin cancers to define cell types and states, understand disease evolution, and develop new therapeutic concepts. This approach has been particularly valuable in characterizing the contribution of immune cells in skin cancer, an area of great clinical importance given the increasing use of immunotherapy in this setting. In this review, we highlight recent skin cancer studies utilizing bulk RNA sequencing, introduce various single-cell transcriptomics approaches, and summarize key findings obtained by applying single-cell transcriptomics to skin cancer.

4.
Cancer Res ; 82(17): 3143-3157, 2022 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-35705526

RESUMO

Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase complex to RET and reduced its ubiquitylation. In SCC organoids and in vivo tumor models, genetic disruption of RET or selective inhibition of RET with BLU-667 (pralsetinib) suppressed SCC growth while inducing concomitant differentiation. Overall, loss of MAB21L4 early during SCC development blocks differentiation by increasing RET expression. These results suggest that targeting RET activation is a potential therapeutic strategy for treating SCC. SIGNIFICANCE: Downregulation of RET mediated by MAB21L4-CacyBP interaction is required to induce epidermal differentiation and suppress carcinogenesis, suggesting RET inhibition as a potential therapeutic approach in squamous cell carcinoma.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Proteínas de Ligação ao Cálcio/metabolismo , Carcinogênese/patologia , Carcinoma de Células Escamosas/patologia , Proliferação de Células , Queratinócitos/patologia , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias Cutâneas/patologia
5.
Oncogene ; 40(44): 6299-6307, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34584216

RESUMO

Collagens are the most abundant proteins in the body and comprise the basement membranes and stroma through which cancerous invasion occurs; however, a pro-neoplastic function for mutant collagens is undefined. Here we identify COL11A1 mutations in 66 of 100 cutaneous squamous cell carcinomas (cSCCs), the second most common U.S. cancer, concentrated in a triple helical region known to produce trans-dominant collagens. Analysis of COL11A1 and other collagen genes found that they are mutated across common epithelial malignancies. Knockout of mutant COL11A1 impairs cSCC tumorigenesis in vivo. Compared to otherwise genetically identical COL11A1 wild-type tissue, gene-edited mutant COL11A1 skin is characterized by induction of ß1 integrin targets and accelerated neoplastic invasion. In mosaic tissue, mutant COL11A1 cells enhanced invasion by neighboring wild-type cells. These results suggest that specific collagens are commonly mutated in cancer and that mutant collagens may accelerate this process.


Assuntos
Carcinoma de Células Escamosas/patologia , Colágeno Tipo XI/genética , Integrina beta1/metabolismo , Mutação , Neoplasias Cutâneas/patologia , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Estudos de Casos e Controles , Colágeno Tipo XI/química , Feminino , Humanos , Camundongos , Invasividade Neoplásica , Transplante de Neoplasias , Estrutura Secundária de Proteína , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Sequenciamento do Exoma
7.
Head Neck ; 39(5): 881-885, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28252823

RESUMO

BACKGROUND: Data lacks to guide treatment of regionally metastatic cutaneous head and neck squamous cell carcinoma (HNSCC). METHODS: We conducted a retrospective review of 80 patients treated for regionally metastatic cutaneous HNSCC. The effect of various clinicopathologic variables on overall survival (OS) was investigated, in addition to outcomes by treatment modality. RESULTS: On multivariate regression, cutaneous primary >2 cm (p = .03) and extracapsular spread (ECS; p = .01) were significantly associated with decreased OS. Location of regional metastasis (neck vs parotid vs both) had no effect on OS (p = .2), nor did the presence of a cutaneous primary at the time of presentation (p = .9). The 3-year survival was 43%, 52%, and 49% for surgery alone, adjuvant radiation, and adjuvant chemoradiation, respectively. Fifty-one percent of patients had a recurrence of their disease. CONCLUSION: Regionally metastatic cutaneous HNSCC is an aggressive disease associated with high recurrence rates. Patients with tumors >2 cm and ECS have poorer OS despite adjuvant therapy. © 2017 Wiley Periodicals, Inc. Head Neck 39: 881-885, 2017.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Idoso , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia Adjuvante , Feminino , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida , Resultado do Tratamento
10.
Nat Genet ; 47(9): 1056-60, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26258847

RESUMO

Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.


Assuntos
Micose Fungoide/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Síndrome de Sézary/genética , Neoplasias Cutâneas/genética , Antineoplásicos/farmacologia , Sequência de Bases , Bortezomib/farmacologia , Antígenos CD28/genética , Antígeno CTLA-4/genética , Linhagem Celular Tumoral , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genômica , Humanos , Proteínas de Fusão Oncogênica/genética , Mutação Puntual , Receptores Tipo II do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais
11.
Nat Genet ; 46(10): 1060-2, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25194279

RESUMO

Here we report the discovery of recurrent mutations concentrated at an ultraviolet signature hotspot in KNSTRN, which encodes a kinetochore protein, in 19% of cutaneous squamous cell carcinomas (SCCs). Cancer-associated KNSTRN mutations, most notably those encoding p.Ser24Phe, disrupt chromatid cohesion in normal cells, occur in SCC precursors, correlate with increased aneuploidy in primary tumors and enhance tumorigenesis in vivo. These findings suggest a role for KNSTRN mutagenesis in SCC development.


Assuntos
Carcinoma de Células Escamosas/genética , Proteínas de Ciclo Celular/genética , Cinetocoros/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Mutação Puntual , Neoplasias Cutâneas/genética , Aneuploidia , Animais , Carcinogênese/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Células Cultivadas , Feminino , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Queratinócitos/transplante , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Transfecção , Transplante Heterólogo
12.
Nature ; 493(7431): 231-5, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23201690

RESUMO

Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized; however, potential roles for lncRNAs in somatic tissue differentiation remain poorly understood. Here we show that a 3.7-kilobase lncRNA, terminal differentiation-induced ncRNA (TINCR), controls human epidermal differentiation by a post-transcriptional mechanism. TINCR is required for high messenger RNA abundance of key differentiation genes, many of which are mutated in human skin diseases, including FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14 and ELOVL3. TINCR-deficient epidermis lacked terminal differentiation ultrastructure, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs. TINCR-mRNA interaction occurs through a 25-nucleotide 'TINCR box' motif that is strongly enriched in interacting mRNAs and required for TINCR binding. A high-throughput screen to analyse TINCR binding capacity to approximately 9,400 human recombinant proteins revealed direct binding of TINCR RNA to the staufen1 (STAU1) protein. STAU1-deficient tissue recapitulated the impaired differentiation seen with TINCR depletion. Loss of UPF1 and UPF2, both of which are required for STAU1-mediated RNA decay, however, did not have differentiation effects. Instead, the TINCR-STAU1 complex seems to mediate stabilization of differentiation mRNAs, such as KRT80. These data identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression.


Assuntos
Diferenciação Celular/genética , Células Epidérmicas , Epiderme/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Sequência de Bases , Células Cultivadas , Proteínas do Citoesqueleto/metabolismo , Proteínas Filagrinas , Regulação da Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Queratinócitos , Mutação , Motivos de Nucleotídeos/genética , Ligação Proteica , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Dermatopatias/genética
13.
Blood ; 120(16): 3288-97, 2012 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-22936659

RESUMO

Sézary syndrome (SS) is an aggressive cutaneous T-cell lymphoma (CTCL) of unknown etiology in which malignant cells circulate in the peripheral blood. To identify viral elements, gene fusions, and gene expression patterns associated with this lymphoma, flow cytometry was used to obtain matched pure populations of malignant Sézary cells (SCs) versus nonmalignant CD4(+) T cells from 3 patients for whole transcriptome, paired-end sequencing with an average depth of 112 million reads per sample. Pathway analysis of differentially expressed genes identified mis-regulation of PI3K/Akt, TGFß, and NF-κB pathways as well as T-cell receptor signaling. Bioinformatic analysis did not detect either nonhuman transcripts to support a viral etiology of SS or recurrently expressed gene fusions, but it did identify 21 SC-associated annotated long noncoding RNAs (lncRNAs). Transcriptome assembly by multiple algorithms identified 13 differentially expressed unannotated transcripts termed Sézary cell-associated transcripts (SeCATs) that include 12 predicted lncRNAs and a novel transcript with coding potential. High-throughput sequencing targeting the 3' end of polyadenylated transcripts in archived tumors from 24 additional patients with tumor-stage CTCL confirmed the differential expression of SC-associated lncRNAs and SeCATs in CTCL. Our findings characterize the SS transcriptome and support recent reports that implicate lncRNA dysregulation in human malignancies.


Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Micose Fungoide/genética , RNA Longo não Codificante/genética , Síndrome de Sézary/genética , Neoplasias Cutâneas/genética , Citometria de Fluxo , Humanos , Micose Fungoide/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome de Sézary/patologia , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas
14.
Bioinformatics ; 28(8): 1174-5, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22377895

RESUMO

UNLABELLED: Rapid identification of non-human sequences (RINS) is an intersection-based pathogen detection workflow that utilizes a user-provided custom reference genome set for identification of non-human sequences in deep sequencing datasets. In <2 h, RINS correctly identified the known virus in the dataset SRR73726 and is compatible with any computer capable of running the prerequisite alignment and assembly programs. RINS accurately identifies sequencing reads from intact or mutated non-human genomes in a dataset and robustly generates contigs with these non-human sequences (Supplementary Material). AVAILABILITY: RINS is available for free download at http://khavarilab.stanford.edu/resources.html.


Assuntos
Genoma , Sequenciamento de Nucleotídeos em Larga Escala , Vírus/genética , Vírus/isolamento & purificação , Genoma Humano , Interações Hospedeiro-Patógeno , Humanos , Análise de Sequência de DNA , Software , Vírus/classificação
15.
Genes Dev ; 26(4): 338-43, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22302877

RESUMO

Long noncoding RNAs (lncRNAs) regulate diverse processes, yet a potential role for lncRNAs in maintaining the undifferentiated state in somatic tissue progenitor cells remains uncharacterized. We used transcriptome sequencing and tiling arrays to compare lncRNA expression in epidermal progenitor populations versus differentiating cells. We identified ANCR (anti-differentiation ncRNA) as an 855-base-pair lncRNA down-regulated during differentiation. Depleting ANCR in progenitor-containing populations, without any other stimuli, led to rapid differentiation gene induction. In epidermis, ANCR loss abolished the normal exclusion of differentiation from the progenitor-containing compartment. The ANCR lncRNA is thus required to enforce the undifferentiated cell state within epidermis.


Assuntos
Diferenciação Celular , Queratinócitos/citologia , RNA não Traduzido/metabolismo , Células-Tronco/citologia , Células Cultivadas , Células Epidérmicas , Regulação da Expressão Gênica no Desenvolvimento , Interferência de RNA , RNA Longo não Codificante , RNA não Traduzido/genética , Transcriptoma
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