Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The landscape of driver mutations in cutaneous squamous cell carcinoma.

ABSTRACT: Cutaneous squamous cell carcinoma is a form of skin cancer originating from keratinocytes in the skin. It is the second most common type of cancer and is responsible for an estimated 8000 deaths per year in the United States. Compared to other cancer subtypes with similar incidences and death tolls, our understanding of the somatic mutations driving cutaneous squamous cell carcinoma is limited. The main challenge is that these tumors have high mutation burdens, primarily a consequence of UV-radiation-induced DNA damage from sunlight, making it difficult to distinguish driver mutations from passenger mutations. We overcame this challenge by performing a meta-analysis of publicly available sequencing data covering 105 tumors from 10 different studies. Moreover, we eliminated tumors with issues, such as low neoplastic cell content, and from the tumors that passed quality control, we utilized multiple strategies to reveal genes under selection. In total, we nominated 30 cancer genes. Among the more novel genes, mutations frequently affected EP300, PBRM1, USP28, and CHUK. Collectively, mutations in the NOTCH and p53 pathways were ubiquitous, and to a lesser extent, mutations affected genes in the Hippo pathway, genes in the Ras/MAPK/PI3K pathway, genes critical for cell-cycle checkpoint control, and genes encoding chromatin remodeling factors. Taken together, our study provides a catalog of driver genes in cutaneous squamous cell carcinoma, offering points of therapeutic intervention and insights into the biology of cutaneous squamous cell carcinoma.

SUBMITTER: Chang D

PROVIDER: S-EPMC8285521 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Mutational landscape of aggressive cutaneous squamous cell carcinoma.

Project description:PurposeAggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC.Experimental designWhole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias.ResultsDespite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion.ConclusionsThe mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC.

| S-EPMC4367811 | biostudies-literature

Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression.

Project description:The molecular basis of disease progression from UV-induced precancerous actinic keratosis (AK) to malignant invasive cutaneous squamous cell carcinoma (cSCC) and potentially lethal metastatic disease remains unclear. DNA sequencing studies have revealed a massive mutational burden but have yet to illuminate mechanisms of disease progression. Here we perform RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation, dynamic modulation of the epidermal differentiation complex, remodelling of the immune landscape and an increase in the preponderance of tumour specific keratinocytes. Comparative systems analysis of human cSCC coupled with the generation of genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genes Tgfbr2, Trp53, and Notch1 coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis. Taken together we provide a comprehensive map of the cSCC disease continuum and reveal potentially actionable events that promote and accompany disease progression.

| S-EPMC10457401 | biostudies-literature

TERT promoter mutations are frequent in cutaneous basal cell carcinoma and squamous cell carcinoma.

Project description:Activating mutations in the TERT promoter were recently identified in up to 71% of cutaneous melanoma. Subsequent studies found TERT promoter mutations in a wide array of other major human cancers. TERT promoter mutations lead to increased expression of telomerase, which maintains telomere length and genomic stability, thereby allowing cancer cells to continuously divide, avoiding senescence or apoptosis. TERT promoter mutations in cutaneous melanoma often show UV-signatures. Non-melanoma skin cancer, including basal cell carcinoma and squamous cell carcinoma, are very frequent malignancies in individuals of European descent. We investigated the presence of TERT promoter mutations in 32 basal cell carcinomas and 34 cutaneous squamous cell carcinomas using conventional Sanger sequencing. TERT promoter mutations were identified in 18 (56%) basal cell carcinomas and in 17 (50%) cutaneous squamous cell carcinomas. The recurrent mutations identified in our cohort were identical to those previously described in cutaneous melanoma, and showed a UV-signature (C>T or CC>TT) in line with a causative role for UV exposure in these common cutaneous malignancies. Our study shows that TERT promoter mutations with UV-signatures are frequent in non-melanoma skin cancer, being present in around 50% of basal and squamous cell carcinomas and suggests that increased expression of telomerase plays an important role in the pathogenesis of these tumors.

| S-EPMC3832433 | biostudies-literature

COL11A1 mutations in cutaneous squamous cell carcinoma [WES]

Project description:Whole exome sequencing was used to identify frequent COL11A1 mutations in cutaneous squamous cell carcinoma (cSCC).

2021-07-23 | GSE179296 | GEO

The genomic landscape of cutaneous squamous cell carcinoma

Project description:This SuperSeries is composed of the SubSeries listed below.

2018-06-14 | GSE98780 | GEO

Deciphering the Molecular Landscape of Cutaneous Squamous Cell Carcinoma for Better Diagnosis and Treatment.

Project description:Cutaneous squamous cell carcinoma (cSCC) is a common type of neoplasia, representing a terrible burden on patients' life and clinical management. Although it seldom metastasizes, and most cases can be effectively treated with surgical intervention, once metastatic cSCC displays considerable aggressiveness leading to the death of affected individuals. No consensus has been reached as to which features better characterize the aggressive behavior of cSCC, an achievement hindered by the high mutational burden caused by chronic ultraviolet light exposure. Even though some subtypes have been recognized as high risk variants, depending on certain tumor features, cSCC that are normally thought of as low risk could pose an increased danger to the patients. In light of this, specific genetic and epigenetic markers for cutaneous SCC, which could serve as reliable diagnostic markers and possible targets for novel treatment development, have been searched for. This review aims to give an overview of the mutational landscape of cSCC, pointing out established biomarkers, as well as novel candidates, and future possible molecular therapies for cSCC.

| S-EPMC7408826 | biostudies-literature

Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma.

Project description: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.

| S-EPMC4324615 | biostudies-literature

COL11A1 mutations in cutaneous squamous cell carcinoma [WES]

Project description:COL11A1 mutations in cutaneous squamous cell carcinoma [WES]

| PRJNA743078 | ENA

The genomic landscape of cutaneous squamous cell carcinoma

Project description:The genomic landscape of cutaneous squamous cell carcinoma

| PRJNA386187 | ENA

Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.

Project description:Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ~75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.

| S-EPMC3203814 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data