The genomic landscape of cutaneous squamous cell carcinoma from immunosuppressed and immunocompetent patients reveals common drivers and a novel mutational signature associated with chronic azathioprine exposure
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PROVIDER: EGAS00001002612 | EGA |
REPOSITORIES: EGA
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Project description:Actinic keratoses (AK) are lesions of epidermal keratinocyte dysplasia and are precursors for invasive cutaneous squamous cell carcinoma (CSCC). Identifying the specific genomic alterations driving progression from normal skin-AK-invasive CSCC is challenging due to the massive ultraviolet radiation-induced mutational burden characteristic at all stages of this progression. Here, we report the largest AK whole exome sequencing study to date and perform mutational signature and candidate driver gene analysis on these lesions. We demonstrate in 37 AK, from both immunosuppressed and immunocompetent patients, that there are significant similarities to CSCC in terms of mutational burden, copy number alterations, mutational signatures and patterns of driver gene mutations. We identify 44 significantly mutated AK driver genes and confirm that these genes are similarly altered in CSCC. We identify the azathioprine mutational signature in all AK from patients exposed to the drug, providing further evidence for its role in keratinocyte carcinogenesis. CSCC differ from AK in having higher levels of intra-sample heterogeneity. Alterations in signaling pathways also differ, with immune-related signaling and TGF-β signaling significantly more mutated in CSCC. Integrating our findings with independent gene expression datasets confirms that dysregulated TGF-β signaling may represent an important event in AK-CSCC progression.
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Project description:High-grade serous ovarian cancer (HGSOC) is an archetypal cancer of genomic instability patterned by distinct mutational processes, tumour heterogeneity and intraperitoneal spread. Immunotherapies have had limited efficacy in HGSOC, highlighting an unmet need to assess how mutational processes and the anatomical sites of tumour foci determine the immunological states of the tumour microenvironment. Here we carried out an integrative analysis of whole-genome sequencing, single-cell RNA sequencing, digital histopathology and multiplexed immunofluorescence of 160 tumour sites from 42 treatment-naive patients with HGSOC. Homologous recombination-deficient HRD-Dup (BRCA1 mutant-like) and HRD-Del (BRCA2 mutant-like) tumours harboured inflammatory signalling and ongoing immunoediting, reflected in loss of HLA diversity and tumour infiltration with highly differentiated dysfunctional CD8+ T cells. By contrast, foldback inversion-bearing tumours exhibited elevated immunosuppressive TGFβ signalling and immune exclusion, with predominantly naive/stem-like and memory T cells. Phenotypic state associations were specific to anatomical sites, highlighting compositional, topological and functional differences between adnexal tumours and distal peritoneal foci. Our findings implicate anatomical sites and mutational processes as determinants of evolutionary phenotypic divergence and immune resistance mechanisms in HGSOC. Our study provides a multi-omic cellular phenotype data substrate from which to develop and interpret future personalized immunotherapeutic approaches and early detection research.
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Project description:Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to investigate the transcriptomes of cSCC and actinic keratoses (AK), to elucidate key differences between precursor AK lesions and invasive carcinoma. This study identified 196 genes that are differentially expressed between AK and cSCC, with enrichment for processes including epidermal differentiation, cell migration, cell cycle regulation and metabolism. Gene set enrichment analysis highlighted a key role for the MAPK pathway in the transition from AK to cSCC. Furthermore, the differentiation status of the tumor influenced the gene expression profile, which may have implications for drug sensitivity and response in clinical trials. These data indicate that progression to cSCC is associated with a complex pattern of molecular changes. We have identified relevant pathways involved in this process, in particular that the MAPK pathway may be pivotal to the transition from AK and may represent a potential therapeutic target. RNA was extracted by laser capture microdissection from 10 AK and 30 cSCC, for analysis using the Affymetrix HG U133 Plus 2.0 microarrays. The cSCC samples included a range of histological diagnoses (well differentiated through to poorly differentiatied) from both immunocompetent and immunosuppressed patients.
2014-01-21 | E-GEOD-45216 | biostudies-arrayexpress
Project description:We leveraged massively parallel sequencing approach to comprehensively characterize the spectrum of somatic mutations and genomic rearrangements in two intestinal-type gastric adenocarcinomas from patients with and without active Helicobacter pylori infections. The tumours exhibited distinct patterns of genomic changes with more than 16,000 somatic substitutions on average, focal amplifications and rearrangements in the non-active infected tumour and a 7-fold enrichment of micro-deletions in the infected tumour. Paired-end sequences from large insert libraries revealed the structure and origins of large amplicons, including one involving the oncogene KRAS. The mutational frequencies of the tumours revealed patterns of H. pylori infection and mutagenesis and a unique exome signature, providing insights into mechanisms that define the mutational landscape of gastric cancer. For the tumour with active infection, we also reconstructed the genome of the pathogenic H. pylori strain from the raw sequence reads, demonstrating the power of whole-genome shotgun sequencing for simultaneously characterizing the tumour and its associated carcinogen genome.
2012-12-05 | GSE30833 | GEO
Project description:Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer type and arises from keratinocytes. Most cSCC progress from a UV-induced precancerous lesion termed actinic keratosis (AK). Despite various efforts to characterize these lesions molecularly, the etiology of AK and its progression to cSCC remain only partially understood. Here we have used Infinium MethylationEPIC BeadChips to interrogate the DNA methylation status of about 850.000 CpGs in epidermal preparations from healthy skin, AK and cSCC. Importantly, we found that the premalignant AK samples displayed classical features of cancer methylomes and were highly similar to cSCC methylomes. Further analysis identified typical features of stem cell methylomes, such as a reduced DNA methylation age, non-CpG methylation and stem cell-related keratin and enhancer methylation patterns. Interestingly, this signature was detected only in one half of the AK and cSCC samples, while the other half showed methylation patterns that were more closely related to the control epidermis. These findings suggest the existence of two distinct subclasses of AK and cSCC that originate from distinct keratinocyte differentiation stages.
2017-12-19 | E-MTAB-5738 | biostudies-arrayexpress
Project description:Primitive neuroectodermal tumours of the central nervous system (CNS PNETs) are highly aggressive, poorly differentiated embryonal tumours occurring predominantly in young children. Using DNA methylation and gene expression profiling we have demonstrated that a significant proportion of institutionally diagnosed CNS PNETs display molecular profiles indistinguishable from those of various other well defined CNS tumour entities, facilitating diagnosis and appropiate therapy for children with these tumours. From the remaining fraction of CNS PNETs, we have identified four distinct new CNS tumour entities extending to other neuroepithelial tumours, each associated with a recurrent genetic alteration and particular histopathological and clinical features. These molecular entities, designated “CNS Neuroblastoma with FOXR2 activation (CNS NB FOXR2)”, “CNS Ewing sarcoma family tumour with CIC alteration (CNS EFT CIC)”, “CNS high grade neuroepithelial tumour with MN1 alteration (CNS HGNET MN1)”, and “CNS high grade neuroepithelial tumour with BCOR alteration (CNS HGNET BCOR)”, will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by these poorly differentiated CNS tumours.
2016-02-25 | GSE73801 | GEO
Project description:We investigated changes to the head and neck tumour microenvironment immune cell transcriptome following treatment with an adenovirus encoding TNFa and IL-2 in the context of a antiPD-L1 refractory model. Murine head and neck cancer cell line was engrafted subcutaneously onto the right flank of immunocompetent mice. Tumours were treated with antiPD-L1 until 'refractory' status as determined by tumour volume. The tumours were than treated with or without an adenovirus encoding TNFa and IL2. Tumours were digested and CD45+/- were isolated using magnetic bead isolation.
2022-03-09 | E-MTAB-11204 | biostudies-arrayexpress
Project description:The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information. We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n=32) and gene expression (n=36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling. From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n=25) had an increased risk of recurrence as a first event (p=0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26-16.0) and death (p=0.04, HR, 4.95; 95% CI, 1.36-31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p=0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes. This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker. 32 tumour samples were profiled by aCGH, in 2-colour hybridisations with common pooled unrelated normal genomic DNA in the reference channel. There were no replicates.
2014-08-30 | E-GEOD-60852 | biostudies-arrayexpress
Project description:The presence of diffuse anaplasia in Wilms tumours (DAWT) is associated with TP53 mutations and poor outcome. As patients receive intensified treatment, we sought to identify whether TP53 mutational status confers additional prognostic information. We studied 40 patients with DAWT with anaplasia in the tissue from which DNA was extracted and analysed for TP53 mutations and 17p loss. The majority of cases were profiled by copy number (n=32) and gene expression (n=36) arrays. TP53 mutational status was correlated with patient event-free and overall survival, genomic copy number instability and gene expression profiling. From the 40 cases, 22 (55%) had TP53 mutations (2 detected only after deep-sequencing), 20 of which also had 17p loss (91%); 18 (45%) cases had no detectable mutation but three had 17p loss. Tumours with TP53 mutations and/or 17p loss (n=25) had an increased risk of recurrence as a first event (p=0.03, hazard ratio (HR), 3.89; 95% confidence interval (CI), 1.26-16.0) and death (p=0.04, HR, 4.95; 95% CI, 1.36-31.7) compared to tumours lacking TP53 abnormalities. DAWT carrying TP53 mutations showed increased copy number alterations compared to those with wild-type, suggesting a more unstable genome (p=0.03). These tumours showed deregulation of genes associated with cell cycle and DNA repair biological processes. This study provides evidence that TP53 mutational analysis improves risk stratification in DAWT. This requires validation in an independent cohort before clinical use as a biomarker. 36 tumour samples were expression profiled in 2-colour hybridisations with Stratagene Universal Human Reference RNA in the reference channel. There were no replicates.
2014-08-30 | E-GEOD-60850 | biostudies-arrayexpress
Project description:Actinic keratoses (AK) are lesions of epidermal keratinocyte dysplasia and are pre-cursor lesions to invasive cutaneous squamous cell carcinoma (cSCC). Identifying the specific genomic alterations driving the progression of normal skin to AK and invasive cSCC is challenging due to the massive, ultraviolet radiation-induced mutational burden characteristic to these lesions. Here, we present the largest whole exome sequencing study to date on AK with matched cSCC and demonstrate that AK and cSCC are almost indistinguishable at the genomic level, in terms of mutational burden, patterns of driver gene mutations and copy number alterations. We identified 44 significantly mutated AK driver genes through our established bioinformatics pipeline and demonstrate these genes are similarly mutated in cSCC. We also identified mutational signature-32 exclusively in AK from patients exposed to azathioprine, providing further, compelling evidence for this drug’s role in keratinocyte carcinogenesis, likely through its blocking of transcription coupled repair. We demonstrated that cSCC had higher levels of intra-sample heterogeneity than AK and that several signaling pathways, including immune-related signaling and TGF-beta signaling were significantly more mutated in cSCC. Integrating our findings with independent gene expression data confirms that dysregulated TGF-beta signaling may represent the critical pathway in the progression from AK to cSCC.
| EGAS00001004243 | EGA