ORCID Profile
0000-0002-8321-9950
Current Organisations
University of Bern
,
Central South University
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Publisher: Archives of Pathology and Laboratory Medicine
Date: 10-2014
Publisher: Springer Science and Business Media LLC
Date: 25-11-2014
DOI: 10.1038/NCOMMS6548
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S42003-019-0741-7
Abstract: Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1 , but not MALAT1 . Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis.
Publisher: Informa UK Limited
Date: 2002
Abstract: There are at present disparate published results with regard to the relevance of the Bcl-2 gene family, levels of apoptosis, and cell proliferation in the development and progression of renal cell carcinoma (RCC). The present study analyses the inter-relationship between the expression of representatives of the anti-apoptotic (Bcl-2, Bcl-XL) or pro-apoptotic (Bax) Bcl-2 proteins, incidence of apoptosis, and mitosis in a selected small group of 22 graded RCCs that had paired normal renal tissue, or non-neoplastic tissue in the renal biopsy specimen. The cases were chosen to determine the feasibility of measuring these parameters as potential surrogate markers of progression or treatment failure of the cancers. The results showed that in approximately 50% of the RCCs, where Bcl-2 and/or Bcl-XL expression was high, apoptosis was not detected, and when expression of these proteins was low or not found, increased levels of apoptosis were seen. In most of the remaining 50% of s les, high levels of Bcl-XL but not Bcl-2 were negatively correlated with low levels of apoptosis (Bcl-XL: r = -0.437, P = 0.07 and Bcl-2: r = +0.560, P = 0.02). For the same group of s les, high Bax expression was found in association with apoptosis (r = +0.578, P = 0.02). A novel finding was an association between low expression of Bcl-2 and/or Bcl-XL in normal tissue and the level of expression of these proteins in the RCCs, an intrinsic variation that may be an in idual patient factor. The results indicate that, in RCCs with increased expression of Bcl-2 and/or Bcl-XL, levels of apoptosis are minimal and these combined factors may assist in progression of the cancers and resistance to treatments.
Publisher: Elsevier BV
Date: 05-2020
Publisher: Springer Science and Business Media LLC
Date: 14-08-2017
DOI: 10.1038/NM.4378
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633058
Abstract: Supplementary Figures
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.EJCA.2021.09.036
Abstract: Innovations in treatments, imaging and molecular characterisation have improved outcomes for people with advanced prostate cancer however, many aspects of clinical management are devoid of high-level evidence. At the Advanced Prostate Cancer Consensus Conference (APCCC) 2019, many of these topics were addressed, and consensus was not always reached. The results from clinical trials will most reliably plus the gaps. An invited panel of 57 experts voted on 123 multiple-choice questions on clinical management at APCCC 2019. No consensus was reached on 88 (71.5%) questions defined as <75% of panellists voting for the same answer option. We reviewed clinicaltrials.gov to identify relevant ongoing phase III trials in these areas of non-consensus. A number of ongoing phase III trials were identified that are relevant to these non-consensus issues. However, many non-consensus issues appear not to be addressed by current clinical trials. Of note, no phase III but only phase II trials were identified, investigating side effects of hormonal treatments and their management. Lack of consensus almost invariably indicates gaps in existing evidence. The high percentage of questions lacking consensus at APCCC 2019 highlights the complexity of advanced prostate cancer care and the need for robust, clinically relevant trials that can fill current gaps with high-level evidence. Our review of these areas of non-consensus and ongoing trials provides a useful summary, indicating areas in which future consensus may soon be reached. This review may facilitate academic investigators to identify and prioritise topics for future research.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Oxford University Press (OUP)
Date: 18-10-2016
DOI: 10.1093/HMG/DDW349
Publisher: Elsevier BV
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 21-11-2014
DOI: 10.1038/NCOMMS6383
Abstract: The androgen receptor (AR) plays a central role in establishing an oncogenic cascade that drives prostate cancer progression. Some prostate cancers escape androgen dependence and are often associated with an aggressive phenotype. The oestrogen receptor alpha (ERα) is expressed in prostate cancers, independent of AR status. However, the role of ERα remains elusive. Using a combination of chromatin immunoprecipitation (ChIP) and RNA-sequencing data, we identified an ERα-specific non-coding transcriptome signature. Among putatively ERα-regulated intergenic long non-coding RNAs (lncRNAs), we identified nuclear enriched abundant transcript 1 (NEAT1) as the most significantly overexpressed lncRNA in prostate cancer. Analysis of two large clinical cohorts also revealed that NEAT1 expression is associated with prostate cancer progression. Prostate cancer cells expressing high levels of NEAT1 were recalcitrant to androgen or AR antagonists. Finally, we provide evidence that NEAT1 drives oncogenic growth by altering the epigenetic landscape of target gene promoters to favour transcription.
Publisher: Elsevier BV
Date: 04-2020
DOI: 10.1016/J.EURURO.2020.01.012
Abstract: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence. To present the results from the APCCC 2019. Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions. The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process. Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material. These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be in idualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials. The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.
Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2020
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.C.6599642.V1
Abstract: Abstract Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive i SPOP /i -mutant or i TMPRSS2-ERG /i fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion s ling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in i SPOP /i -mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand–receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation. Significance: DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases. /
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-05-2018
Abstract: Hyperglycemia leading to increased oxidative stress is implicated in the increased risk for the development of macrovascular and microvascular complications in patients with type 1 diabetes mellitus. A random subcohort of 349 participants was selected from the DCCT / EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) cohort. This included 320 controls and 29 cardiovascular disease cases that were augmented with 98 additional known cases to yield a case cohort of 447 participants (320 controls, 127 cases). Bios les from DCCT baseline, year 1, and closeout of DCCT , and 1 to 2 years post‐ DCCT ( EDIC years 1 and 2) were measured for markers of oxidative stress, including plasma myeloperoxidase, paraoxonase activity, urinary F 2α isoprostanes, and its metabolite, 2,3 dinor‐8 iso prostaglandin F 2α . Following adjustment for glycated hemoblobin and weighting the observations inversely proportional to the s ling selection probabilities, higher paraoxonase activity, reflective of antioxidant activity, and 2,3 dinor‐8 iso prostaglandin F 2α , an oxidative marker, were significantly associated with lower risk of cardiovascular disease (−4.5% risk for 10% higher paraoxonase, P .003 −5.3% risk for 10% higher 2,3 dinor‐8 iso prostaglandin F 2α , P =0.0092). In contrast, the oxidative markers myeloperoxidase and F 2α isoprostanes were not significantly associated with cardiovascular disease after adjustment for glycated hemoblobin. There were no significant differences between DCCT intensive and conventional treatment groups in the change in all biomarkers across time segments. Heightened antioxidant activity (rather than diminished oxidative stress markers) is associated with lower cardiovascular disease risk in type 1 diabetes mellitus, but these biomarkers did not change over time with intensification of glycemic control. URL : www.clinicaltrials.gov . Unique identifiers: NCT 00360815 and NCT 00360893.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2004
DOI: 10.1158/0008-5472.CAN-03-3881
Abstract: Gains in the long arm of chromosome 8 (8q) are believed to be associated with poor outcome and the development of hormone-refractory prostate cancer. Based on a meta-analysis of gene expression microarray data from multiple prostate cancer studies (D. R. Rhodes et al., Cancer Res 2002 :4427–33), a candidate oncogene, Tumor Protein D52 (TPD52), was identified in the 8q21 licon. TPD52 is a coiled-coil motif-bearing protein, potentially involved in vesicle trafficking. Both mRNA and protein levels of TPD52 were highly elevated in prostate cancer tissues. Array comparative genomic hybridization and lification analysis using single nucleotide polymorphism arrays demonstrated increased DNA copy number in the region encompassing TPD52. Fluorescence in situ hybridization on tissue microarrays confirmed TPD52 lification in prostate cancer epithelia. Furthermore, our studies suggest that TPD52 protein levels may be regulated by androgens, consistent with the presence of androgen response elements in the upstream promoter of TPD52. In summary, these findings suggest that dysregulation of TPD52 by genomic lification and androgen induction may play a role in prostate cancer progression.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633058.V1
Abstract: Supplementary Figures
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.CANLET.2022.215901
Abstract: Emergence of small cell prostate cancer is linked to the plasticity of tumour cells and avoidance of environmental pressures. This process is thought to be reversable, however to-date evidence of this has been demonstrated in small-cell prostate cancer. To study the plasticity of prostate tumours, we look to clinical cohorts of patients covering the spectra of malignancy subtypes and utilise in vitro and in vivo models of disease progression. Current models have assisted in the understanding of the extremities of this plasticity, elucidating internal mechanisms and adaptations to stressors through transition to altered cell states. By interrogating the tumour microenvironment and earlier time points, we are beginning to form a deeper understanding of the full spectra of tumour plasticity. It could be proffered that this deeper understanding will lead to better patient outcome, with earlier interventions more likely to reverse plasticity and prevent trans-differentiation to the aggressive, small cell phenotype.
Publisher: Springer Science and Business Media LLC
Date: 04-01-2021
DOI: 10.1007/S00292-020-00888-4
Abstract: Das zunehmende Verständnis molekularer Grundlagen von Tumoren sowie der Fortschritt in der Diversifizierung der onkologischen Therapien versprechen in idualisierte Therapieoptionen, welche bislang jedoch nur ansatzweise in die Therapieplanung von urologischen Tumoren eingegangen sind. Daher hat die Internationale Gesellschaft für Urologische Pathologie (ISUP) im März 2019 eine Konsenskonferenz zur Erarbeitung evidenzbasierter Handlungsempfehlungen zur molekularpathologischen Diagnostik beim Urothelkarzinom, Nierenzellkarzinom, Prostatakarzinom, Peniskarzinom und testikulären Keimzelltumoren durchgeführt. Die auf dieser Konsenskonferenz erarbeiteten Empfehlungen sind kürzlich in 5 separaten Manuskripten veröffentlich worden und werden in der vorliegenden Arbeit zusammengefasst. Im Rahmen der Konferenzvorbereitung wurde eine umfassende Umfrage zur derzeitigen Praxis molekularer Testungen bei urogenitalen Tumoren unter den Mitgliedern der ISUP durchgeführt. Auf der Konferenz wurden die Ergebnisse und die entsprechenden Hintergrundinformationen durch 5 Arbeitsgruppen präsentiert und Handlungsempfehlungen für die Diagnostik erarbeitet. Eine Übereinstimmung von 66 % der Konferenzteilnehmer wurde als Konsens definiert.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2016
Publisher: Elsevier BV
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 30-11-2020
DOI: 10.1038/S41467-020-20128-W
Abstract: Correction to this paper has been published: 0.1038/s41467-020-20128-w
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 05-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Cold Spring Harbor Laboratory
Date: 30-06-2022
DOI: 10.1101/2022.06.28.497937
Abstract: Precision oncology relies on the accurate identification of somatic mutations in cancer patients. While the sequencing of the tumoral tissue is frequently part of routine clinical care, the healthy counterparts are rarely sequenced. We previously published PipeIT, a somatic variant calling workflow specific for Ion Torrent sequencing data enclosed in a Singularity container. PipeIT combines user-friendly execution, reproducibility and reliable mutation identification, but relies on matched germline sequencing data to exclude germline variants. Expanding on the original PipeIT, here we describe PipeIT2 to address the clinical need to define somatic mutations in the absence of germline control. We show that PipeIT2 achieves a % recall for variants with variant allele fraction %, reliably detects driver and actionable mutations and filters out most of the germline mutations and sequencing artifacts. With its performance, reproducibility and ease of execution, PipeIT2 is a valuable addition to molecular diagnostics laboratories.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.C.6599642
Abstract: Abstract Metastases from primary prostate cancers to rare locations, such as the brain, are becoming more common due to longer life expectancy resulting from improved treatments. Epigenetic dysregulation is a feature of primary prostate cancer, and distinct DNA methylation profiles have been shown to be associated with the mutually exclusive i SPOP /i -mutant or i TMPRSS2-ERG /i fusion genetic backgrounds. Using a cohort of prostate cancer brain metastases (PCBM) from 42 patients, with matched primary tumors for 17 patients, we carried out a DNA methylation analysis to examine the epigenetic distinction between primary prostate cancer and PCBM, the association between epigenetic alterations and mutational background, and particular epigenetic alterations that may be associated with PCBM. Multiregion s ling of PCBM revealed epigenetic stability within metastases. Aberrant methylation in PCBM was associated with mutational background and PRC2 complex activity, an effect that is particularly pronounced in i SPOP /i -mutant PCBM. While PCBM displayed a CpG island hypermethylator phenotype, hypomethylation at the promoters of genes involved in neuroactive ligand–receptor interaction and cell adhesion molecules such as GABRB3, CLDN8, and CLDN4 was also observed, suggesting that cells from primary tumors may require specific reprogramming to form brain metastasis. This study revealed the DNA methylation landscapes of PCBM and the potential mechanisms and effects of PCBM-associated aberrant DNA methylation. Significance: DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases. /
Publisher: Springer Science and Business Media LLC
Date: 28-08-2020
DOI: 10.1038/S41467-020-17359-2
Abstract: Sex differences have been observed in multiple facets of cancer epidemiology, treatment and biology, and in most cancers outside the sex organs. Efforts to link these clinical differences to specific molecular features have focused on somatic mutations within the coding regions of the genome. Here we report a pan-cancer analysis of sex differences in whole genomes of 1983 tumours of 28 subtypes as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We both confirm the results of exome studies, and also uncover previously undescribed sex differences. These include sex-biases in coding and non-coding cancer drivers, mutation prevalence and strikingly, in mutational signatures related to underlying mutational processes. These results underline the pervasiveness of molecular sex differences and strengthen the call for increased consideration of sex in molecular cancer research.
Publisher: Springer Science and Business Media LLC
Date: 03-05-2022
DOI: 10.1038/S41467-022-30003-5
Abstract: Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Elsevier BV
Date: 03-2018
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633061.V1
Abstract: Supplementary Tables
Publisher: Springer Science and Business Media LLC
Date: 08-12-2022
Publisher: American Chemical Society (ACS)
Date: 03-08-2023
Publisher: Elsevier BV
Date: 05-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: American Association for Cancer Research (AACR)
Date: 07-02-2023
DOI: 10.1158/0008-5472.CAN-22-2236
Abstract: DNA methylation analysis reveals the molecular characteristics of PCBM and may serve as a starting point for efforts to identify and target susceptibilities of these rare metastases.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2006
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41586-020-1965-X
Abstract: The discovery of drivers of cancer has traditionally focused on protein-coding genes 1–4 . Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of in idual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers 6,7 , raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53 , in the 3′ untranslated regions of NFKBIZ and TOB1 , focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional ex les of these drivers will be found as more cancer genomes become available.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.CCELL.2018.07.001
Abstract: Our comprehensive analysis of alternative splicing across 32 The Cancer Genome Atlas cancer types from 8,705 patients detects alternative splicing events and tumor variants by reanalyzing RNA and whole-exome sequencing data. Tumors have up to 30% more alternative splicing events than normal s les. Association analysis of somatic variants with alternative splicing events confirmed known trans associations with variants in SF3B1 and U2AF1 and identified additional trans-acting variants (e.g., TADA1, PPP2R1A). Many tumors have thousands of alternative splicing events not detectable in normal s les on average, we identified ≈930 exon-exon junctions ("neojunctions") in tumors not typically found in GTEx normals. From Clinical Proteomic Tumor Analysis Consortium data available for breast and ovarian tumor s les, we confirmed ≈1.7 neojunction- and ≈0.6 single nucleotide variant-derived peptides per tumor s le that are also predicted major histocompatibility complex-I binders ("putative neoantigens").
Publisher: Elsevier BV
Date: 2015
Publisher: Elsevier BV
Date: 04-2018
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
DOI: 10.1038/S41467-020-14367-0
Abstract: The catalog of cancer driver mutations in protein-coding genes has greatly expanded in the past decade. However, non-coding cancer driver mutations are less well-characterized and only a handful of recurrent non-coding mutations, most notably TERT promoter mutations, have been reported. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2658 cancer across 38 tumor types, we perform multi-faceted pathway and network analyses of non-coding mutations across 2583 whole cancer genomes from 27 tumor types compiled by the ICGC/TCGA PCAWG project that was motivated by the success of pathway and network analyses in prioritizing rare mutations in protein-coding genes. While few non-coding genomic elements are recurrently mutated in this cohort, we identify 93 genes harboring non-coding mutations that cluster into several modules of interacting proteins. Among these are promoter mutations associated with reduced mRNA expression in TP53 , TLE4 , and TCF4 . We find that biological processes had variable proportions of coding and non-coding mutations, with chromatin remodeling and proliferation pathways altered primarily by coding mutations, while developmental pathways, including Wnt and Notch, altered by both coding and non-coding mutations. RNA splicing is primarily altered by non-coding mutations in this cohort, and s les containing non-coding mutations in well-known RNA splicing factors exhibit similar gene expression signatures as s les with coding mutations in these genes. These analyses contribute a new repertoire of possible cancer genes and mechanisms that are altered by non-coding mutations and offer insights into additional cancer vulnerabilities that can be investigated for potential therapeutic treatments.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 19-07-2013
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2023
DOI: 10.1158/0008-5472.22633061
Abstract: Supplementary Tables
Publisher: Springer Science and Business Media LLC
Date: 16-10-2014
DOI: 10.1007/S00428-014-1668-5
Abstract: Active surveillance (AS) is an important management option for men with low-risk, clinically localized prostate cancer. The clinical parameters for patient selection and definition of progression for AS protocols are evolving as data from several large cohorts matures. Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for AS. These findings need to be reproducible and consistently reported by surgical pathologists. This report highlights the importance of accurate pathology reporting as a critical component of these protocols.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2018
DOI: 10.1158/2159-8290.CD-18-0657
Abstract: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies CREBBP somatic mutation. These results advocate for sequencing TET2 in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors. See related commentary by Shingleton and Dave, p. 1515. This article is highlighted in the In This Issue feature, p. 1494
Publisher: Springer Science and Business Media LLC
Date: 18-02-2021
DOI: 10.1038/S41467-021-21300-6
Abstract: Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1 -like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
Publisher: Elsevier BV
Date: 08-2019
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Cold Spring Harbor Laboratory
Date: 18-03-2020
DOI: 10.1101/2020.03.17.994350
Abstract: Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe a novel androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbours BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1 -like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modelled in vivo . Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 06-2018
Publisher: Springer Science and Business Media LLC
Date: 07-04-2016
DOI: 10.1038/SREP24146
Abstract: Recent large-scale genome analyses of human tissue s les have uncovered a high degree of genetic alterations and tumour heterogeneity in most tumour entities, independent of morphological phenotypes and histopathological characteristics. Assessment of genetic copy-number variation (CNV) and tumour heterogeneity by fluorescence in situ hybridization (ISH) provides additional tissue morphology at single-cell resolution, but it is labour intensive with limited throughput and high inter-observer variability. We present an integrative method combining bright-field dual-colour chromogenic and silver ISH assays with an image-based computational workflow (ISHProfiler), for accurate detection of molecular signals, high-throughput evaluation of CNV, expressive visualization of multi-level heterogeneity (cellular, inter- and intra-tumour heterogeneity), and objective quantification of heterogeneous genetic deletions ( PTEN ) and lifications (19q12, HER2 ) in erse human tumours (prostate, endometrial, ovarian and gastric), using various tissue sizes and different scanners, with unprecedented throughput and reproducibility.
Publisher: Elsevier BV
Date: 10-2018
Publisher: Elsevier BV
Date: 04-2018
Location: United States of America
Location: United States of America
Start Date: 2007
End Date: 2010
Funder: Australian Research Council
View Funded ActivityStart Date: 2005
End Date: 2007
Funder: Australian Research Council
View Funded Activity