ORCID Profile
0000-0002-0557-9379
Current Organisations
University of Nottingham
,
Leeds radiology training scheme
,
North Staffordshire Medical training scheme
,
Institute of Cancer Research Sutton
,
Royal Marsden Hospital Chelsea
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Publications
Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study
Publisher: Springer Science and Business Media LLC
Date: 23-12-2021
DOI: 10.1038/S41559-021-01586-X
Abstract: Genetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal ersification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal ersification, enabling interpretation of clonal ersity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and micro ersity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal ersification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution.
Supplementary Tables S1-S8 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283213
Abstract: S. Table 1: List of PEACE Consortium members. S. Table 2: S le database used for the study for Panel, Exome and RNASeq s les. S. Table 3: Overview of lines of treatment given to each patient. S. Table 4: Lesions and patients included in the lesion-level response to ICI analysis. S. Table 5: Hallmark genesets significantly upregulated in normal tissue vs tumor tissue. Table shows p-values for tissue type, purity T value for tissue type, purity q-value for tissue type, purity (FDR corrected). S. Table 6: Hallmark genesets significantly upregulated in tumor tissue vs normal tissue. Table shows p-values for tissue type, purity T value for tissue type, purity q-value for tissue type, purity (FDR corrected). S. Table 7: Genes included in the target panel. S. Table 8: Tree topology comparisons between manually constructed trees and pairtree-constructed trees.
Figure 1 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283237
Abstract: Driver mutations and SCNA overview. b A, /b Genomic landscape of the cohort, illustrating mutations in key melanoma driver genes, TMB (total mutations/Mb), ploidy, WGD status, weighted genome instability index (wGII, an SCNA burden metric), and the anatomic site of each s le. “Multi-variant” indicates the presence of more than one variant in the same gene within one s le. Panel and WES s les are included. AD, adrenal BR, brain LI, liver LMS, leptomeninges LN, lymph node LU, lung PE, peritoneum PR, primary ST, soft tissue. b B, /b The proportion of the genome altered by copy-number gains and losses per s le in diploid and WGD tumor s les. b C, /b The frequency of copy-number gains and losses along the genome (based on WES data only). Dark red and blue indicate clonal events, and light red and blue indicate subclonal events. Also shown are frequency of clonal and subclonal LOH and AI.
A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors
Publisher: Springer Science and Business Media LLC
Date: 06-02-2013
DOI: 10.1007/S00280-013-2099-8
Abstract: The CC-chemokine ligand 2 (CCL2) is highly expressed in various malignancies and promotes carcinogenesis. Blocking CCL2 has preclinical antitumor activity. A phase 1 trial of carlumab (CNTO 888), a human anti-CCL2 IgG1κ mAb, was conducted to evaluate the safety, tolerability, pharmacokinetic-pharmacodynamic profile, and antitumor activity. Patients with advanced solid malignancy received escalating doses of carlumab 0.3, 1, 3, 10, or 15 mg/kg by 90-min intravenous infusion on days 1, 28, and every 2 weeks thereafter (dose escalation) or 10 or 15 mg/kg every 2 weeks (dose-expansion). Pharmacodynamic assessments were also performed. Forty-four patients received 206 doses of carlumab. MTD was not established. Carlumab-related adverse events included grade 1-2 fatigue (9 %), nausea (7 %), headache (7 %), vomiting (5 %), and pruritus (5 %). The recommended phase II dose was 15 mg/kg every 2 weeks. Carlumab concentrations declined bi-exponentially with a terminal half-life of 6.6-9.6 days. Free CCL2 was transiently suppressed, while total CCL2 increased dose-dependently >1,000-fold post-treatment. A patient with ovarian cancer and a patient with prostate cancer achieved CA125 and PSA reductions of >50 % and RECIST SD for 10.5 and 5 months, respectively. Two other patients had RECIST SD for 7.2 and 15.7 months. Carlumab was well tolerated with evidence of transient free CCL2 suppression and preliminary antitumor activity.
Supplementary Figures S1-S25 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283216
Abstract: Supplementary figure 1: Cohort overview. Number of s les sequenced with whole exome, panel or whole RNA sequencing. Supplementary figure 2: Phylogeny and WGD events in CRUKP1047. Supplementary figure 3: Ploidy and SCNA burden. Supplementary figure 4: Overview of each case. Supplementary figure 5: MEDICC2 copy number s le trees. Supplementary figure 6: MEDICC tree of all exome s les demonstrating that s les cluster together by patient, and not by melanoma subtype. Supplementary figure 7: SCNA frequency of cutaneous (a), acral (b) and melanoma of unknown primary (MUP, c). Supplementary figure 8: Correlation between liver copy number distance to other sites and time of emergence after stage IV diagnosis. Supplementary figure 9: Examination of tumour heterogeneity of alterations to antigen-presentation machinery genes,with site and patient annotation. Supplementary figure 10: Boxplots indicating the proportion of losses in the cohort for each segment. Supplementary figure 11: Balance of expression between nonsynonymous mutations that were not predicted to be neoantigens and clonal predicted neoantigens. Supplementary figure 12: Barplot of TIL infiltration score frequencies, determined by pathologist assessment of histology, across all s les. Supplementary figure 13: Number of s les per patient that are classified as either none-low in terms of TILs or moderate-heavy. Supplementary figure 14: Histogram of purity for s les with RNA-seq data. Supplementary figure 15: TME deconvolution. Supplementary figure 16: The effect of metastatic site on transcriptional profiles. Supplementary figure 17: Association of PHF3 copy number with expression. Supplementary figure 18: Overview of gene fusions identified in RNA-seq data. Supplementary figure 19: Comparison of ploidy estimates from panel sequencing data, exome data and FISH. Supplementary figure 20: Comparison of ploidy estimates in panel, exome, FISH and single cell data. Supplementary figure 21: FACs sort plot for CRUKP2567 diaphragmatic metastasis. Supplementary figure 22: Ploidy and wGII values from single cell sequencing of FACS-sorted tumour cells. Supplementary figure 23: Copy number profiles on chromosome 5 for bulk s les from primary and DI_2_R2, a diaphragmatic metastasis. Supplementary figure 24: Histogram of purity of s les for which RNA-seq was performed faceted by patient. Supplementary figure 25: Histogram of purity of s les for which RNA-seq was performed faceted by tissue site.
Figure 3 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283231
Abstract: Late-emerging brain metastases have a lower copy-number burden. b A, /b wGII per metastatic site. Site-specific null distributions of mean wGII were generated by randomizing s le sets (from any metastatic site) while keeping patient contributions constant (see Methods). **, i P /i ≤ 0.01. Leptomen., leptomeninges. b B, /b Correlation between brain copy-number (CN) distance to other sites and time of emergence of brain metastases after stage IV diagnosis in days. b C, /b Growth dynamics of tumors in patient CRUKP5107. The brain lesion (in orange) was detected in only the last two scans after the targeted therapy [BRAF inhibitor (i) + MEKi], ICI (PD-1i + CTLA4i), and chemotherapy courses. PD, progressive disease PR, partial response SD, stable disease. b D, /b SNV and indel phylogenetic tree of tumor clones in patient CRUKP5107. b E, /b The mutational signature contributions to each clone in the phylogeny in b D /b are shown. MMR, mismatch repair. b F, /b The anatomic distribution of clones. Each pie chart represents a s le with its clonal composition indicated by the colors. A multiregional s ling of the same tumor is indicated by the gray dashed lines. BR, brain LI, liver LU, lung PC, pericardium ST, soft tissue.
Supplementary Figures S1-S25 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/2159-8290.22841335.V1
Abstract: Supplementary figure 1: Cohort overview. Number of s les sequenced with whole exome, panel or whole RNA sequencing. Supplementary figure 2: Phylogeny and WGD events in CRUKP1047. Supplementary figure 3: Ploidy and SCNA burden. Supplementary figure 4: Overview of each case. Supplementary figure 5: MEDICC2 copy number s le trees. Supplementary figure 6: MEDICC tree of all exome s les demonstrating that s les cluster together by patient, and not by melanoma subtype. Supplementary figure 7: SCNA frequency of cutaneous (a), acral (b) and melanoma of unknown primary (MUP, c). Supplementary figure 8: Correlation between liver copy number distance to other sites and time of emergence after stage IV diagnosis. Supplementary figure 9: Examination of tumour heterogeneity of alterations to antigen-presentation machinery genes, with site and patient annotation. Supplementary figure 10: Boxplots indicating the proportion of losses in the cohort for each segment. Supplementary figure 11: Balance of expression between nonsynonymous mutations that were not predicted to be neoantigens and clonal predicted neoantigens. Supplementary figure 12: Barplot of TIL infiltration score frequencies, determined by pathologist assessment of histology, across all s les. Supplementary figure 13: Number of s les per patient that are classified as either none-low in terms of TILs or moderate-heavy. Supplementary figure 14: Histogram of purity for s les with RNA-seq data. Supplementary figure 15: TME deconvolution. Supplementary figure 16: The effect of metastatic site on transcriptional profiles. Supplementary figure 17: Association of PHF3 copy number with expression. Supplementary figure 18: Overview of gene fusions identified in RNA-seq data. Supplementary figure 19: Comparison of ploidy estimates from panel sequencing data, exome data and FISH. Supplementary figure 20: Comparison of ploidy estimates in panel, exome, FISH and single cell data. Supplementary figure 21: FACs sort plot for CRUKP2567 diaphragmatic metastasis. Supplementary figure 22: Ploidy and wGII values from single cell sequencing of FACS-sorted tumour cells. Supplementary figure 23: Copy number profiles on chromosome 5 for bulk s les from primary and DI_2_R2, a diaphragmatic metastasis. Supplementary figure 24: Histogram of purity of s les for which RNA-seq was performed faceted by patient. Supplementary figure 25: Histogram of purity of s les for which RNA-seq was performed faceted by tissue site.
Figure 2 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283234
Abstract: b A, /b Phylogenies inferred for the 14 patients. Only WES s les are included. Letters in brackets indicate melanoma subtype: A = acral, C = cutaneous, M = mucosal, U = melanoma of unknown primary. Branch length is proportional to the number of mutations. Branch colors represent the mutational signatures of the mutations. For clarity, only the most common mutational signatures are shown the remainder are categorized as “unknown.” Scale bars indicate the number of mutations. The legend includes etiologies for each signature ( a href="#bib24" target="_blank" /a ). MMR, mismatch repair. b B, /b Boxplots indicate the ratio of subclonal mutations (length of branches) to clonal mutations (length of the trunk) by subtype and chemotherapy status. Values smaller than zero indicate the dominance of truncal mutations. Mann–Whitney i U /i test was used for statistical comparisons (**, i P /i 0.01 ***, i P /i 0.001). Cut., cutaneous mut., mutation.
Figure 3 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283231.V1
Abstract: Late-emerging brain metastases have a lower copy-number burden. b A, /b wGII per metastatic site. Site-specific null distributions of mean wGII were generated by randomizing s le sets (from any metastatic site) while keeping patient contributions constant (see Methods). **, i P /i ≤ 0.01. Leptomen., leptomeninges. b B, /b Correlation between brain copy-number (CN) distance to other sites and time of emergence of brain metastases after stage IV diagnosis in days. b C, /b Growth dynamics of tumors in patient CRUKP5107. The brain lesion (in orange) was detected in only the last two scans after the targeted therapy [BRAF inhibitor (i) + MEKi], ICI (PD-1i + CTLA4i), and chemotherapy courses. PD, progressive disease PR, partial response SD, stable disease. b D, /b SNV and indel phylogenetic tree of tumor clones in patient CRUKP5107. b E, /b The mutational signature contributions to each clone in the phylogeny in b D /b are shown. MMR, mismatch repair. b F, /b The anatomic distribution of clones. Each pie chart represents a s le with its clonal composition indicated by the colors. A multiregional s ling of the same tumor is indicated by the gray dashed lines. BR, brain LI, liver LU, lung PC, pericardium ST, soft tissue.
Report of the 6th International Workshop on PET in lymphoma
Publisher: Informa UK Limited
Date: 07-03-2017
DOI: 10.1080/10428194.2017.1298752
Abstract: Two hundred and ten nuclear medicine physicians, radiologists, and hematologists from 26 countries attended the 6th International Workshop on Positron Emission Tomography (PET) in Lymphoma and Myeloma held in Menton, France, in September 2016. The meeting was under the auspices of the European Lymphoma Institute (ELI), the European Association of Nuclear Medicine (EANM) the Lymphoma Study Association (LYSA), the Italian Foundation on Lymphoma (FIL) and the Carnot Institute for Lymphoma (CALYM). Forty scientific posters were presented. For the first time, specialists in the field of multiple myeloma (MM) were involved in the expert session. The aim was to establish from the experience of Italian and French studies new guidelines of FDG-PET/CT reporting for myeloma staging and restaging. The meeting dedicated an entire session to MM imaging followed by a session on the role of PET in Peripheral T cell Lymphoma. An entire session addressed the issues of Deauville scale particularly for end treatment assessment and the challenging consequences of immunomodulatory treatments on PET reporting. A specific session presented the potential role of baseline metabolic tumor measurement to predict outcome and identify different risk categories and the main results obtained in different lymphoma entities were described. Whether it could replace clinical staging has been extensively discussed. The more recent results obtained in the H10 trial have been presented and compared to the published data in early stage Hodgkin lymphoma. Finally, the ongoing studies using PET for guiding therapeutic strategies have been reported by the various lymphoma cooperative groups that participated to the meeting.
Determining the incidence of interstitial pneumonitis and chronic kidney disease following full intensity haemopoetic stem cell transplant conditioned using a forward-planned intensity modulated total
Publisher: Elsevier BV
Date: 05-2021
Data from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.C.6649132.V2
Abstract: Abstract Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing s les from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found i KIT /i extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, i MYC /i lifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that erged early in molecular evolution emerge late in disease. Overall, our study illustrates the erse evolutionary landscape of advanced melanoma. Significance: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense s ling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0340" target="_blank" See related commentary by Shain, p. 1294. /a /i i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-6-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1275 /a /i /
Supplementary Figures S1-S25 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283216.V1
Abstract: Supplementary figure 1: Cohort overview. Number of s les sequenced with whole exome, panel or whole RNA sequencing. Supplementary figure 2: Phylogeny and WGD events in CRUKP1047. Supplementary figure 3: Ploidy and SCNA burden. Supplementary figure 4: Overview of each case. Supplementary figure 5: MEDICC2 copy number s le trees. Supplementary figure 6: MEDICC tree of all exome s les demonstrating that s les cluster together by patient, and not by melanoma subtype. Supplementary figure 7: SCNA frequency of cutaneous (a), acral (b) and melanoma of unknown primary (MUP, c). Supplementary figure 8: Correlation between liver copy number distance to other sites and time of emergence after stage IV diagnosis. Supplementary figure 9: Examination of tumour heterogeneity of alterations to antigen-presentation machinery genes,with site and patient annotation. Supplementary figure 10: Boxplots indicating the proportion of losses in the cohort for each segment. Supplementary figure 11: Balance of expression between nonsynonymous mutations that were not predicted to be neoantigens and clonal predicted neoantigens. Supplementary figure 12: Barplot of TIL infiltration score frequencies, determined by pathologist assessment of histology, across all s les. Supplementary figure 13: Number of s les per patient that are classified as either none-low in terms of TILs or moderate-heavy. Supplementary figure 14: Histogram of purity for s les with RNA-seq data. Supplementary figure 15: TME deconvolution. Supplementary figure 16: The effect of metastatic site on transcriptional profiles. Supplementary figure 17: Association of PHF3 copy number with expression. Supplementary figure 18: Overview of gene fusions identified in RNA-seq data. Supplementary figure 19: Comparison of ploidy estimates from panel sequencing data, exome data and FISH. Supplementary figure 20: Comparison of ploidy estimates in panel, exome, FISH and single cell data. Supplementary figure 21: FACs sort plot for CRUKP2567 diaphragmatic metastasis. Supplementary figure 22: Ploidy and wGII values from single cell sequencing of FACS-sorted tumour cells. Supplementary figure 23: Copy number profiles on chromosome 5 for bulk s les from primary and DI_2_R2, a diaphragmatic metastasis. Supplementary figure 24: Histogram of purity of s les for which RNA-seq was performed faceted by patient. Supplementary figure 25: Histogram of purity of s les for which RNA-seq was performed faceted by tissue site.
Data from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/2159-8290.C.6649132.V1
Abstract: Abstract Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing s les from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found i KIT /i extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, i MYC /i lifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that erged early in molecular evolution emerge late in disease. Overall, our study illustrates the erse evolutionary landscape of advanced melanoma. Significance: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense s ling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. /
Figure 1 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283237.V1
Abstract: Driver mutations and SCNA overview. b A, /b Genomic landscape of the cohort, illustrating mutations in key melanoma driver genes, TMB (total mutations/Mb), ploidy, WGD status, weighted genome instability index (wGII, an SCNA burden metric), and the anatomic site of each s le. “Multi-variant” indicates the presence of more than one variant in the same gene within one s le. Panel and WES s les are included. AD, adrenal BR, brain LI, liver LMS, leptomeninges LN, lymph node LU, lung PE, peritoneum PR, primary ST, soft tissue. b B, /b The proportion of the genome altered by copy-number gains and losses per s le in diploid and WGD tumor s les. b C, /b The frequency of copy-number gains and losses along the genome (based on WES data only). Dark red and blue indicate clonal events, and light red and blue indicate subclonal events. Also shown are frequency of clonal and subclonal LOH and AI.
Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study
Publisher: Springer Science and Business Media LLC
Date: 27-10-2021
DOI: 10.1038/S43018-021-00274-W
Abstract: Coronavirus disease 2019 (COVID-19) antiviral response in a pan-tumor immune monitoring (CAPTURE) ( NCT03226886 ) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable titers of neutralizing antibodies (NAbT) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) versus wild-type (WT) SARS-CoV-2. Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT than those with solid cancers against both SARS-CoV-2 WT and VOC. By comparison with in iduals without cancer, patients with hematological, but not solid, malignancies had reduced neutralizing antibody (NAb) responses. Seroconversion showed poor concordance with NAbT against VOC. Previous SARS-CoV-2 infection boosted the NAb response including against VOC, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T cell responses were detected in 80% of patients and were comparable between vaccines or cancer types. Our results have implications for the management of patients with cancer during the ongoing COVID-19 pandemic.
Figure 5 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283225.V1
Abstract: Tissue-level lifications and deletions associated with response to ICI. A large proportion of s les underwent WGD ( b A /b ), with successive WGD events associated with increasing wGII ( b B /b ). Letters in brackets indicate melanoma subtype: A = acral, C = cutaneous, M = mucosal, U = melanoma of unknown primary. ***, i P /i 0.001. GISTIC permutation analysis ( b C /b ) associated i MYC /i lification (chromosome 8q) with a nonresponsive phenotype, as well as chromosome 1 lification with a responsive phenotype. Horizontal black dashed lines in top two panels of b C /b indicate significance ( i P /i 0.05). NR, nonresponse R, response. b D, /b Significant lifications on chromosomes 1 and 8 from b C /b with COSMIC genes labeled.
Figure 4 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283228
Abstract: Mechanisms of resistance to therapy. b A, /b i KIT /i copy number vs. KIT expression in matching exome and RNA-seq s les. TPM, transcripts per million. b B, /b Hierarchical clustering tree of SCNAs found in the single cells of a representative s le of CRUKP9359. Bars on the right show the copy number of i KIT /i in each cell. b C, /b Diagram of split reads mapping at the edges of the lified region, from which a circular structure can be inferred. Created with a href="BioRender.com" target="_blank" BioRender.com /a . b D, /b Images showing FISH probes against i KIT /i (red) in in idual cells. b E, /b Heat map of alterations in antigen-presentation genes in the exome data. Each column represents a s le. LOH events are shown in red and blue, and nonsynonymous mutations are in red and purple. Bars on the i x /i -axis show the number of genes altered in each s le, whereas i y /i -axis bars show the number of s les altered per gene, colored by the type of event.
Figure 4 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283228.V1
Abstract: Mechanisms of resistance to therapy. b A, /b i KIT /i copy number vs. KIT expression in matching exome and RNA-seq s les. TPM, transcripts per million. b B, /b Hierarchical clustering tree of SCNAs found in the single cells of a representative s le of CRUKP9359. Bars on the right show the copy number of i KIT /i in each cell. b C, /b Diagram of split reads mapping at the edges of the lified region, from which a circular structure can be inferred. Created with a href="BioRender.com" target="_blank" BioRender.com /a . b D, /b Images showing FISH probes against i KIT /i (red) in in idual cells. b E, /b Heat map of alterations in antigen-presentation genes in the exome data. Each column represents a s le. LOH events are shown in red and blue, and nonsynonymous mutations are in red and purple. Bars on the i x /i -axis show the number of genes altered in each s le, whereas i y /i -axis bars show the number of s les altered per gene, colored by the type of event.
Figure 5 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283225
Abstract: Tissue-level lifications and deletions associated with response to ICI. A large proportion of s les underwent WGD ( b A /b ), with successive WGD events associated with increasing wGII ( b B /b ). Letters in brackets indicate melanoma subtype: A = acral, C = cutaneous, M = mucosal, U = melanoma of unknown primary. ***, i P /i 0.001. GISTIC permutation analysis ( b C /b ) associated i MYC /i lification (chromosome 8q) with a nonresponsive phenotype, as well as chromosome 1 lification with a responsive phenotype. Horizontal black dashed lines in top two panels of b C /b indicate significance ( i P /i 0.05). NR, nonresponse R, response. b D, /b Significant lifications on chromosomes 1 and 8 from b C /b with COSMIC genes labeled.
Validating a robust double‐quantum‐filtered 1H MRS lactate measurement method in high‐grade brain tumours
Publisher: Wiley
Date: 11-08-2016
DOI: 10.1002/NBM.3587
Abstract: (1) H MRS measurements of lactate are often confounded by overlapping lipid signals. Double-quantum (DQ) filtering eliminates lipid signals and permits single-shot measurements, which avoid subtraction artefacts in moving tissues. This study evaluated a single-voxel-localized DQ filtering method qualitatively and quantitatively for measuring lactate concentrations in the presence of lipid, using high-grade brain tumours in which the results could be compared with standard acquisition as a reference. Paired standard acquisition and DQ-filtered (1) H MR spectra were acquired at 3T from patients receiving treatment for glioblastoma, using fLASER (localization by adiabatic selective refocusing using frequency offset corrected inversion pulses) single-voxel localization. Data were acquired from 2 × 2 × 2 cm(3) voxels, with a repetition time of 1 s and 128 averages (standard acquisition) or 256 averages (DQ-filtered acquisition), requiring 2.15 and 4.3 min respectively. Of 37 evaluated data pairs, 20 cases (54%) had measureable lactate (fitted Cramér-Rao lower bounds ≤ 20%) in either the DQ-filtered or the standard acquisition spectra. The measured DQ-filtered lactate signal was consistently downfield of lipid (1.33 ± 0.03 ppm vs 1.22 ± 0.08 ppm p = 0.002), showing that it was not caused by lipid breakthrough, and that it matched the lactate signal seen in standard measurements (1.36 ± 0.02 ppm). In the absence of lipid, similar lactate concentrations were measured by the two methods (mean ratio DQ filtered/standard acquisition = 1.10 ± 0.21). In 7/20 cases with measurable lactate, signal was not measureable in the standard acquisition owing to lipid overlap but was quantified in the DQ-filtered acquisition. Conversely, lactate was undetected in seven DQ-filtered acquisitions but visible using the standard acquisition. In conclusion, the DQ filtering method has proven robust in eliminating lipid and permits uncontaminated measurement of lactate. This is important validation prior to use in tissues outside the brain, which contain large amounts of lipid and which are often susceptible to motion.
Functional antibody and T cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study
Publisher: Springer Science and Business Media LLC
Date: 27-10-2021
DOI: 10.1038/S43018-021-00275-9
Abstract: Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study, integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2 positive, 94 were symptomatic and 2 died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies and 82% had neutralizing antibodies against wild type SARS-CoV-2, whereas neutralizing antibody titers against the Alpha, Beta and Delta variants were substantially reduced. S1-reactive antibody levels decreased in 13% of patients, whereas neutralizing antibody titers remained stable for up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4 + responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment specific, but presented compensatory cellular responses, further supported by clinical recovery in all but one patient. Overall, these findings advance the understanding of the nature and duration of the immune response to SARS-CoV-2 in patients with cancer.
Figure 2 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283234.V1
Abstract: b A, /b Phylogenies inferred for the 14 patients. Only WES s les are included. Letters in brackets indicate melanoma subtype: A = acral, C = cutaneous, M = mucosal, U = melanoma of unknown primary. Branch length is proportional to the number of mutations. Branch colors represent the mutational signatures of the mutations. For clarity, only the most common mutational signatures are shown the remainder are categorized as “unknown.” Scale bars indicate the number of mutations. The legend includes etiologies for each signature ( a href="#bib24" target="_blank" /a ). MMR, mismatch repair. b B, /b Boxplots indicate the ratio of subclonal mutations (length of branches) to clonal mutations (length of the trunk) by subtype and chemotherapy status. Values smaller than zero indicate the dominance of truncal mutations. Mann–Whitney i U /i test was used for statistical comparisons (**, i P /i 0.01 ***, i P /i 0.001). Cut., cutaneous mut., mutation.
Supplementary Figures S1-S25 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/2159-8290.22841335
Abstract: Supplementary figure 1: Cohort overview. Number of s les sequenced with whole exome, panel or whole RNA sequencing. Supplementary figure 2: Phylogeny and WGD events in CRUKP1047. Supplementary figure 3: Ploidy and SCNA burden. Supplementary figure 4: Overview of each case. Supplementary figure 5: MEDICC2 copy number s le trees. Supplementary figure 6: MEDICC tree of all exome s les demonstrating that s les cluster together by patient, and not by melanoma subtype. Supplementary figure 7: SCNA frequency of cutaneous (a), acral (b) and melanoma of unknown primary (MUP, c). Supplementary figure 8: Correlation between liver copy number distance to other sites and time of emergence after stage IV diagnosis. Supplementary figure 9: Examination of tumour heterogeneity of alterations to antigen-presentation machinery genes, with site and patient annotation. Supplementary figure 10: Boxplots indicating the proportion of losses in the cohort for each segment. Supplementary figure 11: Balance of expression between nonsynonymous mutations that were not predicted to be neoantigens and clonal predicted neoantigens. Supplementary figure 12: Barplot of TIL infiltration score frequencies, determined by pathologist assessment of histology, across all s les. Supplementary figure 13: Number of s les per patient that are classified as either none-low in terms of TILs or moderate-heavy. Supplementary figure 14: Histogram of purity for s les with RNA-seq data. Supplementary figure 15: TME deconvolution. Supplementary figure 16: The effect of metastatic site on transcriptional profiles. Supplementary figure 17: Association of PHF3 copy number with expression. Supplementary figure 18: Overview of gene fusions identified in RNA-seq data. Supplementary figure 19: Comparison of ploidy estimates from panel sequencing data, exome data and FISH. Supplementary figure 20: Comparison of ploidy estimates in panel, exome, FISH and single cell data. Supplementary figure 21: FACs sort plot for CRUKP2567 diaphragmatic metastasis. Supplementary figure 22: Ploidy and wGII values from single cell sequencing of FACS-sorted tumour cells. Supplementary figure 23: Copy number profiles on chromosome 5 for bulk s les from primary and DI_2_R2, a diaphragmatic metastasis. Supplementary figure 24: Histogram of purity of s les for which RNA-seq was performed faceted by patient. Supplementary figure 25: Histogram of purity of s les for which RNA-seq was performed faceted by tissue site.
Figure 6 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283222
Abstract: Identification of a likely non–whole-genome–doubled clone that was not identifiable from bulk sequencing data in CRUKP2567. Clonal phylogeny of CRUKP2567 ( b A /b ), with anatomic diagram b (B) /b based on bulk SNVs mapping s les to clones on the tree. The scale indicates the number of mutations. b C, /b MEDICC2 copy-number tree for bulk exome s les from CRUKP2567. The cluster highlighted in blue has undergone one WGD event, while the other nonhighlighted cluster, containing brain metastasis and primary tumor s les, has not. Diamonds indicate the s les for which bulk copy-number profiles are displayed in Supplementary Fig. S23. b D, /b Hierarchical clustering tree containing all single cells (SS) from FACs-high-ploidy sorting (FH) and FACs-low-ploidy sorting (FL), as well as WGD bulk s les and non-WGD bulk s les. b E, /b Radiologic images of the patient indicating thorax upon initiation of stage IV disease and complete extracranial response to BRAF inhibitor, followed by rapid recolonization of the thorax with resistant clones (left to right). BR, brain BRAFi, BRAF inhibitor CR, complete response DI, diaphragm LN, lymph node LU, lung MEKi, MEK inhibitor PC, pericardium, PLFa, pleural fluid (archival) PR, primary.
Supplementary Tables S1-S8 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283213.V1
Abstract: S. Table 1: List of PEACE Consortium members. S. Table 2: S le database used for the study for Panel, Exome and RNASeq s les. S. Table 3: Overview of lines of treatment given to each patient. S. Table 4: Lesions and patients included in the lesion-level response to ICI analysis. S. Table 5: Hallmark genesets significantly upregulated in normal tissue vs tumor tissue. Table shows p-values for tissue type, purity T value for tissue type, purity q-value for tissue type, purity (FDR corrected). S. Table 6: Hallmark genesets significantly upregulated in tumor tissue vs normal tissue. Table shows p-values for tissue type, purity T value for tissue type, purity q-value for tissue type, purity (FDR corrected). S. Table 7: Genes included in the target panel. S. Table 8: Tree topology comparisons between manually constructed trees and pairtree-constructed trees.
Supplementary Tables S1-S8 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/2159-8290.22841332.V1
Abstract: S. Table 1: List of PEACE Consortium members. S. Table 2: S le database used for the study for Panel, Exome and RNASeq s les. S. Table 3: Overview of lines of treatment given to each patient. S. Table 4: Lesions and patients included in the lesion-level response to ICI analysis. S. Table 5: Hallmark genesets significantly upregulated in normal tissue vs tumor tissue. Table shows p-values for tissue type, purity T value for tissue type, purity q-value for tissue type, purity (FDR corrected). S. Table 6: Hallmark genesets significantly upregulated in tumor tissue vs normal tissue. Table shows p-values for tissue type, purity T value for tissue type, purity q-value for tissue type, purity (FDR corrected). S. Table 7: Genes included in the target panel. S. Table 8: Tree topology comparisons between manually constructed trees and pairtree-constructed trees.
Supplementary Tables S1-S8 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 16-05-2023
DOI: 10.1158/2159-8290.22841332
Abstract: S. Table 1: List of PEACE Consortium members. S. Table 2: S le database used for the study for Panel, Exome and RNASeq s les. S. Table 3: Overview of lines of treatment given to each patient. S. Table 4: Lesions and patients included in the lesion-level response to ICI analysis. S. Table 5: Hallmark genesets significantly upregulated in normal tissue vs tumor tissue. Table shows p-values for tissue type, purity T value for tissue type, purity q-value for tissue type, purity (FDR corrected). S. Table 6: Hallmark genesets significantly upregulated in tumor tissue vs normal tissue. Table shows p-values for tissue type, purity T value for tissue type, purity q-value for tissue type, purity (FDR corrected). S. Table 7: Genes included in the target panel. S. Table 8: Tree topology comparisons between manually constructed trees and pairtree-constructed trees.
Adaptive immunity to SARS-CoV-2 in cancer patients: The CAPTURE study
Publisher: Cold Spring Harbor Laboratory
Date: 23-12-2020
DOI: 10.1101/2020.12.21.20248608
Abstract: There is a pressing need to characterise the nature, extent and duration of immune response to SARS-CoV-2 in cancer patients and inform risk-reduction strategies and preserve cancer outcomes. CAPTURE is a prospective, longitudinal cohort study of cancer patients and healthcare workers (HCWs) integrating longitudinal immune profiling and clinical annotation. We evaluated 529 blood s les and 1051 oronasopharyngeal swabs from 144 cancer patients and 73 HCWs and correlated with clinical variables. In patients with solid cancers and HCWs, S1-reactive and neutralising antibodies to SARS-CoV-2 were detectable five months post-infection. SARS-CoV-2-specific T-cell responses were detected, and CD4 + T-cell responses correlated with S1 antibody levels. Patients with haematological malignancies had impaired but partially compensated immune responses. Overall, cancer stage, disease status, and therapies did not correlate with immune responses. These findings have implications for understanding in idual risks and potential effectiveness of SARS-CoV-2 vaccination in the cancer population.
Figure 6 from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.23283222.V1
Abstract: Identification of a likely non–whole-genome–doubled clone that was not identifiable from bulk sequencing data in CRUKP2567. Clonal phylogeny of CRUKP2567 ( b A /b ), with anatomic diagram b (B) /b based on bulk SNVs mapping s les to clones on the tree. The scale indicates the number of mutations. b C, /b MEDICC2 copy-number tree for bulk exome s les from CRUKP2567. The cluster highlighted in blue has undergone one WGD event, while the other nonhighlighted cluster, containing brain metastasis and primary tumor s les, has not. Diamonds indicate the s les for which bulk copy-number profiles are displayed in Supplementary Fig. S23. b D, /b Hierarchical clustering tree containing all single cells (SS) from FACs-high-ploidy sorting (FH) and FACs-low-ploidy sorting (FL), as well as WGD bulk s les and non-WGD bulk s les. b E, /b Radiologic images of the patient indicating thorax upon initiation of stage IV disease and complete extracranial response to BRAF inhibitor, followed by rapid recolonization of the thorax with resistant clones (left to right). BR, brain BRAFi, BRAF inhibitor CR, complete response DI, diaphragm LN, lymph node LU, lung MEKi, MEK inhibitor PC, pericardium, PLFa, pleural fluid (archival) PR, primary.
Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 28-03-2023
DOI: 10.1158/2159-8290.CD-22-1427
Abstract: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense s ling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275
Data from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Publisher: American Association for Cancer Research (AACR)
Date: 02-06-2023
DOI: 10.1158/2159-8290.C.6649132
Abstract: Abstract Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing s les from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found i KIT /i extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, i MYC /i lifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that erged early in molecular evolution emerge late in disease. Overall, our study illustrates the erse evolutionary landscape of advanced melanoma. Significance: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense s ling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0340" target="_blank" See related commentary by Shain, p. 1294. /a /i i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-13-6-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 1275 /a /i /
Related Organisations
University Of Nottingham
Location: United Kingdom of Great Britain and Northern Ireland
Leeds Radiology Training Scheme
Location: United Kingdom of Great Britain and Northern Ireland
North Staffordshire Medical Training Scheme
Location: United Kingdom of Great Britain and Northern Ireland
Institute Of Cancer Research Sutton
Location: United Kingdom of Great Britain and Northern Ireland
Royal Marsden Hospital Chelsea
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Christina Messiou.