Charlotte Lewis
A5032480730- Cancer Genomics and Diagnostics
- Melanoma and MAPK Pathways
- Cutaneous Melanoma Detection and Management
- Computational Drug Discovery Methods
- Cell Image Analysis Techniques
- vaccines and immunoinformatics approaches
- Genomics and Chromatin Dynamics
Royal Marsden Hospital
2023
Royal Marsden NHS Foundation Trust
2023
Abstract Understanding the evolutionary pathways to metastasis and resistance immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present most comprehensive intrapatient metastatic dataset assembled date as part of Posthumous Evaluation Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed...
<div>Abstract<p>Understanding the evolutionary pathways to metastasis and resistance immune checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here we present most comprehensive intra-patient metastatic dataset assembled date as part of PEACE research autopsy programme, including 222 exome, 493 panel-sequenced, 161 RNA-seq, 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent doubling widespread loss...
<p>Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or RNA sequencing. Supplementary 2: Phylogeny and WGD events in CRUKP1047. 3: Ploidy SCNA burden. 4: Overview each case. 5: MEDICC2 copy number sample trees. 6: MEDICC tree all exome demonstrating that cluster together by patient, not melanoma subtype. 7: frequency cutaneous (a), acral (b) unknown primary (MUP, c). 8: Correlation between liver distance to other sites time emergence after...
<p>Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or RNA sequencing. Supplementary 2: Phylogeny and WGD events in CRUKP1047. 3: Ploidy SCNA burden. 4: Overview each case. 5: MEDICC2 copy number sample trees. 6: MEDICC tree all exome demonstrating that cluster together by patient, not melanoma subtype. 7: frequency cutaneous (a), acral (b) unknown primary (MUP, c). 8: Correlation between liver distance to other sites time emergence after...
<p>Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or RNA sequencing. Supplementary 2: Phylogeny and WGD events in CRUKP1047. 3: Ploidy SCNA burden. 4: Overview each case. 5: MEDICC2 copy number sample trees. 6: MEDICC tree all exome demonstrating that cluster together by patient, not melanoma subtype. 7: frequency cutaneous (a), acral (b) unknown primary (MUP, c). 8: Correlation between liver distance to other sites time emergence after...
<div>Abstract<p>Understanding the evolutionary pathways to metastasis and resistance immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present most comprehensive intrapatient metastatic dataset assembled date as part of Posthumous Evaluation Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients....
<div>Abstract<p>Understanding the evolutionary pathways to metastasis and resistance immune checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here we present most comprehensive intra-patient metastatic dataset assembled date as part of PEACE research autopsy programme, including 222 exome, 493 panel-sequenced, 161 RNA-seq, 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent doubling widespread loss...
<p>Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or RNA sequencing. Supplementary 2: Phylogeny and WGD events in CRUKP1047. 3: Ploidy SCNA burden. 4: Overview each case. 5: MEDICC2 copy number sample trees. 6: MEDICC tree all exome demonstrating that cluster together by patient, not melanoma subtype. 7: frequency cutaneous (a), acral (b) unknown primary (MUP, c). 8: Correlation between liver distance to other sites time emergence after...
<p>Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or RNA sequencing. Supplementary 2: Phylogeny and WGD events in CRUKP1047. 3: Ploidy SCNA burden. 4: Overview each case. 5: MEDICC2 copy number sample trees. 6: MEDICC tree all exome demonstrating that cluster together by patient, not melanoma subtype. 7: frequency cutaneous (a), acral (b) unknown primary (MUP, c). 8: Correlation between liver distance to other sites time emergence after...
<p>Late-emerging brain metastases have a lower copy-number burden. <b>A,</b> wGII per metastatic site. Site-specific null distributions of mean were generated by randomizing sample sets (from any site) while keeping patient contributions constant (see Methods). **, <i>P</i> ≤ 0.01. Leptomen., leptomeninges. <b>B,</b> Correlation between (CN) distance to other sites and time emergence after stage IV diagnosis in days. <b>C,</b> Growth...
<p><b>A,</b> Phylogenies inferred for the 14 patients. Only WES samples are included. Letters in brackets indicate melanoma subtype: A = acral, C cutaneous, M mucosal, U of unknown primary. Branch length is proportional to number mutations. colors represent mutational signatures For clarity, only most common shown; remainder categorized as “unknown.” Scale bars The legend includes etiologies each signature (<a href="#bib24" target="_blank">24</a>). MMR, mismatch...
<p>Late-emerging brain metastases have a lower copy-number burden. <b>A,</b> wGII per metastatic site. Site-specific null distributions of mean were generated by randomizing sample sets (from any site) while keeping patient contributions constant (see Methods). **, <i>P</i> ≤ 0.01. Leptomen., leptomeninges. <b>B,</b> Correlation between (CN) distance to other sites and time emergence after stage IV diagnosis in days. <b>C,</b> Growth...
<p>Tissue-level amplifications and deletions associated with response to ICI. A large proportion of samples underwent WGD (<b>A</b>), successive events increasing wGII (<b>B</b>). Letters in brackets indicate melanoma subtype: = acral, C cutaneous, M mucosal, U unknown primary. ***, <i>P</i> < 0.001. GISTIC permutation analysis (<b>C</b>) <i>MYC</i> amplification (chromosome 8q) a nonresponsive phenotype, as well chromosome...
<p>Identification of a likely non–whole-genome–doubled clone that was not identifiable from bulk sequencing data in CRUKP2567. Clonal phylogeny CRUKP2567 (<b>A</b>), with anatomic diagram <b>(B)</b> based on SNVs mapping samples to clones the tree. The scale indicates number mutations. <b>C,</b> MEDICC2 copy-number tree for exome cluster highlighted blue has undergone one WGD event, while other nonhighlighted cluster, containing brain metastasis and...
<p>Mechanisms of resistance to therapy. <b>A,</b><i>KIT</i> copy number vs. KIT expression in matching exome and RNA-seq samples. TPM, transcripts per million. <b>B,</b> Hierarchical clustering tree SCNAs found the single cells a representative sample CRUKP9359. Bars on right show <i>KIT</i> each cell. <b>C,</b> Diagram split reads mapping at edges amplified region, from which circular structure can be inferred. Created with...
<p>Driver mutations and SCNA overview. <b>A,</b> Genomic landscape of the cohort, illustrating in key melanoma driver genes, TMB (total mutations/Mb), ploidy, WGD status, weighted genome instability index (wGII, an burden metric), anatomic site each sample. “Multi-variant” indicates presence more than one variant same gene within Panel WES samples are included. AD, adrenal; BR, brain; LI, liver; LMS, leptomeninges; LN, lymph node; LU, lung; PE, peritoneum; PR, primary; ST,...
<p>Supplementary figure 1: Cohort overview. Number of samples sequenced with whole exome, panel or RNA sequencing. Supplementary 2: Phylogeny and WGD events in CRUKP1047. 3: Ploidy SCNA burden. 4: Overview each case. 5: MEDICC2 copy number sample trees. 6: MEDICC tree all exome demonstrating that cluster together by patient, not melanoma subtype. 7: frequency cutaneous (a), acral (b) unknown primary (MUP, c). 8: Correlation between liver distance to other sites time emergence after...
<p>Mechanisms of resistance to therapy. <b>A,</b><i>KIT</i> copy number vs. KIT expression in matching exome and RNA-seq samples. TPM, transcripts per million. <b>B,</b> Hierarchical clustering tree SCNAs found the single cells a representative sample CRUKP9359. Bars on right show <i>KIT</i> each cell. <b>C,</b> Diagram split reads mapping at edges amplified region, from which circular structure can be inferred. Created with...
<p>Tissue-level amplifications and deletions associated with response to ICI. A large proportion of samples underwent WGD (<b>A</b>), successive events increasing wGII (<b>B</b>). Letters in brackets indicate melanoma subtype: = acral, C cutaneous, M mucosal, U unknown primary. ***, <i>P</i> < 0.001. GISTIC permutation analysis (<b>C</b>) <i>MYC</i> amplification (chromosome 8q) a nonresponsive phenotype, as well chromosome...