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posted on 2023-06-02, 08:21 authored by Lavinia Spain, Alexander Coulton, Irene Lobon, Andrew Rowan, Desiree Schnidrig, Scott T.C. Shepherd, Benjamin Shum, Fiona Byrne, Maria Goicoechea, Elisa Piperni, Lewis Au, Kim Edmonds, Eleanor Carlyle, Nikki Hunter, Alexandra Renn, Christina Messiou, Peta Hughes, Jaime Nobbs, Floris Foijer, Hilda van den Bos, Rene Wardenaar, Diana C.J. Spierings, Charlotte Spencer, Andreas M. Schmitt, Zayd Tippu, Karla Lingard, Lauren Grostate, Kema Peat, Kayleigh Kelly, Sarah Sarker, Sarah Vaughan, Mary Mangwende, Lauren Terry, Denise Kelly, Jennifer Biano, Aida Murra, Justine Korteweg, Charlotte Lewis, Molly O'Flaherty, Anne-Laure Cattin, Max Emmerich, Camille L. Gerard, Husayn Ahmed Pallikonda, Joanna Lynch, Robert Mason, Aljosja Rogiers, Hang Xu, Ariana Huebner, Nicholas McGranahan, Maise Al Bakir, Jun Murai, Cristina Naceur-Lombardelli, Elaine Borg, Miriam Mitchison, David A. Moore, Mary Falzon, Ian Proctor, Gordon W.H. Stamp, Emma L. Nye, Kate Young, Andrew J.S. Furness, Lisa Pickering, Ruby Stewart, Ula Mahadeva, Anna Green, James Larkin, Kevin Litchfield, Charles Swanton, Mariam Jamal-Hanjani, Samra Turajlic Mechanisms of resistance to therapy. A,KIT copy number vs. KIT expression in matching exome and RNA-seq samples. TPM, transcripts per million. B, Hierarchical clustering tree of SCNAs found in the single cells of a representative sample of CRUKP9359. Bars on the right show the copy number of KIT in each cell. C, Diagram of split reads mapping at the edges of the amplified region, from which a circular structure can be inferred. Created with BioRender.com. D, Images showing FISH probes against KIT (red) in individual cells. E, Heat map of alterations in antigen-presentation genes in the exome data. Each column represents a sample. LOH events are shown in red and blue, and nonsynonymous mutations are in red and purple. Bars on the x-axis show the number of genes altered in each sample, whereas y-axis bars show the number of samples altered per gene, colored by the type of event.
Funding
Francis Crick Institute (FCI)
Cancer Research UK (CRUK)
Melanoma Research Alliance (MRA)
Rosetrees Trust (Rosetrees)
Institute of Cancer Research (ICR)
Bjorn Saven Fellowship Fund
History
ARTICLE 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 samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications 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 diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.
Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling 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
