Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

PEACE Consortium, 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 FoijerHilda 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, Samra Turajlic*

*Corresponding author voor dit werk

    Onderzoeksoutput: ArticleAcademicpeer review

    31 Citaten (Scopus)
    126 Downloads (Pure)

    Samenvatting

    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.

    SIGNIFICANCE: 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.

    Originele taal-2English
    Pagina's (van-tot)1364-1385
    Aantal pagina's22
    TijdschriftCancer Discovery
    Volume13
    Nummer van het tijdschrift6
    DOI's
    StatusPublished - 2-jun.-2023

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