Data from Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways
Authors: Spain Lavinia , Coulton Alexander , Lobon Irene , Rowan Andrew , Schnidrig Desiree , Shepherd Scott T.C. , Shum Benjamin , Byrne Fiona , Goicoechea Maria , Piperni Elisa , Au Lewis , Edmonds Kim , Carlyle Eleanor , Hunter Nikki , Renn Alexandra , Messiou Christina , Hughes Peta , Nobbs Jaime , Foijer Floris , van den Bos Hilda , Wardenaar Rene , Spierings Diana C.J. , Spencer Charlotte , Schmitt Andreas M. , Tippu Zayd , Lingard Karla , Grostate Lauren , Peat Kema , Kelly Kayleigh , Sarker Sarah , Vaughan Sarah , Mangwende Mary , Terry Lauren , Kelly Denise , Biano Jennifer , Murra Aida , Korteweg Justine , Lewis Charlotte , O'Flaherty Molly , Cattin Anne-Laure , Emmerich Max , Gerard Camille L. , Pallikonda Husayn Ahmed , Lynch Joanna , Mason Robert , Rogiers Aljosja , Xu Hang , Huebner Ariana , McGranahan Nicholas , Al Bakir Maise , Murai Jun , Naceur-Lombardelli Cristina , Borg Elaine , Mitchison Miriam , Moore David A. , Falzon Mary , Proctor Ian , Stamp Gordon W.H. , Nye Emma L. , Young Kate , Furness Andrew J.S. , Pickering Lisa , Stewart Ruby , Mahadeva Ula , Green Anna , Larkin James , Litchfield Kevin , Swanton Charles , Jamal-Hanjani Mariam , Turajlic Samra 
Published: June 2023

<div>Abstract<p>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 <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> 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.</p>Significance:<p>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.</p><p><i><a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-23-0340" target="_blank">See related commentary by Shain, p. 1294.</a></i></p><p><i><a href="https://aacrjournals.org/cancerdiscovery/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></p></div>