Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways.
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Authors
Spain, L
Coulton, A
Lobon, I
Rowan, A
Schnidrig, D
Shepherd, STC
Shum, B
Byrne, F
Goicoechea, M
Piperni, E
Au, L
Edmonds, K
Carlyle, E
Hunter, N
Renn, A
Messiou, C
Hughes, P
Nobbs, J
Foijer, F
van den Bos, H
Wardenaar, R
Spierings, DCJ
Spencer, C
Schmitt, AM
Tippu, Z
Lingard, K
Grostate, L
Peat, K
Kelly, K
Sarker, S
Vaughan, S
Mangwende, M
Terry, L
Kelly, D
Biano, J
Murra, A
Korteweg, J
Lewis, C
O'Flaherty, M
Cattin, A-L
Emmerich, M
Gerard, CL
Pallikonda, HA
Lynch, J
Mason, R
Rogiers, A
Xu, H
Huebner, A
McGranahan, N
Al Bakir, M
Murai, J
Naceur-Lombardelli, C
Borg, E
Mitchison, M
Moore, DA
Falzon, M
Proctor, I
Stamp, GWH
Nye, EL
Young, K
Furness, AJS
Pickering, L
Stewart, R
Mahadeva, U
Green, A
Larkin, J
Litchfield, K
Swanton, C
Jamal-Hanjani, M
PEACE Consortium,
Turajlic, S
Coulton, A
Lobon, I
Rowan, A
Schnidrig, D
Shepherd, STC
Shum, B
Byrne, F
Goicoechea, M
Piperni, E
Au, L
Edmonds, K
Carlyle, E
Hunter, N
Renn, A
Messiou, C
Hughes, P
Nobbs, J
Foijer, F
van den Bos, H
Wardenaar, R
Spierings, DCJ
Spencer, C
Schmitt, AM
Tippu, Z
Lingard, K
Grostate, L
Peat, K
Kelly, K
Sarker, S
Vaughan, S
Mangwende, M
Terry, L
Kelly, D
Biano, J
Murra, A
Korteweg, J
Lewis, C
O'Flaherty, M
Cattin, A-L
Emmerich, M
Gerard, CL
Pallikonda, HA
Lynch, J
Mason, R
Rogiers, A
Xu, H
Huebner, A
McGranahan, N
Al Bakir, M
Murai, J
Naceur-Lombardelli, C
Borg, E
Mitchison, M
Moore, DA
Falzon, M
Proctor, I
Stamp, GWH
Nye, EL
Young, K
Furness, AJS
Pickering, L
Stewart, R
Mahadeva, U
Green, A
Larkin, J
Litchfield, K
Swanton, C
Jamal-Hanjani, M
PEACE Consortium,
Turajlic, S
Document Type
Journal Article
Date
2023-06-02
Date Accepted
2023-03-17
Abstract
UNLABELLED: 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.
Citation
Cancer Discovery, 2023, pp. CD-22-1427 -
Source Title
Cancer Discovery
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
2159-8274
eISSN
2159-8290
2159-8290
2159-8290
Collections
Research Team
Melanoma & Kidney Cancer
Cell Death and Immunity
Experimental Pathology
Skin Unit
Cell Death and Immunity
Experimental Pathology
Skin Unit