Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways.
Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways.
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DOI：
10.1158/2159-8290.cd-22-1427
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发表时间：
2023-06-02
期刊：
影响因子：
28.2
通讯作者：
Turajlic, Samra
中科院分区：
文献类型：
--
作者：
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
通过研究尸检和广泛的多组学分析说明了转移性黑色素瘤的演变，并揭示了治疗耐药的多种途径，包括广泛的拷贝数改变、关键驱动因子突变和染色体外DNA。了解黑色素瘤转移和免疫检查点抑制剂（ICI）耐药性的进化途径对于改善预后至关重要。在这里，我们提出了迄今为止最全面的患者内转移性黑色素瘤数据集，作为晚期癌症环境死后评估（PEACE）研究尸检计划的一部分，包括222个外显子组测序，493个面板测序，161个RNA测序和22个单细胞全基因组测序样本，来自14名ICI治疗的患者。我们观察到频繁的全基因组加倍和广泛的杂合性丢失，通常涉及抗原呈递机制。我们发现KIT染色体外DNA可能导致KIT驱动的黑色素瘤对KIT抑制剂缺乏反应。在病变水平，MYC扩增在ICI无应答者中富集。单细胞测序显示，在一名患者中，来自不同倍性克隆的转移瘤的多克隆接种。最后，我们观察到在分子进化早期分化的脑转移瘤在疾病晚期出现。总的来说，我们的研究说明了晚期黑色素瘤的多样性进化景观。尽管治疗进展，黑色素瘤仍然是一种致命的疾病，在第四阶段。通过研究性尸检和转移灶的密集采样，结合广泛的多组学分析，我们的研究阐明了黑色素瘤逃避治疗和免疫系统的许多机制，无论是通过突变，广泛的拷贝数改变，还是染色体外DNA。 参见Shain的相关评注，第1294页。 这篇文章在本期专题中突出显示，第1275页
Metastatic melanoma evolution was illustrated through research autopsy and extensive multiomic profiling and revealed the diverse routes to treatment resistance, including extensive copy-number alterations, mutations in key drivers, and extrachromosomal DNA. 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