Dataset Information

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

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.

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.

SUBMITTER: Spain L

PROVIDER: S-EPMC10236155 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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

Spain Lavinia L Coulton Alexander A Lobon Irene I Rowan Andrew A Schnidrig Desiree D Shepherd Scott T C STC Shum Benjamin B Byrne Fiona F Goicoechea Maria M Piperni Elisa E Au Lewis L Edmonds Kim K Carlyle Eleanor E Hunter Nikki N Renn Alexandra A Messiou Christina C Hughes Peta P Nobbs Jaime J Foijer Floris F van den Bos Hilda H Wardenaar Rene R Spierings Diana C J DCJ Spencer Charlotte C Schmitt Andreas M AM Tippu Zayd Z Lingard Karla K Grostate Lauren L Peat Kema K Kelly Kayleigh K Sarker Sarah S Vaughan Sarah S Mangwende Mary M Terry Lauren L Kelly Denise D Biano Jennifer J Murra Aida A Korteweg Justine J Lewis Charlotte C O'Flaherty Molly M Cattin Anne-Laure AL Emmerich Max M Gerard Camille L CL Pallikonda Husayn Ahmed HA Lynch Joanna J Mason Robert R Rogiers Aljosja A Xu Hang H Huebner Ariana A McGranahan Nicholas N Al Bakir Maise M Murai Jun J Naceur-Lombardelli Cristina C Borg Elaine E Mitchison Miriam M Moore David A DA Falzon Mary M Proctor Ian I Stamp Gordon W H GWH Nye Emma L EL Young Kate K Furness Andrew J S AJS Pickering Lisa L Stewart Ruby R Mahadeva Ula U Green Anna A Larkin James J Litchfield Kevin K Swanton Charles C Jamal-Hanjani Mariam M Turajlic Samra S

Cancer discovery 20230601 6

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 ...[more]

PMID: 36977461

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Project description:ImportanceThe gut microbiome modulates the immune system and responses to immunotherapy in patients with late-stage melanoma. It is unknown whether fecal microbiota profiles differ between healthy individuals and patients with melanoma or if microbiota profiles differ among patients with different stages of melanoma. Defining gut microbiota profiles in individuals without melanoma and those with early-stage and late-stage melanoma may reveal features associated with disease progression.ObjectiveTo characterize and compare gut microbiota profiles between healthy volunteers and patients with melanoma and between patients with early-stage and late-stage melanoma.Design, setting, and participantsThis single-site case-control study took place at an academic comprehensive cancer center. Fecal samples were collected from systemic treatment-naive patients with stage I to IV melanoma from June 1, 2015, to January 31, 2019, and from healthy volunteers from June 1, 2021, to January 31, 2022. Patients were followed up for disease recurrence until November 30, 2021.Main outcomes and measuresFecal microbiota was profiled by 16S ribosomal RNA sequencing. Clinical and pathologic characteristics, treatment, and disease recurrence were extracted from electronic medical records. Fecal microbiome diversity, taxonomic profiles and inferred functional profiles were compared between groups.ResultsA total of 228 participants were enrolled (126 men [55.3%]; median age, 59 [range, 21-90] years), including 49 volunteers without melanoma, 38 patients with early-stage melanoma (29 with stage I or melanoma in situ and 9 with stage II), and 141 with late-stage melanoma (66 with stage III and 75 with stage IV). Community differences were observed between patients with melanoma and volunteers. Patients with melanoma had a higher relative abundance of Fusobacterium compared with controls on univariate analysis (0.19% vs 0.003%; P < .001), but this association was attenuated when adjusted for covariates (log2 fold change of 5.18 vs controls; P = .09). Microbiomes were distinct between patients with early-stage and late-stage melanoma. Early-stage melanoma had a higher alpha diversity (Inverse Simpson Index 14.6 [IQR, 9.8-23.0] vs 10.8 [IQR, 7.2-16.8]; P = .003), and a higher abundance of the genus Roseburia on univariate analysis (2.4% vs 1.2%; P < .001) though statistical significance was lost with covariate adjustment (log2 fold change of 0.86 vs controls; P = .13). Multiple functional pathways were differentially enriched between groups. No associations were observed between the microbial taxa and disease recurrence in patients with stage III melanoma treated with adjuvant immunotherapy.Conclusions and relevanceThe findings of this case-control study suggest that fecal microbiota profiles were significantly different among patients with melanoma and controls and between patients with early-stage and late-stage melanoma. Prospective investigations of the gut microbiome and changes that occur with disease progression may identify future microbial targets for intervention.

Dataset Information

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

Significance

Publications

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

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