. 2024 Nov:8:e2400375.

doi: 10.1200/PO-24-00375. Epub 2024 Nov 7.

DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance

Kathleen Conway^{1

2

3}, Sharon N Edmiston^{2

3

4}, Amanda Vondras³, Allison Reiner⁵, David L Corcoran^{3

4}, Ronglai Shen⁵, Eloise A Parrish³, Honglin Hao², Lan Lin², Jessica M Kenney⁵, Gbemisola Ilelaboye⁵, Caroline E Kostrzewa⁵, Pei Fen Kuan⁶, Klaus J Busam⁷, Cecilia Lezcano⁷, Tim K Lee⁸, Eva Hernando⁹, Paul B Googe^{2

3

10}, David W Ollila^{3

11}, Stergios Moschos^{3

12}, Ivan Gorlov¹³, Christopher I Amos¹³, Marc S Ernstoff¹⁴, Anne E Cust^{15

16

17}, James S Wilmott¹⁶, Richard A Scolyer^{16

18

19

20}, Graham J Mann^{16

21}, Ismael A Vergara^{16

18

20}, Jennifer Ko²², Judy R Rees²³, Shaofeng Yan²⁴, Eduardo Nagore^{25

26}, Marcus Bosenberg²⁷, Bonnie Gould Rothberg²⁸, Iman Osman⁹, Jeffrey E Lee²⁹, Yvonne Saenger^{30

31}, Paul Bogner³², Cheryl L Thompson^{33

34}, Meg Gerstenblith³³, Sheri L Holmen³⁵, Pauline Funchain³⁶, Elise Brunsgaard³⁷, Natalie D Depcik-Smith³⁸, Li Luo³⁹, Tawny Boyce³⁹, Irene Orlow⁵, Colin B Begg⁵, Marianne Berwick³⁹, Nancy E Thomas^{2

3}; InterMEL Study Group

Collaborators, Affiliations

Collaborators

InterMEL Study Group:
Marianne Berwick, Li Luo, Tawny W Boyce, Adam Z Reynolds, Charles Wiggins, Nancy E Thomas, Kathleen Conway, Sharon N Edmiston, David W Ollila, Honglin Hao, Eloise Parrish, Paul B Googe, Stergios J Moschos, David Corcoran, Amanda Vondras, Yihsuan S Tsai, Lan Lin, Ronglai Shen, Colin B Begg, Arshi Arora, Venkatraman Seshan, Allie Reiner, Caroline E Kostrzewa, Klaus J Busam, Irene Orlow, Cecilia Lezcano, Jessica M Kenney, Keimya D Sadeghi, Kelli O'Connell, Gbemisola Elizabeth Ilelaboye, Heta Parmar, Siok Leong, Sergio Corrales, Richard A Scolyer, Anne E Cust, James S Wilmott, Graham J Mann, Ping Shang, Hazel Burke, Peter M Ferguson, Valerie Jakrot, Tim K Lee, Eva Hernando, Iman Osman, Douglas Hanniford, Diana Argibay, Una Moran, Adriana Heguy, Sitharam Ramaswami, Christopher I Amos, Ivan P Gorlov, Dakai Zhu, Marc Ernstoff, Paul N Bogner, Jeffrey E Lee, Judy R Rees, Shaofeng Yan, Meg R Gerstenblith, Cheryl Thompson, Jennifer S Ko, Pauline Funchain, Peter Ngo, Marcus Bosenberg, Bonnie E Gould Rothberg, Gauri Panse, Yvonne M Saenger, Benjamin T Fullerton, Sheri L Holmen, Howard Colman, Elise K Brunsgaard, David Wada, Eduardo Nagore, Esperanza Manrique-Silva, Celia Requena, Victor Traves, David Millan-Esteban, Michelle Rainka

Affiliations

¹ Department of Epidemiology, University of North Carolina, Chapel Hill, NC.
² Department of Dermatology, University of North Carolina, Chapel Hill, NC.
³ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁴ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁵ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
⁶ Department of Applied Mathematics and Statistics, State University of New York, Stony Brook, NY.
⁷ Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
⁸ British Columbia Cancer Research Center, Vancouver, BC, Canada.
⁹ Grossman School of Medicine, New York University, New York, NY.
¹⁰ Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹¹ Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹² Division of Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹³ Department of Medicine, Baylor Medical Center, Houston, TX.
¹⁴ ImmunoOncology Branch, National Cancer Institute, Rockville, MD.
¹⁵ The Daffodil Centre, The University of Sydney, a Joint Venture with Cancer Council NSW, Sydney, NSW, Australia.
¹⁶ Melanoma Institute of Australia, The University of Sydney, Sydney, NSW, Australia.
¹⁷ Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia.
¹⁸ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
¹⁹ Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia.
²⁰ Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
²¹ John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
²² Cleveland Clinic Foundation, Cleveland, OH.
²³ Department of Epidemiology, Dartmouth Medical School, Lebanon, NH.
²⁴ Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH.
²⁵ Instituto Valenciano de Oncologia, Valencia, Spain.
²⁶ Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain.
²⁷ Department of Pathology, Yale University, New Haven, CT.
²⁸ Leonard Miller School of Medicine, University of Miami, Miami, FL.
²⁹ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
³⁰ Columbia University Medical School, New York, NY.
³¹ Albert Einstein School of Medicine, New York, NY.
³² Departments of Pathology and Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
³³ Case Western Reserve University, Cleveland, OH.
³⁴ Penn State University, Hershey, PA.
³⁵ Department of Surgery, University of Utah Health Sciences Center and Huntsman Cancer Institute, Salt Lake City, UT.
³⁶ Stanford University, Palo Alto, CA.
³⁷ Department of Dermatology, Rush University Medical Center, Chicago, IL.
³⁸ GPA Laboratories, Sonic Healthcare, Greensboro, NC.
³⁹ Department of Internal Medicine and the UNM Comprehensive Cancer Center, Albuquerque, NM.

PMID: 39509669
PMCID: PMC11737429 (available on 2025-11-07)
DOI: 10.1200/PO-24-00375

DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance

Kathleen Conway et al. JCO Precis Oncol. 2024 Nov.

. 2024 Nov:8:e2400375.

doi: 10.1200/PO-24-00375. Epub 2024 Nov 7.

Authors

Collaborators

InterMEL Study Group:
Marianne Berwick, Li Luo, Tawny W Boyce, Adam Z Reynolds, Charles Wiggins, Nancy E Thomas, Kathleen Conway, Sharon N Edmiston, David W Ollila, Honglin Hao, Eloise Parrish, Paul B Googe, Stergios J Moschos, David Corcoran, Amanda Vondras, Yihsuan S Tsai, Lan Lin, Ronglai Shen, Colin B Begg, Arshi Arora, Venkatraman Seshan, Allie Reiner, Caroline E Kostrzewa, Klaus J Busam, Irene Orlow, Cecilia Lezcano, Jessica M Kenney, Keimya D Sadeghi, Kelli O'Connell, Gbemisola Elizabeth Ilelaboye, Heta Parmar, Siok Leong, Sergio Corrales, Richard A Scolyer, Anne E Cust, James S Wilmott, Graham J Mann, Ping Shang, Hazel Burke, Peter M Ferguson, Valerie Jakrot, Tim K Lee, Eva Hernando, Iman Osman, Douglas Hanniford, Diana Argibay, Una Moran, Adriana Heguy, Sitharam Ramaswami, Christopher I Amos, Ivan P Gorlov, Dakai Zhu, Marc Ernstoff, Paul N Bogner, Jeffrey E Lee, Judy R Rees, Shaofeng Yan, Meg R Gerstenblith, Cheryl Thompson, Jennifer S Ko, Pauline Funchain, Peter Ngo, Marcus Bosenberg, Bonnie E Gould Rothberg, Gauri Panse, Yvonne M Saenger, Benjamin T Fullerton, Sheri L Holmen, Howard Colman, Elise K Brunsgaard, David Wada, Eduardo Nagore, Esperanza Manrique-Silva, Celia Requena, Victor Traves, David Millan-Esteban, Michelle Rainka

Affiliations

¹ Department of Epidemiology, University of North Carolina, Chapel Hill, NC.
² Department of Dermatology, University of North Carolina, Chapel Hill, NC.
³ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁴ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
⁵ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
⁶ Department of Applied Mathematics and Statistics, State University of New York, Stony Brook, NY.
⁷ Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
⁸ British Columbia Cancer Research Center, Vancouver, BC, Canada.
⁹ Grossman School of Medicine, New York University, New York, NY.
¹⁰ Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹¹ Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹² Division of Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹³ Department of Medicine, Baylor Medical Center, Houston, TX.
¹⁴ ImmunoOncology Branch, National Cancer Institute, Rockville, MD.
¹⁵ The Daffodil Centre, The University of Sydney, a Joint Venture with Cancer Council NSW, Sydney, NSW, Australia.
¹⁶ Melanoma Institute of Australia, The University of Sydney, Sydney, NSW, Australia.
¹⁷ Sydney School of Public Health, The University of Sydney, Sydney, NSW, Australia.
¹⁸ Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
¹⁹ Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia.
²⁰ Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
²¹ John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia.
²² Cleveland Clinic Foundation, Cleveland, OH.
²³ Department of Epidemiology, Dartmouth Medical School, Lebanon, NH.
²⁴ Department of Pathology and Laboratory Medicine, Dartmouth Hitchcock Medical Center, Lebanon, NH.
²⁵ Instituto Valenciano de Oncologia, Valencia, Spain.
²⁶ Universidad Católica de Valencia San Vicente Mártir, Valencia, Spain.
²⁷ Department of Pathology, Yale University, New Haven, CT.
²⁸ Leonard Miller School of Medicine, University of Miami, Miami, FL.
²⁹ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
³⁰ Columbia University Medical School, New York, NY.
³¹ Albert Einstein School of Medicine, New York, NY.
³² Departments of Pathology and Dermatology, Roswell Park Comprehensive Cancer Center, Buffalo, NY.
³³ Case Western Reserve University, Cleveland, OH.
³⁴ Penn State University, Hershey, PA.
³⁵ Department of Surgery, University of Utah Health Sciences Center and Huntsman Cancer Institute, Salt Lake City, UT.
³⁶ Stanford University, Palo Alto, CA.
³⁷ Department of Dermatology, Rush University Medical Center, Chicago, IL.
³⁸ GPA Laboratories, Sonic Healthcare, Greensboro, NC.
³⁹ Department of Internal Medicine and the UNM Comprehensive Cancer Center, Albuquerque, NM.

PMID: 39509669
PMCID: PMC11737429 (available on 2025-11-07)
DOI: 10.1200/PO-24-00375

Abstract

Purpose: Patients with stage II and III cutaneous primary melanoma vary considerably in their risk of melanoma-related death. We explore the ability of methylation profiling to distinguish primary melanoma methylation classes and their associations with clinicopathologic characteristics and survival.

Materials and methods: InterMEL is a retrospective case-control study that assembled primary cutaneous melanomas from American Joint Committee on Cancer (AJCC) 8th edition stage II and III patients diagnosed between 1998 and 2015 in the United States and Australia. Cases are patients who died of melanoma within 5 years from original diagnosis. Controls survived longer than 5 years without evidence of melanoma recurrence or relapse. Methylation classes, distinguished by consensus clustering of 850K methylation data, were evaluated for their clinicopathologic characteristics, 5-year survival status, and differentially methylated gene sets.

Results: Among 422 InterMEL melanomas, consensus clustering revealed three primary melanoma methylation classes (MethylClasses): a CpG island methylator phenotype (CIMP) class, an intermediate methylation (IM) class, and a low methylation (LM) class. CIMP and IM were associated with higher AJCC stage (both P = .002), Breslow thickness (CIMP P = .002; IM P = .006), and mitotic index (both P < .001) compared with LM, while IM had higher N stage than CIMP (P = .01) and LM (P = .007). CIMP and IM had a 2-fold higher likelihood of 5-year death from melanoma than LM (CIMP odds ratio [OR], 2.16 [95% CI, 1.18 to 3.96]; IM OR, 2.00 [95% CI, 1.12 to 3.58]) in a multivariable model adjusted for age, sex, log Breslow thickness, ulceration, mitotic index, and N stage. Despite more extensive CpG island hypermethylation in CIMP, CIMP and IM shared similar patterns of differential methylation and gene set enrichment compared with LM.

Conclusion: Melanoma MethylClasses may provide clinical value in predicting 5-year death from melanoma among patients with primary melanoma independent of other clinicopathologic factors.

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Conflict of interest statement

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

RAS has received fees for professional services from SkylineDx BV, IO Biotech ApS, etaOptima Technology Inc., F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. PF has received research grants to current and former institutions from Ideaya, BMS, Pfizer and Taiho Oncology, as well as personal professional fees from BMS, Merck, GigaGen, Eisai, Novartis, Array, Hexal AG, Replimune, and Immunocore. BGR or spouse have stock ownership in Butterfly Networks, Inc, Quantum Si, Hyperfine Research, OrphAI Therapeutics, IdentifEye, Detect Labs, Protein Evolution, Inc, and spouse is on the board of directors of the above companies. The remaining authors state no conflict of interest.

References

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DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance

Collaborators

Affiliations

DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical