DNA Methylation Classes of Stage II and III Primary Melanomas and Their Clinical and Prognostic Significance
Authors: Conway Kathleen , Edmiston Sharon N. , Vondras Amanda , Reiner Allison , Corcoran David L. , Shen Ronglai , Parrish Eloise A. , Hao Honglin , Lin Lan , Kenney Jessica M. , Ilelaboye Gbemisola , Kostrzewa Caroline E. , Kuan Pei Fen , Busam Klaus J. , Lezcano Cecilia , Lee Tim K. , Hernando Eva , Googe Paul B. , Ollila David W. , Moschos Stergios , Gorlov Ivan , Amos Christopher I. , Ernstoff Marc S. , Cust Anne E. , Wilmott James S. , Scolyer Richard A. , Mann Graham J. , Vergara Ismael A. , Ko Jennifer , Rees Judy R. , Yan Shaofeng , Nagore Eduardo , Bosenberg Marcus , Rothberg Bonnie Gould , Osman Iman , Lee Jeffrey E. , Saenger Yvonne , Bogner Paul , Thompson Cheryl L. , Gerstenblith Meg , Holmen Sheri L. , Funchain Pauline , Brunsgaard Elise , Depcik-Smith Natalie D. , Luo Li , Boyce Tawny , Orlow Irene , Begg Colin B. , Berwick Marianne , Thomas Nancy E. ,   for the InterMEL Study Group, Berwick Marianne , Luo Li , Boyce Tawny W. , Reynolds Adam Z. , Wiggins Charles , Thomas Nancy E. , Conway Kathleen , Edmiston Sharon N. , Ollila David W. , Hao Honglin , Parrish Eloise , Googe Paul B. , Moschos Stergios J. , Corcoran David , Vondras Amanda , Tsai Yihsuan S. , Lin Lan , Shen Ronglai , Begg Colin B. , Arora Arshi , Seshan Venkatraman , Reiner Allie , Kostrzewa Caroline E. , Busam Klaus J. , Orlow Irene , Lezcano Cecilia , Kenney Jessica M. , Sadeghi Keimya D. , O'Connell Kelli , Ilelaboye Gbemisola Elizabeth , Parmar Heta , Leong Siok , Corrales Sergio , Scolyer Richard A. , Cust Anne E. , Wilmott James S. , Mann Graham J. , Shang Ping , Burke Hazel , Ferguson Peter M. , Jakrot Valerie , Lee Tim K. , Hernando Eva , Osman Iman , Hanniford Douglas , Argibay Diana , Moran Una , Heguy Adriana , Ramaswami Sitharam , Amos Christopher I. , Gorlov Ivan P. , Zhu Dakai , Ernstoff Marc , Bogner Paul N. , Lee Jeffrey E. , Rees Judy R. , Yan Shaofeng , Gerstenblith Meg R. , Thompson Cheryl , Ko Jennifer S. , Funchain Pauline , Ngo Peter , Bosenberg Marcus , Gould Rothberg Bonnie E. , Panse Gauri , Saenger Yvonne M. , Fullerton Benjamin T. , Holmen Sheri L. , Colman Howard , Brunsgaard Elise K. , Wada David , Nagore Eduardo , Manrique-Silva Esperanza , Requena Celia , Traves Victor , Millan-Esteban David , Rainka Michelle 
Published: November 2024

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.