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<p>In our study, we investigated the role of the chromatin remodeler ATRX in the progression of cutaneous melanoma. We analyzed ATRX protein expression in over 350 melanomas, correlating findings with clinical data, tumor proliferation rates, and vessel density. Additionally, we examined whole-genome sequencing data from 70 melanoma metastases to assess ATRX genetic alterations and compared these with protein expression patterns. We observed a significant reduction in ATRX protein expression in metastases compared to primary tumors: 51% of primary melanomas showed ATRX positivity in over 50% of tumor cells, versus only 25% of metastases (<i>p</i> = 0.01). ATRX loss was associated with earlier metastasis (median 17 vs. 46&#xa0;months), reduced overall survival (median 69 vs. 162.5&#xa0;months), and worse tumor-specific survival (<i>p</i> = 0.01). ATRX expression correlated positively with vessel density (r<sub>s</sub> = 0.3) and negatively with proliferation (r<sub>s</sub> = – 0.3), suggesting a role in hypoxia response. Genetically, intronic mutations were most frequent (80%), followed by copy number variations (loss: 29%, gain: 37%). Interestingly, ATRX copy number changes did not correlate with protein levels, pointing to epigenetic regulation. Our findings highlight ATRX loss as an early and prognostically relevant event in melanoma, with potential as a therapeutic target.</p>

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The chromatin guardian ATRX is a strong prognostic biomarker in melanoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月18日

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  • Céline Arlette Frei,
  • Cassandra Litchfield,
  • Alanna Mihic,
  • Fabiola Prutek,
  • André Fitsche,
  • Fabius Wiesmann,
  • Miriam Wanner,
  • Bettina Sobottka,
  • Daniela Mihic-Probst,
  • Rudolf Aebersold,
  • Melike Ak,
  • Faisal S. Al-Quaddoomi,
  • Silvana I. Albert,
  • Jonas Albinus,
  • Ilaria Alborelli,
  • Sonali Andani,
  • Per-Olof Attinger,
  • Marina Bacac,
  • Monica-Andreea Baciu-Drăgan,
  • Daniel Baumhoer,
  • Beatrice Beck-Schimmer,
  • Niko Beerenwinkel,
  • Christian Beisel,
  • Lara Bernasconi,
  • Anne Bertolini,
  • Bernd Bodenmiller,
  • Ximena Bonilla,
  • Lars Bosshard,
  • Byron Calgua,
  • Ruben Casanova,
  • Stéphane Chevrier,
  • Natalia Chicherova,
  • Ricardo Coelho,
  • Maya D’Costa,
  • Esther Danenberg,
  • Natalie R. Davidson,
  • Reinhard Dummer,
  • Stefanie Engler,
  • Martin Erkens,
  • Katja Eschbach,
  • Cinzia Esposito,
  • André Fedier,
  • Pedro F. Ferreira,
  • Joanna Ficek-Pascual,
  • Anja L. Frei,
  • Bruno Frey,
  • Sandra Goetze,
  • Linda Grob,
  • Gabriele Gut,
  • Detlef Günther,
  • Pirmin Haeuptle,
  • Viola Heinzelmann-Schwarz,
  • Sylvia Herter,
  • Rene Holtackers,
  • Tamara Huesser,
  • Alexander Immer,
  • Anja Irmisch,
  • Francis Jacob,
  • Andrea Jacobs,
  • Tim M. Jaeger,
  • Alva R. James,
  • Philip M. Jermann,
  • André Kahles,
  • Abdullah Kahraman,
  • Viktor H. Koelzer,
  • Werner Kuebler,
  • Jack Kuipers,
  • Christian P. Kunze,
  • Christian Kurzeder,
  • Kjong-Van Lehmann,
  • Mitchell Levesque,
  • Ulrike Lischetti,
  • Flavio C. Lombardo,
  • Sebastian Lugert,
  • Gerd Maass,
  • Markus G. Manz,
  • Philipp Markolin,
  • Martin Mehnert,
  • Julien Mena,
  • Julian M. Metzler,
  • Nicola Miglino,
  • Emanuela S. Milani,
  • Holger Moch,
  • Simone Muenst,
  • Riccardo Murri,
  • Charlotte K. Y. Ng,
  • Stefan Nicolet,
  • Marta Nowak,
  • Monica Nunez Lopéz,
  • Patrick G. A. Pedrioli,
  • Lucas Pelkmans,
  • Salvatore Piscuoglio,
  • Michael Prummer,
  • Laurie Prélot,
  • Natalie Rimmer,
  • Mathilde Ritter,
  • Christian Rommel,
  • María L. Rosano-González,
  • Gunnar Rätsch,
  • Natascha Santacroce,
  • Jacobo Sarabia del Castillo,
  • Ramona Schlenker,
  • Petra C. Schwalie,
  • Severin Schwan,
  • Tobias Schär,
  • Gabriela Senti,
  • Wenguang Shao,
  • Franziska Singer,
  • Sujana Sivapatham,
  • Berend Snijder,
  • Bettina Sobottka,
  • Vipin T. Sreedharan,
  • Stefan Stark,
  • Daniel J. Stekhoven,
  • Tanmay Tanna,
  • Alexandre P. A. Theocharides,
  • Tinu M. Thomas,
  • Markus Tolnay,
  • Vinko Tosevski,
  • Nora C. Toussaint,
  • Mustafa A. Tuncel,
  • Marina Tusup,
  • Audrey Van Drogen,
  • Marcus Vetter,
  • Tatjana Vlajnic,
  • Sandra Weber,
  • Walter P. Weber,
  • Rebekka Wegmann,
  • Michael Weller,
  • Fabian Wendt,
  • Norbert Wey,
  • Andreas Wicki,
  • Mattheus H. E. Wildschut,
  • Bernd Wollscheid,
  • Shuqing Yu,
  • Johanna Ziegler,
  • Marc Zimmermann,
  • Martin Zoche,
  • Gregor Zuend

摘要

In our study, we investigated the role of the chromatin remodeler ATRX in the progression of cutaneous melanoma. We analyzed ATRX protein expression in over 350 melanomas, correlating findings with clinical data, tumor proliferation rates, and vessel density. Additionally, we examined whole-genome sequencing data from 70 melanoma metastases to assess ATRX genetic alterations and compared these with protein expression patterns. We observed a significant reduction in ATRX protein expression in metastases compared to primary tumors: 51% of primary melanomas showed ATRX positivity in over 50% of tumor cells, versus only 25% of metastases (p = 0.01). ATRX loss was associated with earlier metastasis (median 17 vs. 46 months), reduced overall survival (median 69 vs. 162.5 months), and worse tumor-specific survival (p = 0.01). ATRX expression correlated positively with vessel density (rs = 0.3) and negatively with proliferation (rs = – 0.3), suggesting a role in hypoxia response. Genetically, intronic mutations were most frequent (80%), followed by copy number variations (loss: 29%, gain: 37%). Interestingly, ATRX copy number changes did not correlate with protein levels, pointing to epigenetic regulation. Our findings highlight ATRX loss as an early and prognostically relevant event in melanoma, with potential as a therapeutic target.