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Background <p>While adjuvant therapies are currently recommended for patients with stage IIB-IV melanoma, biomarkers are missing to improve risk stratification to select the most efficient treatment and patients to be included in clinical trials. We genetically characterized a large cohort of patients with stage-II-melanoma to identify predictive and prognostic biomarkers.</p> Methods <p>Clinical data of 193 stage-II-melanoma patients from the German Central Malignant Melanoma Registry were identified. All patients were therapy-naïve at the time of primary resection and received no adjuvant treatment until recurrence. Tumour-normal pairs were sequenced with a comprehensive cancer panel.</p> Results <p>30.1% of the tumours were classified as <i>BRAF</i>-mutated, 28.0% as <i>RAS-</i>, 18.1% as <i>NF1-</i>, and 23.8% as Triple-WT. In-silico prediction identified a potential new candidate driver, <i>CBL</i>, in 10.4% of the patients. GISTIC nominated deletions of region 11q23.1-3 containing <i>CBL</i> as a potential driver alteration. Enrichment of mutations in <i>CBL</i> was replicated in published cohorts. Patients with <i>RAS</i>-mutated tumours and <i>CBL</i> deletions showed worse OS (<i>p</i> = 0.004) and RFS (<i>p</i> = 0.044). Point mutations in <i>CBL</i> were highly enriched in patients with <i>NF1</i>-mutated tumours, showing a trend (<i>p</i> = 0.18) towards worse OS.</p> Conclusions <p>Our findings suggest <i>CBL</i> as a novel driver gene in melanoma, which is mutated in a relevant fraction of patients. Deletions of 11q23.1-3 including <i>CBL</i> were identified as a prognostic marker indicating a higher risk of recurrence and shorter survival. Furthermore, <i>CBL</i> could support patient stratification to identify high-risk patients who may benefit from adjuvant therapies or intensified monitoring strategies.</p>

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Genetic landscape of stage II melanoma identifies CBL as a new driver gene and prognostic biomarker

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月9日

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  • Elena Sophia Lindner,
  • Jakob Admard,
  • German Demidov,
  • Sorin Armeanu-Ebinger,
  • Tobias Sinnberg,
  • Heike Niessner,
  • Teresa Amaral,
  • Claus Garbe,
  • Andrea Forschner,
  • Olga Kelemen,
  • Franz Joachim Hilke,
  • Irina Bonzheim,
  • Martin Röcken,
  • Olaf Rieß,
  • Stephan Ossowski,
  • Christopher Schroeder

摘要

Background

While adjuvant therapies are currently recommended for patients with stage IIB-IV melanoma, biomarkers are missing to improve risk stratification to select the most efficient treatment and patients to be included in clinical trials. We genetically characterized a large cohort of patients with stage-II-melanoma to identify predictive and prognostic biomarkers.

Methods

Clinical data of 193 stage-II-melanoma patients from the German Central Malignant Melanoma Registry were identified. All patients were therapy-naïve at the time of primary resection and received no adjuvant treatment until recurrence. Tumour-normal pairs were sequenced with a comprehensive cancer panel.

Results

30.1% of the tumours were classified as BRAF-mutated, 28.0% as RAS-, 18.1% as NF1-, and 23.8% as Triple-WT. In-silico prediction identified a potential new candidate driver, CBL, in 10.4% of the patients. GISTIC nominated deletions of region 11q23.1-3 containing CBL as a potential driver alteration. Enrichment of mutations in CBL was replicated in published cohorts. Patients with RAS-mutated tumours and CBL deletions showed worse OS (p = 0.004) and RFS (p = 0.044). Point mutations in CBL were highly enriched in patients with NF1-mutated tumours, showing a trend (p = 0.18) towards worse OS.

Conclusions

Our findings suggest CBL as a novel driver gene in melanoma, which is mutated in a relevant fraction of patients. Deletions of 11q23.1-3 including CBL were identified as a prognostic marker indicating a higher risk of recurrence and shorter survival. Furthermore, CBL could support patient stratification to identify high-risk patients who may benefit from adjuvant therapies or intensified monitoring strategies.