PO.TB03.04 · 肿瘤生物学

黑色素瘤脑转移的基因组学图谱：真实世界分析及与公共黑色素瘤队列的比较

Genomic landscape of melanoma brain metastases: Real-world analysis and comparison with public melanoma cohorts

编号 2107 展板 5 时间 4/20 09:00–12:00 区域 Section 27 主讲 Brandon Parker, MD

分会场 Characterization of Metastases by Imaging and Profiling

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作者与单位 Authors & Affiliations

Dina Elantably¹, Joseph B. Parker¹, Jakob Hamilton¹, Ahmed Abdelhakeem¹, Oluwatayo Adeoye¹, Saivaishnavi Kamatham¹, Winston Tan¹, Arkadiusz Z. Dudek², Anastasios Dimou², Matthew S. Block², Robert McWilliams², Svetomir Markovic², Mahesh Seetharam³, Roxana Dronca¹, Ruqin Chen¹

¹Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL,²Mayo Clinic Comprehensive Cancer Center, Rochester, MN,³Mayo Clinic Comprehensive Cancer Center, Phoenix, AZ

摘要 Abstract

中文摘要

背景：黑色素瘤脑转移（MBM）代表黑色素瘤中一个生物学上独特且临床上侵袭性强的亚群。聚焦颅内疾病的全面分子表征仍然有限。我们旨在定义MBM的基因组学图谱，并将这些发现与公共黑色素瘤数据集进行比较。方法：我们回顾性地在Mayo Clinic三个院区（2011-2025年）中鉴定出166例经组织学确诊的MBM患者。123例患者（74.1%）进行了分子检测。41例患者（24.7%）可获得全面的二代测序（NGS；≥300基因平台，包括Tempus、FoundationOne、Caris、NeoGenomics和MayoComplete实体瘤检测组）。21例患者（12.7%）使用MayoComplete黑色素瘤检测组（17个基因）进行了中等深度分析，52例患者（31.3%）使用靶向5基因黑色素瘤驱动检测组（BRAF、NRAS、KIT、GNAQ、GNA11）进行分析。12例患者（7.2%）可获得基于cfDNA的NGS。基因组改变通过cBioPortal进行汇总，并与TCGA-SKCM和MSK-IMPACT数据集进行基准比较。我们考虑了检测异质性，因为Mayo检测组在测序深度和CNV覆盖方面各不相同，且杂交捕获平台常常低估TERT启动子热点。结果：患者中位年龄为67岁，63%为男性。BRAF突变发生率为48.8%（BRAF V600E/K 41.6%；非V600 7.2%）。其他MAPK改变包括NRAS（17.5%）、KIT（5.4%）、GNAQ（1.2%）和GNA11（0.6%）。在全面NGS亚组中，肿瘤抑制基因改变包括CDKN2A（17.5%）、PTEN（7.8%）、NF1（9.0%）、TP53（8.4%）和TERT启动子突变（22.9%）。中位TMB为11.55 mut/Mb（IQR 5.0-25.5）。共改变包括BRAF+CDKN2A（7.2%）、BRAF+PTEN（4.2%）、NRAS+CDKN2A（4.2%）、NRAS+PTEN（1.2%）和CDKN2A+PTEN（3.6%）；总体而言，18.1%携带MAPK驱动因子+肿瘤抑制基因共改变。与TCGA和MSK队列相比，MBM显示出相似的MAPK驱动因子频率，但MAPK+肿瘤抑制基因共改变较少，CDKN2A、PTEN和TP53破坏较低，同时TERT启动子突变更为普遍（22.9% vs 7%和2.1%），这可能部分反映了覆盖度差异。结论：MBM表现出独特的基因组特征，其特点是肿瘤抑制基因缺失减少、MAPK-肿瘤抑制基因共改变较少以及TERT启动子突变的患病率更高。虽然检测异质性限制了直接的跨队列比较，但这些模式提示颅内黑色素瘤可能具有独特的生物学特征，并强调需要开展协调一致的、针对MBM的分子研究以指导治疗开发。

查看英文原文 English abstract

Background: Melanoma brain metastases (MBM) represent a biologically distinct and clinically aggressive subset of melanoma. Comprehensive molecular characterization focused on intracranial disease remains limited. We aimed to define the genomic landscape of MBM and compare these findings with public melanoma datasets. Methods: We retrospectively identified 166 patients with histologically confirmed MBM across Mayo Clinic tri-sites (2011-2025). Molecular testing was performed in 123 patients (74.1%). Comprehensive next-generation sequencing (NGS; ≥300-gene platforms including Tempus, FoundationOne, Caris, NeoGenomics, and MayoComplete Solid Tumor Panel) was available in 41 patients (24.7%). Intermediate-depth profiling using the MayoComplete Melanoma Panel (17 genes) was performed in 21 patients (12.7%), and a targeted 5-gene melanoma driver panel (BRAF, NRAS, KIT, GNAQ, GNA11) in 52 patients (31.3%). cfDNA-based NGS was available in 12 patients (7.2%). Genomic alterations were summarized and benchmarked against TCGA-SKCM and MSK-IMPACT datasets via cBioPortal. We considered assay heterogeneity, as Mayo panels varied in sequencing depth and CNV coverage, and hybrid-capture platforms often under-detect TERT promoter hotspots. Results: Patients had a median age of 67 years, and 63% were male. BRAF mutations occurred in 48.8% (BRAF V600E/K 41.6%; non-V600 7.2%). Additional MAPK alterations included NRAS (17.5%), KIT (5.4%), GNAQ (1.2%), and GNA11 (0.6%). In the comprehensive NGS subset, tumor-suppressor alterations included CDKN2A (17.5%), PTEN (7.8%), NF1 (9.0%), TP53 (8.4%), and TERT promoter mutations (22.9%). Median TMB was 11.55 mut/Mb (IQR 5.0-25.5). Co-alterations included BRAF+CDKN2A (7.2%), BRAF+PTEN (4.2%), NRAS+CDKN2A (4.2%), NRAS+PTEN (1.2%), and CDKN2A+PTEN (3.6%); overall, 18.1% harbored MAPK driver + tumor-suppressor co-alterations. Compared with TCGA and MSK cohorts, MBM showed similar MAPK driver frequencies but fewer MAPK + tumor-suppressor co-alterations and lower CDKN2A, PTEN, and TP53 disruption, alongside a more prevalent of TERT promoter mutations (22.9% vs 7% and 2.1%), which may partly reflect coverage differences. Conclusion: MBM exhibit a distinct genomic profile characterized by reduced tumor-suppressor loss, fewer MAPK-tumor-suppressor co-alterations, and higher prevalence of TERT promoter mutations. While assay heterogeneity limits direct cross-cohort comparisons, these patterns suggest potentially distinct biological features of intracranial melanoma and underscore the need for harmonized, MBM-specific molecular studies to guide therapeutic development.

利益披露 Disclosure

D. Elantably, None.. J. B. Parker, None.. J. Hamilton, None.. A. Abdelhakeem, None.. O. Adeoye, None.. S. Kamatham, None.. W. Tan, None. A. Z. Dudek, Iovance Other, Participating in advisory board. TTC Oncology, LLC g., Board of Directors, non-salaried role), Stock. IDEAYA Biosciences Other. Immunocore Other. Kumquat Biosciences, INC Other. Replimune Other. Pierre Fabre Medicament Other. A. Dimou, TP Therapeutics Other, Advisory Board. Guardant Health Other, Advisory board. AnHeart Therapeutics Other, Advisory Board. ChromaCode Other, Advisory Board. Rigel Pharmaceuticals Inc Other, Advisory Board. Nuvation Bio Other, Advisory Board. Syntrix Pharmaceuticals ). Novartis ). Merck ). AnHeart Therapeutics ). AstraZeneca ). Sorrento Therapeutics ). Guardant Health ). Philogen ). Nuvation Bio ). Erasca ). M. S. Block, Alkermes ). Bristol-Myers Squibb ). Genentech ). Merck ). nFerence ). Perspective Therapeutics ). Pharmacyclics ). Regeneron ). Sorrento ). TILT Biotherapeutics ). Transgene ). R. McWilliams, None.. S. Markovic, None. M. Seetharam, Immunocore Other, Advisory Board. Replimune Other, Advisory Board. Deciphera Other, Advisory Board. R. Dronca, None. R. Chen, Immunocore ). Replimune ). Regeneron ). Erasca ). Elephas ). Merck ). Pierre Fabre ).

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