Kennedy Lucy Boyce, Van Swearingen Amanda E D, Lee Marissa R, Rogers Layne W, Sibley Alexander B, Sheng Jeff, Zhang Dadong, Qin Xiaodi, Lipp Eric S, Kumar Swaminathan, Joon Aron, Shi Pixu, Davies Michael A, Owzar Kouros, Anders Carey K, Salama April K S
Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
The Department of Hematology and Medical Oncology, Cleveland Clinic, 9500 Euclid Avenue CA-60, Cleveland, OH, 44195, USA.
Acta Neuropathol Commun. 2025 Jun 2;13(1):123. doi: 10.1186/s40478-025-02035-7.
Melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biological features and clinical outcomes of MBM will facilitate the design of rational therapies.
We examined the mutational landscape and gene expression profiles of MBM (74 patients) and ECM (34 patients) in paired patient samples from a previously published dataset with whole-exome sequencing (WES) and RNA sequencing (RNAseq) data from MD Anderson Cancer Center (MDACC). We also present findings from MBM from a new cohort of 14 patients from Duke University to strengthen investigation of somatic mutations and gene expression profiles. Gene Set Enrichment Analysis (GSEA) was used to compare paired MBM versus lymph node (LN) metastases and skin metastases. Relative immune cell abundance was inferred using deconvolution methods. Survival outcomes from craniotomy and associations with biological features, BRAF mutation status, and PTEN expression were assessed.
GSEA found that autophagy signaling pathways are enriched in MBM versus LN and skin metastases. BRAF was the most frequently mutated clinically relevant gene in MBM and ECM, with NRAS and PTEN also frequently altered in MBM. The most strongly upregulated genes in autophagy pathways were glial fibrillary acidic protein (GFAP) and hemoglobin beta (HBB). An increased proportion of immune-suppressive M2 compared to tumor-suppressive M1 macrophages in MBM and ECM was identified. There was not sufficient evidence for an association between BRAF V600 mutation status or expression and overall survival (OS) from craniotomy.
The mutational landscape and gene expression of MBM from the Duke cohort resembled those previously reported in the MDACC cohort. Upregulation of autophagy pathways was observed in patient-matched MBM versus LN and skin metastases due to upregulation of two genes, GFAP and HBB. In MBM, higher M2:M1 ratio may contribute to a therapeutically relevant immune-suppressive tumor microenvironment (TME).
与颅外转移（ECM）相比，黑色素瘤脑转移（MBM）具有独特的分子特征。描述MBM的生物学特征和临床结局将有助于合理治疗方案的设计。
我们利用来自MD安德森癌症中心（MDACC）的全外显子测序（WES）和RNA测序（RNAseq）数据，在一个先前发表的数据集中的配对患者样本中，检测了74例MBM患者和34例ECM患者的突变图谱和基因表达谱。我们还展示了来自杜克大学的14例新队列MBM患者的研究结果，以加强对体细胞突变和基因表达谱的研究。基因集富集分析（GSEA）用于比较配对的MBM与淋巴结（LN）转移和皮肤转移。使用反卷积方法推断相对免疫细胞丰度。评估开颅手术的生存结局以及与生物学特征、BRAF突变状态和PTEN表达的关联。
GSEA发现，与LN和皮肤转移相比，自噬信号通路在MBM中富集。BRAF是MBM和ECM中最常发生突变的临床相关基因，NRAS和PTEN在MBM中也经常发生改变。自噬通路中上调最强烈的基因是胶质纤维酸性蛋白（GFAP）和血红蛋白β（HBB）。在MBM和ECM中，与具有肿瘤抑制作用的M1巨噬细胞相比，免疫抑制性M2巨噬细胞的比例增加。没有足够的证据表明BRAF V600突变状态或表达与开颅手术的总生存期（OS）之间存在关联。
杜克队列中MBM的突变图谱和基因表达与MDACC队列中先前报道的相似。由于GFAP和HBB这两个基因的上调，在患者匹配的MBM与LN和皮肤转移中观察到自噬通路的上调。在MBM中，较高的M2:M1比值可能导致具有治疗相关性的免疫抑制性肿瘤微环境（TME）。
