全面的基因组和肿瘤免疫特征分析揭示了恶性胸膜间皮瘤的潜在治疗靶点。
Comprehensive genomic and tumour immune profiling reveals potential therapeutic targets in malignant pleural mesothelioma.
机构信息
National Centre for Asbestos Related Disease, Medical School, University of Western Australia, Level 5, QQ Block, QEII Medical Centre, 6 Verdun Street, Nedlands, WA, 6009, Australia.
Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
出版信息
Genome Med. 2022 May 30;14(1):58. doi: 10.1186/s13073-022-01060-8.
BACKGROUND
Malignant pleural mesothelioma (MPM) has a poor overall survival with few treatment options. Whole genome sequencing (WGS) combined with the immune features of MPM offers the prospect of identifying changes that could inform future clinical trials.
METHODS
We analysed somatic mutations from 229 MPM samples, including previously published data and 58 samples that had undergone WGS within this study. This was combined with RNA-seq analysis to characterize the tumour immune environment.
RESULTS
The comprehensive genome analysis identified 12 driver genes, including new candidate genes. Whole genome doubling was a frequent event that correlated with shorter survival. Mutational signature analysis revealed SBS5/40 were dominant in 93% of samples, and defects in homologous recombination repair were infrequent in our cohort. The tumour immune environment contained high M2 macrophage infiltrate linked with MMP2, MMP14, TGFB1 and CCL2 expression, representing an immune suppressive environment. The expression of TGFB1 was associated with overall survival. A small subset of samples (less than 10%) had a higher proportion of CD8 T cells and a high cytolytic score, suggesting a 'hot' immune environment independent of the somatic mutations.
CONCLUSIONS
We propose accounting for genomic and immune microenvironment status may influence therapeutic planning in the future.
背景
恶性胸膜间皮瘤（MPM）总体存活率低，治疗选择有限。全基因组测序（WGS）结合 MPM 的免疫特征，有望识别可能为未来临床试验提供信息的变化。
方法
我们分析了 229 个 MPM 样本的体细胞突变，包括之前发表的数据和本研究中进行 WGS 的 58 个样本。这与 RNA-seq 分析相结合，以描绘肿瘤免疫环境。
结果
全面的基因组分析确定了 12 个驱动基因，包括新的候选基因。全基因组倍增是一个常见的事件，与较短的生存时间相关。突变特征分析显示，SBS5/40 在 93%的样本中占主导地位，而我们的队列中同源重组修复缺陷很少。肿瘤免疫环境中含有高 M2 巨噬细胞浸润，与 MMP2、MMP14、TGFB1 和 CCL2 的表达相关，代表了一种免疫抑制环境。TGFB1 的表达与总生存期相关。一小部分样本（不到 10%）具有更高比例的 CD8 T 细胞和更高的细胞溶解评分，提示存在一种独立于体细胞突变的“热”免疫环境。
结论
我们提出，考虑基因组和免疫微环境状况可能会影响未来的治疗计划。
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