Homo sapiens Raw sequence reads. Homo sapiens

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20-50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Exomic intratumour heterogeneity varied widely across the cohort. Phylogenetic tree topology ranged from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detected repeated evolution, resolving 5 clusters that were prognostic, with temporally ordered clonal drivers. BAP1/- 3p21 and FBXW7/-chr4 events were always early clonal. In contrast, NF2/-22q events leading to Hippo pathway inactivation were predominantly late clonal, positively selected, and when subclonal, exhibited parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictated MPM inflammation and immune evasion.

恶性胸膜间皮瘤（Malignant Pleural Mesothelioma, MPM）通常在石棉暴露后20至50年被确诊，其演化轨迹至今尚未明确。为阐明该病的演化路径，本研究对22例经手术切除的MPM患者的90份肿瘤样本开展了多区域外显子组测序。队列中肿瘤内外显子异质性差异显著。系统发育树的拓扑结构从线性到高度分支化不等，反映出基因组不稳定性存在显著的梯度差异。本研究通过迁移学习检测到重复演化现象，解析出5个具有预后价值的克隆簇，并明确了各簇对应的具有时间顺序的克隆驱动事件。BAP1/-3p21与FBXW7/-chr4突变事件始终属于早期克隆事件。与之相反，导致Hippo信号通路失活的NF2/-22q突变事件多为晚期克隆事件，且受到正向选择；当该突变为亚克隆状态时，会呈现平行演化现象，提示存在演化约束。1例患者在术后12年仍出现了NF2/22q的极晚期体细胞突变。克隆结构与演化簇决定了MPM的炎症状态与免疫逃逸能力。