Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
J Pathol. 2024 Dec;264(4):357-370. doi: 10.1002/path.6348. Epub 2024 Oct 3.
Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular may progress from a low/intermediate to a high-grade disease. The aim of this work was to understand the molecular mechanisms underlying metastatic progression as well as PanNET transformation from a low/intermediate to a high-grade disease. We performed multi-omics analysis (genome/exome sequencing, total RNA-sequencing and methylation array) of 32 longitudinal samples from six patients with metastatic low/intermediate grade PanNET. The clonal composition of tumour lesions and underlying phylogeny of each patient were determined with bioinformatics analyses. Findings were validated in post-alkylating chemotherapy samples from 24 patients with PanNET using targeted next generation sequencing. We validate the current PanNET evolutionary model with MEN1 inactivation that occurs very early in tumourigenesis. This was followed by pronounced genetic diversity on both spatial and temporal levels, with parallel and convergent tumour evolution involving the ATRX/DAXX and mechanistic target of the rapamycin (mTOR) pathways. Following alkylating chemotherapy treatment, some PanNETs developed mismatch repair deficiency and acquired a hypermutational phenotype. This was validated among 16 patients with PanNET who had high-grade progression after alkylating chemotherapy, of whom eight had a tumour mutational burden >50 (50%). In comparison, among the eight patients who did not show high-grade progression, 0 had a tumour mutational burden >50 (0%; odds ratio 'infinite', 95% confidence interval 1.8 to 'infinite', p = 0.02). Our findings contribute to broaden the understanding of metastatic/high-grade PanNETs and suggests that therapy driven disease evolution is an important hallmark of this disease. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
肿瘤获得侵袭性疾病特征的进化是癌症扩散的标志。特别是转移性胰腺神经内分泌肿瘤（PanNET）可能会从低/中级别疾病进展为高级别疾病。这项工作的目的是了解导致转移性进展以及 PanNET 从低/中级别疾病向高级别疾病转化的分子机制。我们对来自 6 名转移性低/中级别 PanNET 患者的 32 个纵向样本进行了多组学分析（基因组/外显子测序、总 RNA 测序和甲基化阵列）。通过生物信息学分析确定了肿瘤病变的克隆组成和每个患者的潜在系统发育。在使用靶向下一代测序的 24 名 PanNET 患者的烷基化化疗后样本中验证了这些发现。我们用 MEN1 失活验证了当前的 PanNET 进化模型，该失活发生在肿瘤发生的早期。随后在空间和时间水平上表现出明显的遗传多样性，涉及 ATRX/DAXX 和雷帕霉素（mTOR）途径的平行和趋同肿瘤进化。在烷基化化疗治疗后，一些 PanNET 出现错配修复缺陷并获得高突变表型。在接受烷基化化疗后发生高级别进展的 16 名 PanNET 患者中验证了这一点，其中 8 名患者的肿瘤突变负担>50（50%）。相比之下，在 8 名未表现出高级别进展的患者中，0 名患者的肿瘤突变负担>50（0%；优势比“无限”，95%置信区间 1.8 至“无限”，p=0.02）。我们的发现有助于拓宽对转移性/高级别 PanNET 的理解，并表明治疗驱动的疾病进化是该疾病的一个重要标志。 © 2024 作者。John Wiley & Sons Ltd 代表英国和爱尔兰的病理学会出版的《病理学杂志》。本文由美国政府雇员贡献，其工作在美国属于公有领域。
