Background: Small intestinal neuroendocrine tumours (siNETs) are rare neoplasms which present with low mutational burden and can be subtyped based on copy number variation (CNV). Currently, siNETs can be molecularly classified as having chromosome 18 loss of heterozygosity (18LOH), multiple CNVs (MultiCNV), or no CNVs. 18LOH tumours have better progression free survival when compared to MultiCNV and NoCNV tumours, however the mechanism underlying this is unknown, and clinical practice does not currently consider CNV status. Methods: Here, we use genome-wide tumour DNA methylation (n=54) and gene expression (n=20 matched to DNA methylation) to better understand how gene regulation varies by 18LOH status. We then use multiple cell deconvolution methods to analyse how cell composition varies between 18LOH status, and determine potential associations with progression free survival. Results: We identified 27,464 differentially methylated CpG sites and 12 differentially expressed genes between 18LOH and non-18LOH (MultiCNV + NoCNV) siNETs. Although few differentially expressed genes were identified, these genes were highly enriched with the differentially methylated CpG sites compared to the rest of the genome. We identified differences in tumour micro-environment between 18LOH and non-18LOH tumours, including CD14+ infiltration in a subset of non-18LOH tumours which had the poorest clinical outcomes. Conclusions: We identify a small number of genes which appear to be linked to the 18LOH status of siNETs, and find evidence of potential epigenetic dysregulation of these genes. We also find a potential prognostic marker for worse progression free outcomes in the form of higher CD14 infiltration in non-18LOH siNETs.


中文翻译：

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小肠神经内分泌肿瘤中 18 号染色体杂合性缺失：多组学和肿瘤成分分析

背景：小肠神经内分泌肿瘤（siNET）是一种罕见的肿瘤，其突变负荷较低，可以根据拷贝数变异（CNV）进行亚型分类。目前，siNET在分子水平上可分为18号染色体杂合性丢失（18LOH）、多个CNV（MultiCNV）或无CNV。与 MultiCNV 和 NoCNV 肿瘤相比，18LOH 肿瘤具有更好的无进展生存期，但其背后的机制尚不清楚，临床实践目前不考虑 CNV 状态。方法：在这里，我们使用全基因组肿瘤 DNA 甲基化 (n=54) 和基因表达（n=20 与 DNA 甲基化匹配）来更好地了解基因调控如何因 18LOH 状态而变化。然后，我们使用多种细胞反卷积方法来分析 18LOH 状态之间的细胞组成如何变化，并确定与无进展生存的潜在关联。结果：我们在 18LOH 和非 18LOH (MultiCNV + NoCNV) siNET 之间鉴定了 27,464 个差异甲基化 CpG 位点和 12 个差异表达基因。尽管鉴定出的差异表达基因很少，但与基因组的其余部分相比，这些基因的差异甲基化 CpG 位点高度富集。我们确定了 18LOH 和非 18LOH 肿瘤之间肿瘤微环境的差异，包括临床结果最差的非 18LOH 肿瘤子集中的 CD14+ 浸润。结论：我们鉴定了少数似乎与 siNET 的 18LOH 状态相关的基因，并找到了这些基因潜在表观遗传失调的证据。我们还发现了一个潜在的预后标志，即非 18LOH siNET 中 CD14 浸润较高，从而导致更差的无进展结果。