微卫星不稳定结直肠癌 (MSI-CRC) 可能是由林奇综合征 (LS) 个体错配修复 (MMR) 基因的种系突变引起的，或者偶尔是由于 MMR 基因 MLH1 的启动子甲基化引起的。尽管遗传性和散发性 MSI 肿瘤的起源不同，但它们的基因组特征尚未得到广泛比较。 MMR 缺陷基因组的一个显着特征是短重复序列中出现许多插入缺失，由于这些区域中变体调用的技术挑战，这是一种尚未研究的突变类型。在这项研究中，我们对 29 个散发性和 14 个遗传性 MSI-CRC 进行了全基因组测序和 RNA 测序。我们通过分析全基因组突变密度、微卫星重复插入缺失、重复出现的蛋白质编码变异、单碱基、双联碱基和插入缺失突变的特征以及基因表达的变化来比较肿瘤组。我们表明，遗传性和散发性 MSI-CRC 的突变景观（包括全基因组和微卫星的突变特征和突变密度）高度相似。仅发现少量差异表达基因，这些基因富集于干扰素-γ调节的免疫反应途径。对每个肿瘤组中体细胞变异等位基因部分的方差分析揭示了散发性 MSI-CRC 中较高的克隆异质性。我们的结果表明，遗传性和散发性 MSI-CRC 中 MMR 缺陷的不同分子起源不会导致这些肿瘤的突变情况存在显着差异。肿瘤组之间克隆进化的不同模式可能具有临床意义，因为高克隆异质性与肿瘤免疫监视的降低和对免疫治疗的反应性降低有关。© 作者 2024。由牛津大学出版社出版。

Microsatellite unstable colorectal cancer (MSI-CRC) can arise through germline mutations in mismatch repair (MMR) genes in individuals with Lynch syndrome (LS), or sporadically through promoter methylation of the MMR gene MLH1. Despite the different origins of hereditary and sporadic MSI tumours, their genomic features have not been extensively compared. A prominent feature of MMR-deficient genomes is the occurrence of many indels in short repeat sequences, an understudied mutation type due to the technical challenges of variant calling in these regions. In this study, we performed whole genome sequencing and RNA-sequencing on 29 sporadic and 14 hereditary MSI-CRCs. We compared the tumour groups by analysing genome-wide mutation densities, microsatellite repeat indels, recurrent protein-coding variants, signatures of single base, doublet base, and indel mutations, and changes in gene expression. We show that the mutational landscapes of hereditary and sporadic MSI-CRCs, including mutational signatures and mutation densities genome-wide and in microsatellites, are highly similar. Only a low number of differentially expressed genes were found, enriched to interferon-γ regulated immune response pathways. Analysis of the variance in allelic fractions of somatic variants in each tumour group revealed higher clonal heterogeneity in sporadic MSI-CRCs. Our results suggest that the differing molecular origins of MMR deficiency in hereditary and sporadic MSI-CRCs do not result in substantial differences in the mutational landscapes of these tumours. The divergent patterns of clonal evolution between the tumour groups may have clinical implications, as high clonal heterogeneity has been associated with decreased tumour immunosurveillance and reduced responsiveness to immunotherapy.© The Author(s) 2024. Published by Oxford University Press.