林奇综合征相关和零星的微卫星不稳定结直肠癌：克隆进化的不同模式产生高度相似的肿瘤
Lynch syndrome-associated and sporadic microsatellite unstable colorectal cancers: different patterns of clonal evolution yield highly similar tumours
影响因子:3.20000
分区:生物学2区 / 生化与分子生物学3区 遗传学3区
发表日期:2024 Nov 05
作者:
Samantha Martin, Riku Katainen, Aurora Taira, Niko Välimäki, Ari Ristimäki, Toni Seppälä, Laura Renkonen-Sinisalo, Anna Lepistö, Kyösti Tahkola, Anne Mattila, Selja Koskensalo, Jukka-Pekka Mecklin, Kristiina Rajamäki, Kimmo Palin, Lauri A Aaltonen
摘要
微卫星不稳定的结直肠癌（MSI-CRC）可以通过lynch综合征（LS）的个体中的不匹配修复（MMR）基因中的种系突变或通过MMR基因MLH1的启动子甲基化而偶发地产生。尽管遗传性和零星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缺陷基因组的一个突出特征是在短序列中出现了许多indels，这是由于这些区域中变体呼叫的技术挑战而导致的研究的突变类型。在这项研究中，我们对29个零星和14个遗传性MSI-CRC进行了整个基因组测序和RNA测序。我们通过分析全基因组突变密度，微卫星重复插入，复发性蛋白质编码变体，单基碱基的特征，双重碱基和indel突变的特征以及基因表达的变化来比较肿瘤组。我们表明，遗传性和零星MSI-CRC的突变景观，包括突变特征和突变密度全基因组和微卫星中的突变景观非常相似。仅发现较少的差异表达基因，富含干扰素 - γ调控的免疫反应途径。分析每个肿瘤组体细胞变异的等位基因分数的方差显示出零星MSI-CRC中的克隆异质性较高。我们的结果表明，遗传性和零星MSI-CRC中MMR缺乏的分子起源不同不会导致这些肿瘤的突变景观存在实质性差异。肿瘤组之间克隆演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疗法的反应性降低有关。
Abstract
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.