林奇综合征相关与散发性微卫星不稳定结直肠癌：不同的克隆演化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

HUMAN MOLECULAR GENETICS

影响因子:3.2

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

DOI: 10.1093/hmg/ddae124

摘要

微卫星不稳定的结直肠癌（MSI-CRC）可以通过林奇综合征（LS）患者的错配修复（MMR）基因的胚系突变发生，或偶发性通过MMR基因MLH1的启动子甲基化引起。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被广泛比较。MMR缺失基因组的一个显著特征是在短重复序列中发生大量插入缺失突变（indels），这是因为在这些区域进行变异检测存在技术挑战，导致此类突变类型未被充分研究。本研究对29例散发性和14例遗传性MSI-CRC进行了全基因组测序和RNA测序。通过分析基因组范围内的突变密度、微卫星重复序列的indels、反复出现的蛋白编码变异、单碱基、双碱基和indel突变的特征以及基因表达变化，比较了不同肿瘤组。结果显示，遗传性和散发性MSI-CRC的突变景观，包括突变特征和突变密度（在基因组全局和微卫星区域）高度相似。仅发现少量差异表达基因，富集于干扰素γ调控的免疫反应通路。变异等位基因频率的变异分析揭示，散发性MSI-CRC具有更高的克隆异质性。结果提示，遗传性和散发性MSI-CRC中MMR缺失的分子起源不同，但并未导致肿瘤突变景观的显著差异。两者在克隆演化模式上的差异可能具有临床意义，因为高度克隆异质性与肿瘤免疫监视减弱和免疫治疗反应下降相关。

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.