Dept. of Medical Oncology, Amsterdam University Medical Centers, University of Amsterdam, Cancer Center Amsterdam, Amsterdam, The Netherlands.
Dept. of Experimental Immunology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Infection & Immunity, Amsterdam, The Netherlands.
PLoS One. 2021 Jun 28;16(6):e0251630. doi: 10.1371/journal.pone.0251630. eCollection 2021.
Approximately 15% of Colon Cancers are Microsatellite Instable (MSI). Frameshift Peptides (FPs) formed in MSI Colon Cancer are potential targets for immunotherapeutic strategies. Here we comprehensively characterize the mutational landscape of 71 MSI Colon Cancer patients from the cancer genome atlas (TCGA). We confirm that the mutations in MSI Colon Cancers are frequently frameshift deletions (23% in MSI; 1% in microsatellite stable), We find that these mutations cluster at specific locations in the genome which are mutated in up to 41% of the patients. We filter these for an adequate variant allele frequency, a sufficient mean mRNA level and the formation of a Super Neo Open Reading Frame (SNORF). Finally, we check the influence of Nonsense Mediated Decay (MMD) by comparing RNA and DNA sequencing results. Thereby we identify a set of 20 NMD-escaping Public FPs (PFPs) that cover over 90% of MSI Colon, 62.2% of MSI Endometrial and 58.8% of MSI Stomach cancer patients and 3 out of 4 Lynch patients in the TCGA-COAD. This underlines the potential for PFP directed immunotherapy, both in a therapeutic and a prophylactic setting in multiple types of MSI cancers.
约 15%的结肠癌为微卫星不稳定型（MSI）。MSI 结肠癌中形成的移码肽（FP）是免疫治疗策略的潜在靶点。在这里，我们全面描述了来自癌症基因组图谱（TCGA）的 71 例 MSI 结肠癌患者的突变景观。我们证实，MSI 结肠癌中的突变通常是移码缺失（MSI 中为 23%，微卫星稳定中为 1%）。我们发现这些突变聚集在基因组的特定位置，在多达 41%的患者中发生突变。我们对这些突变进行了适当的变异等位基因频率、足够的平均 mRNA 水平和超新开放阅读框（SNORF）的形成过滤。最后，我们通过比较 RNA 和 DNA 测序结果来检查无义介导的衰变（NMD）的影响。因此，我们确定了一组 20 个 NMD 逃逸的公共 FP（PFPs），它们覆盖了超过 90%的 MSI 结肠癌、62.2%的 MSI 子宫内膜癌和 58.8%的 MSI 胃癌患者，以及 TCGA-COAD 中 4 个 Lynch 患者中的 3 个。这强调了 FP 指导的免疫治疗的潜力，无论是在多种类型的 MSI 癌症的治疗还是预防环境中。
