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The shared frameshift mutation landscape of microsatellite-unstable cancers suggests immunoediting during tumor evolution.
Nature Communications ( IF 14.7 ) Pub Date : 2020-09-21 , DOI: 10.1038/s41467-020-18514-5
Alexej Ballhausen 1, 2, 3 , Moritz Jakob Przybilla 1, 2, 3 , Michael Jendrusch 1, 2, 3 , Saskia Haupt 4 , Elisabeth Pfaffendorf 1, 2, 3 , Florian Seidler 1, 2, 3 , Johannes Witt 1, 2, 3 , Alejandro Hernandez Sanchez 1, 2, 3 , Katharina Urban 1, 2, 3 , Markus Draxlbauer 1, 2, 3 , Sonja Krausert 1, 2, 3 , Aysel Ahadova 1, 2, 3 , Martin Simon Kalteis 1, 2, 3 , Pauline L Pfuderer 1, 2, 3 , Daniel Heid 1, 2, 3 , Damian Stichel 1, 5 , Johannes Gebert 1, 2, 3 , Maria Bonsack 6, 7, 8 , Sarah Schott 9 , Hendrik Bläker 10 , Toni Seppälä 11 , Jukka-Pekka Mecklin 12, 13 , Sanne Ten Broeke 14 , Maartje Nielsen 14 , Vincent Heuveline 4 , Julia Krzykalla 15 , Axel Benner 15 , Angelika Beate Riemer 6, 7 , Magnus von Knebel Doeberitz 1, 2, 3 , Matthias Kloor 1, 2, 3
Affiliation  

The immune system can recognize and attack cancer cells, especially those with a high load of mutation-induced neoantigens. Such neoantigens are abundant in DNA mismatch repair (MMR)-deficient, microsatellite-unstable (MSI) cancers. MMR deficiency leads to insertion/deletion (indel) mutations at coding microsatellites (cMS) and to neoantigen-inducing translational frameshifts. Here, we develop a tool to quantify frameshift mutations in MSI colorectal and endometrial cancer. Our results show that frameshift mutation frequency is negatively correlated to the predicted immunogenicity of the resulting peptides, suggesting counterselection of cell clones with highly immunogenic frameshift peptides. This correlation is absent in tumors with Beta-2-microglobulin mutations, and HLA-A*02:01 status is related to cMS mutation patterns. Importantly, certain outlier mutations are common in MSI cancers despite being related to frameshift peptides with functionally confirmed immunogenicity, suggesting a possible driver role during MSI tumor evolution. Neoantigens resulting from shared mutations represent promising vaccine candidates for prevention of MSI cancers.



中文翻译:


微卫星不稳定癌症的共同移码突变景观表明肿瘤进化过程中存在免疫编辑。



免疫系统可以识别并攻击癌细胞,尤其是那些含有大量突变诱导新抗原的癌细胞。这种新抗原在 DNA 错配修复 (MMR) 缺陷、微卫星不稳定 (MSI) 癌症中含量丰富。 MMR 缺陷导致编码微卫星 (cMS) 插入/缺失 (indel) 突变以及新抗原诱导的翻译移码。在这里,我们开发了一种工具来量化 MSI 结直肠癌和子宫内膜癌中的移码突变。我们的结果表明,移码突变频率与所得肽的预测免疫原性呈负相关,这表明具有高免疫原性移码肽的细胞克隆的反选择。在具有Beta-2-微球蛋白突变的肿瘤中不存在这种相关性,并且 HLA-A*02:01 状态与 cMS 突变模式相关。重要的是,某些异常突变在 MSI 癌症中很常见,尽管与功能上已证实具有免疫原性的移码肽有关,这表明在 MSI 肿瘤进化过程中可能具有驱动作用。由共同突变产生的新抗原代表了预防 MSI 癌症的有希望的候选疫苗。

更新日期:2020-09-21
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