Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1-/- Mice
Unraveling the Heterogeneous Mutational Signature of Spontaneously Developing Tumors in MLH1-/- Mice
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DOI：
10.3390/cancers11101485
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发表时间：
2019-10-01
期刊：
影响因子：
5.2
通讯作者：
Maletzki, Claudia
中科院分区：
文献类型：
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作者：
Gladbach, Yvonne Saara;Wiegele, Leonie;Maletzki, Claudia
错配修复缺陷（MMR-D）肿瘤是典型的超突变表型。由于高突变率，大量的新抗原出现在肿瘤细胞表面，理想情况下，不同类型的癌症之间是共享的。MLH1敲除小鼠代表了一种临床前模型，类似于人类MMR-D的特征。虽然这些小鼠以顺序双峰方式发展肿瘤（淋巴瘤和胃肠道肿瘤（GIT）），但我们旨在确定潜在的分子机制。使用全基因组测序，我们专注于(I)共享和（II）互斥突变，并描述肿瘤源性细胞培养中正在进行的突变事件的过程。MLH1（-/-）肿瘤的特征是异质性的，在不同的肿瘤实体（ARID1A和IDH2）中仅检测到少数共享突变。对于mmr - d相关靶基因的编码微卫星分析，可以检测到部分重叠，但可以识别共享抗原。目前的研究是第一个报告的结果比较自发发展的肿瘤在MMR-D驱动的肿瘤发生。除了将ARID1A确定为潜在的致病突变热点外，对突变景观的全面描述可能是完善治疗概念的一个良好起点。
Mismatch repair deficient (MMR-D) tumors exemplify the prototypic hypermutator phenotype. Owing to the high mutation rates, plenty of neo-antigens are present on the tumor cells' surface, ideally shared among different cancer types. The MLH1 knock out mouse represents a preclinical model that resembles features of the human MMR-D counterpart. While these mice develop neoplasias in a sequential twin-peaked manner (lymphomas > gastrointestinal tumors (GIT)) we aimed at identification of underlying molecular mechanisms. Using whole-genome sequencing, we focused on (I) shared and (II) mutually exclusive mutations and describe the process of ongoing mutational events in tumor-derived cell cultures. The landscape of MLH1(-/-) tumors is heterogeneous with only a few shared mutations being detectable among different tumor entities (ARID1A and IDH2). With respect to coding microsatellite analysis of MMR-D-related target genes, partial overlap was detectable, yet recognizing shared antigens. The present study is the first reporting results of a comparison between spontaneously developing tumors in MMR-D driven tumorigenesis. Additionally to identifying ARID1A as potential causative mutation hotspot, this comprehensive characterization of the mutational landscape may be a good starting point to refine therapeutic concepts.