The resurgence of immune therapies in cancer medicine has elicited a corresponding interest in understanding the basis of patient response or resistance to these treatments. One aspect of patient response clearly lies in the genomic alterations that are associated with cancer onset and progression, including those that contribute to genomic instability and the resulting creation of novel peptide sequences that may present as neoantigens. The immune reaction to these unique 'non-self' peptides is frequently suppressed by the tumor itself, but the use of checkpoint blockade therapies, personalized vaccines, or a combination of these treatments may elicit a tumor-specific immune response that results in cell death. Massively parallel sequencing, coupled with different computational analyses, provides unbiased identification of the germline and somatic alterations that drive cancer development, and of those alterations that lead to neoantigens. These range from simple point mutations that change single amino acids to complex alterations, such as frameshift insertion or deletion mutations, splice-site alterations that lead to exon skipping, structural alterations that lead to the formation of fusion proteins, and other forms of collateral damage caused by genome instability that result in new protein sequences unique to the cancer. The various genome instability phenotypes can be identified as alterations that impact DNA replication or mismatch repair pathways or by their genomic signatures. This review provides an overview of current knowledge regarding the fundamentals of genome replication and of both germline and somatic alterations that disrupt normal replication, leading to various forms of genomic instability in cancers, to the resulting generation of neoantigens and, ultimately, to immune-responsive and resistant phenotypes.

中文翻译：

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新抗原和基因组不稳定性：对免疫基因组表型和免疫治疗反应的影响。

免疫疗法在癌症医学中的兴起引起了人们对了解患者对这些疗法的反应或耐药性的基础的兴趣。患者反应的一个方面显然在于与癌症发作和进展相关的基因组改变，包括那些导致基因组不稳定性和由此产生的可能以新抗原形式出现的新型肽序列的基因改变。对这些独特的“非自身”肽的免疫反应通常会被肿瘤本身抑制，但是使用检查点封锁疗法，个性化疫苗或这些疗法的结合可能会引起肿瘤特异性免疫反应，从而导致细胞死亡。 。大规模并行测序，结合不同的计算分析，提供了对导致癌症发展的种系和体细胞变化以及导致新抗原的那些变化的公正鉴定。这些变化范围从简单的单点突变到单个氨基酸的变化，再到复杂的改变，例如移码插入或缺失突变，导致外显子跳跃的剪接位点改变，导致融合蛋白形成的结构改变以及其他形式的附带损害由基因组不稳定引起的，导致癌症特有的新蛋白质序列。可以将各种基因组不稳定性表型鉴定为影响DNA复制或错配修复途径的改变，或通过其基因组特征识别的改变。