Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity.
Germline-mediated immunoediting sculpts breast cancer subtypes and metastatic proclivity.
复制标题
种系介导的免疫编辑塑造乳腺癌亚型和转移倾向。
DOI：
10.1101/2023.03.15.532870
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Curtis,Christina
中科院分区：
文献类型：
--
作者：
Houlahan,KathleenE;Khan,Aziz;Greenwald,NoahF;West,RobertB;Angelo,Michael;Curtis,Christina
相同诊断的肿瘤可能有不同的分子图谱和对治疗的反应。目前尚不清楚这些差异是在何时以及为什么会出现的。体细胞基因组异常发生在高度可变的生殖系基因组的背景下。通过对5870个乳腺癌病变的询问，我们证明了在重复扩增的基因中胚系衍生的表位通过介导免疫编辑来影响体细胞进化。与其他亚型相比，人类表皮生长因子受体2(HER2/ERBB2)具有高种系表位负荷的个体患HER2阳性乳腺癌的可能性较小。这同样适用于定义三个雌激素受体(ER)阳性亚群的重复扩增。克服这种免疫介导的负选择的肿瘤更具侵袭性，并表现出“免疫寒冷”的表型。这些数据表明，生殖系基因组在决定体细胞进化方面发挥了作用。
Tumors with the same diagnosis can have different molecular profiles and response to treatment. It remains unclear when and why these differences arise. Somatic genomic aberrations occur within the context of a highly variable germline genome. Interrogating 5870 breast cancer lesions, we demonstrated that germline-derived epitopes in recurrently amplified genes influence somatic evolution by mediating immunoediting. Individuals with a high germline-epitope burden in human epidermal growth factor receptor 2 (HER2/ERBB2) are less likely to develop HER2-positive breast cancer compared with other subtypes. The same holds true for recurrent amplicons defining three aggressive estrogen receptor (ER)–positive subgroups. Tumors that overcome such immune-mediated negative selection are more aggressive and demonstrate an “immune cold” phenotype. These data show that the germline genome plays a role in dictating somatic evolution.