APOBEC Alteration Contributes to Tumor Growth and Immune Escape in Pan-Cancer.
APOBEC Alteration Contributes to Tumor Growth and Immune Escape in Pan-Cancer.
复制标题
APOBEC 改变有助于泛癌中的肿瘤生长和免疫逃逸
作者：
APOBEC 3家族（载脂蛋白B mRNA编辑酶催化多肽样）被证明通过异常DNA编辑机制诱导肿瘤突变。在这项研究中，我们发现APOBEC基因在16种癌症类型的正常和癌症样本之间存在广泛而显著的差异表达，并且它们的表达水平与17种癌症类型的预后价值显著相关。对APOBEC家族的进一步分析揭示了广泛的调控机制，通过这些机制，它们影响肿瘤微环境、肿瘤发生和发展的过程，以及它们与泛癌患者预后的相关性。越来越多的证据表明，载脂蛋白B mRNA编辑酶催化多肽样（APOBEC），即DNA编辑蛋白在肿瘤的分子发病机制中起着重要作用。特别是，APOBEC3家族显示通过异常DNA编辑机制诱导肿瘤突变。然而，关于跨癌症类型的APOBEC家族基因的重建的知识仍然缺乏。在这里，我们系统地分析了APOBEC家族在泛癌中的分子改变、免疫肿瘤学特征和临床相关性。我们发现APOBEC基因在16种癌症类型的正常和癌症样本之间广泛且显著差异表达，并且它们的表达水平与17种癌症类型的预后价值显著相关。此外，两种模式的APOBEC介导的分层具有不同的免疫特征，分别在不同的癌症类型。例如，在ACC中，APOBEC介导的分层的第一种模式与免疫活化的表型密切相关，其特征在于高免疫评分、CD8 T细胞浸润增加和较高的存活率。APOBEC介导的分层的另一种模式与低浸润免疫表型密切相关，其特征在于低免疫评分，缺乏有效的免疫浸润和较差的存活率。此外，我们发现APOBEC介导的低浸润免疫模式也与晚期肿瘤亚型和CIMP高肿瘤亚型（CpG岛高甲基化）高度相关。具有APOBEC介导的免疫激活模式的患者更可能在ICB（免疫检查点阻断）治疗中具有治疗优势。总的来说，我们的研究结果提供了一个有价值的资源，将有助于指导肿瘤学和治疗分析APOBEC家族在癌症中的作用。
Simple Summary The APOBEC3 family (apolipoprotein B mRNA editing enzyme catalytic polypeptide-like) was shown to induce tumor mutations through an aberrant DNA editing mechanism. In this study, we found that APOBEC genes were widely and significantly differentially expressed between normal and cancer samples in 16 cancer types, and their expression levels were significantly correlated with the prognostic value in 17 cancer types. Further analysis of the APOBEC family revealed extensive regulatory mechanisms by which they affect the tumor microenvironment, the process of tumor oncogenesis and development, and their association with patient prognosis in pan-cancer. Abstract The accumulating evidence demonstrates that the apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. In particular, the APOBEC3 family was shown to induce tumor mutations by an aberrant DNA editing mechanism. However, knowledge regarding the reconstitution of the APOBEC family genes across cancer types is still lacking. Here, we systematically analyzed the molecular alterations, immuno-oncological features, and clinical relevance of the APOBEC family in pan-cancer. We found that APOBEC genes were widely and significantly differentially expressed between normal and cancer samples in 16 cancer types, and that their expression levels are significantly correlated with the prognostic value in 17 cancer types. Moreover, two patterns of APOBEC-mediated stratification with distinct immune characteristics were identified in different cancer types, respectively. In ACC, for example, the first pattern of APOBEC-mediated stratification was closely correlated with the phenotype of immune activation, which was characterized by a high immune score, increased infiltration of CD8 T cells, and higher survival. The other pattern of APOBEC-mediated stratification was closely correlated with the low-infiltration immune phenotype, which was characterized by a low immune score, lack of effective immune infiltration, and poorer survival. Further, we found the APOBEC-mediated pattern with low-infiltration immune was also highly associated with the advanced tumor subtype and the CIMP-high tumor subtype (CpG island hypermethylation). Patients with the APOBEC-mediated pattern with immune activation were more likely to have therapeutic advantages in ICB (immunological checkpoint blockade) treatment. Overall, our results provide a valuable resource that will be useful in guiding oncologic and therapeutic analyses of the role of APOBEC family in cancer.
登录
查看更多内容
影响因子：
30.8
作者：
Burns, Michael B.;Temiz, Nuri A.;Harris, Reuben S.
通讯作者：
Harris, Reuben S.
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
DOI：
10.1186/s13058-014-0498-3
发表时间：
2015-01-21
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Harris RS
通讯作者：
Harris RS
影响因子：
30.8
作者：
Miao D;Margolis CA;Vokes NI;Liu D;Taylor-Weiner A;Wankowicz SM;Adeegbe D;Keliher D;Schilling B;Tracy A;Manos M;Chau NG;Hanna GJ;Polak P;Rodig SJ;Signoretti S;Sholl LM;Engelman JA;Getz G;Jänne PA;Haddad RI;Choueiri TK;Barbie DA;Haq R;Awad MM;Schadendorf D;Hodi FS;Bellmunt J;Wong KK;Hammerman P;Van Allen EM
通讯作者：
Van Allen EM