Association of LRP1B Mutation With Tumor Mutation Burden and Outcomes in Melanoma and Non-small Cell Lung Cancer Patients Treated With Immune Check-Point Blockades
Association of LRP1B Mutation With Tumor Mutation Burden and Outcomes in Melanoma and Non-small Cell Lung Cancer Patients Treated With Immune Check-Point Blockades
复制标题
LRP1B 突变与接受免疫检查点阻断治疗的黑色素瘤和非小细胞肺癌患者的肿瘤突变负担和结果之间的关系
DOI：
10.3389/fimmu.2019.01113
复制
发表时间：
2019-05-21
影响因子：
7.3
通讯作者：
Wang, Xin
中科院分区：
文献类型：
--
作者：
Chen, Hao;Chong, Wei;Wang, Xin
背景：肿瘤突变负荷（TMB）已被用作预测免疫治疗反应的最流行的生物标志物。LRP1B（低密度脂蛋白受体相关蛋白1B）是经常突变的黑色素瘤，非小细胞肺癌（NSCLC）和其他肿瘤，然而，其与TMB和患者的生存与immunotherapy.Methods：我们策划的体细胞突变数据和临床病理信息，从332黑色素瘤免疫治疗样本的发现和113 NSCLC样本的进一步确证。使用贝叶斯变体非负矩阵因子分解来提取肿瘤突变特征。采用多因素考克斯和logistic回归模型校正混杂因素。分别使用CIBERSORT和GSEA算法来推断白细胞相对丰度和显着富集的途径。结果：在两个免疫治疗队列中，发现LRP 1B突变患者与生存期延长相关。在LRP1B突变患者中发现了更高的肿瘤突变负荷，并且在控制年龄，性别，分期，TP53和ATR突变以及突变特征后，这种关联仍然显着。免疫反应和细胞周期调控电路是与LRP1B mutations.Conclusion样品中的顶级富集途径之一：我们的研究表明，即使是一个单一的，频繁突变的基因测序可以提供洞察全基因组的突变负担，并可能作为一个生物标志物来预测免疫反应。
Background: Tumor mutation burden (TMB) have been served as the most prevalent biomarkers to predict immunotherapy response. LRP1B (low-density lipoprotein receptor-related protein 1B) is frequently mutated in melanoma, non-small cell lung cancer (NSCLC) and other tumors; however, its association with TMB and survival in patients with immunotherapy remains unknown.Methods: We curated somatic mutation data and clinicopathologic information from 332 melanoma immunotherapy samples for discovery and 113 NSCLC samples for further corroboration. Bayesian variants non-negative matrix factorization was used to extract tumor mutational signatures. Multivariate Cox and logistic regression models were applied to adjust confounding factors. The CIBERSORT and GSEA algorithm were separately used to infer leukocyte relative abundance and significantly enriched pathways.Results: Patients with LRP1B mutation were identified to be associated with prolonged survival in both immunotherapy cohort. Higher tumor mutation burden was found in LRP1B mutated patients, and the association remained significant after controlling for age, gender, stage, mutations in TP53 and ATR, and mutational signatures. Immune response and cell cycle regulation circuits were among the top enriched pathways in samples with LRP1B mutations.Conclusion: Our studies suggested sequencing even a single, frequently mutated gene may provide insight into genome-wide mutational burden, and may serve as a biomarker to predict immune response.