Tumor Mutational Burden Is Polygenic and Genetically Associated with Complex Traits and Diseases
Tumor Mutational Burden Is Polygenic and Genetically Associated with Complex Traits and Diseases
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肿瘤突变负担是多基因的，并且与复杂的性状和疾病有遗传相关性
DOI：
10.1158/0008-5472.can-20-3459
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发表时间：
2021
期刊：
影响因子：
11.2
通讯作者：
Jian Yang
中科院分区：
文献类型：
--
作者：
Xiwei Sun;Angli Xue;Ting Qi;Dan Chen;Dandan Shi;Yang Wu;Zhili Zheng;Jian Zeng;Jian Yang
这项研究为肿瘤突变负荷的多基因结构提供了证据，并为使用全基因组种系遗传变异对癌症患者进行免疫治疗提供了途径。肿瘤突变负荷（TMB）是一种新兴的实体瘤免疫治疗反应的生物标志物。然而，患者之间TMB的变异在多大程度上归因于生殖系遗传变异仍然是难以捉摸的。在这里，使用来自癌症基因组图谱的33种癌症类型的7，004名无关的欧洲血统患者，我们表明泛癌TMB是多基因的，大约13%的变异可以由大约110万种常见变异解释。我们鉴定了通过改变BAG5和KLC 1的表达水平来影响胃腺癌中TMB的种系变异。进一步的分析提供的证据表明，TMB与复杂的性状和疾病（如吸烟、类风湿性关节炎、身高和癌症）有遗传相关性，其中一些相关性可能是因果关系。总的来说，这些结果为肿瘤体细胞突变的遗传基础提供了新的见解，并可能为未来使用遗传变异对患者进行免疫治疗的努力提供信息。重要性：这项研究为肿瘤突变负荷的多基因结构提供了证据，并为使用全基因组种系遗传变异对癌症患者进行免疫治疗提供了途径。
This study provides evidence for a polygenic architecture of tumor mutational burden and opens an avenue for the use of whole-genome germline genetic variations to stratify patients with cancer for immunotherapy. Tumor mutational burden (TMB) is an emerging biomarker of response to immunotherapy in solid tumors. However, the extent to which variation in TMB between patients is attributable to germline genetic variation remains elusive. Here, using 7,004 unrelated patients of European descent across 33 cancer types from The Cancer Genome Atlas, we show that pan-cancer TMB is polygenic with approximately 13% of its variation explained by approximately 1.1 million common variants altogether. We identify germline variants that affect TMB in stomach adenocarcinoma through altering the expression levels of BAG5 and KLC1. Further analyses provide evidence that TMB is genetically associated with complex traits and diseases, such as smoking, rheumatoid arthritis, height, and cancers, and some of the associations are likely causal. Overall, these results provide new insights into the genetic basis of somatic mutations in tumors and may inform future efforts to use genetic variants to stratify patients for immunotherapy. Significance: This study provides evidence for a polygenic architecture of tumor mutational burden and opens an avenue for the use of whole-genome germline genetic variations to stratify patients with cancer for immunotherapy.
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
7.7
作者：
Hemani G;Zheng J;Elsworth B;Wade KH;Haberland V;Baird D;Laurin C;Burgess S;Bowden J;Langdon R;Tan VY;Yarmolinsky J;Shihab HA;Timpson NJ;Evans DM;Relton C;Martin RM;Davey Smith G;Gaunt TR;Haycock PC
通讯作者：
Haycock PC