来自杂志 Nature Biotechnology 的文献。
当前共找到 1 篇文献分享。
1.
笑对人生
(2022-10-07 00:02):
#paper doi: 10.1038/nbt.3344. PMID: 26372948. Comprehensive analysis of cancer-associated somatic mutations in class I HLA genes. Nat Biotechnol. 2015 Nov;33(11):1152-8. 主要组织相容性复合物（major histocompatibility complex，MHC）是一群紧密连锁并呈现高度多态性的基因群的统称。MHC编码的蛋白通常称为MHC分子或MHC抗原。MHC的发现源自异种移植产生免疫排斥反应。研究表明，脊椎动物都具有MHC抗原，但它们的命名并不相同。人的MHC抗原称为人类白细胞抗原（human leucocyte antigen，HLA）。编码HLA的DNA序列为6号染色体短臂上一段长度约为3600kb的区域。该区域含有224个基因座，每个基因座又分别含有众多等位基因，是目前人类已知的基因多态性最丰富的区域。HLA的生物学功能包括参与抗原呈递，制约细胞间相互识别和诱导免疫应答等。HLA主要分成三类，MHC I类分子几乎在集体所有细胞中表达，能够被CD8+ T细胞识别；MHC II类分子主要表达在抗原呈递细胞（APC），能够被CD4+T细胞识别；MHC III类分子包括补体系统的成分和与炎症相关的分子，例如C4、TNF和热休克蛋白。肿瘤细胞自身能够表达与正常细胞不同的抗原，称为肿瘤新生抗原（neoantigen）。新生抗原属于肿瘤特异性抗原(tumor specific antigen，TSA)。为了让TSA不被免疫细胞发现，肿瘤细胞会通过让HLA基因发生杂合性缺失（LOH）、下调HLA基因表达（突变）和分泌PD-L1来隐藏自身。既往的研究表明，体细胞HLA基因的突变增加是导致HLA功能缺失的重要原因。基于NGS的全外显子测序技术（WES）因性价比高和能有效检测几乎所有基因的突变，目前在临床和科研肿瘤基因组检测得到广泛应用。然而，由于HLA基因序列单一和高GC含量的序列特点，利用WES进行HLA分型仍旧存在不少挑战。为此，本研究开发了一个名为POLYSOLVER（POLYmorphic loci reSOLVER）的高精确度HLA分型算法，适用于低覆盖度的WES数据。该算法在7930位癌症患者的WES数据得到验证，并在检测体细胞HLA基因突变表现出高的灵敏度和特异度。
Abstract:
Detection of somatic mutations in human leukocyte antigen (HLA) genes using whole-exome sequencing (WES) is hampered by the high polymorphism of the HLA loci, which prevents alignment of sequencing reads …
>>>
Detection of somatic mutations in human leukocyte antigen (HLA) genes using whole-exome sequencing (WES) is hampered by the high polymorphism of the HLA loci, which prevents alignment of sequencing reads to the human reference genome. We describe a computational pipeline that enables accurate inference of germline alleles of class I HLA-A, B and C genes and subsequent detection of mutations in these genes using the inferred alleles as a reference. Analysis of WES data from 7,930 pairs of tumor and healthy tissue from the same patient revealed 298 nonsilent HLA mutations in tumors from 266 patients. These 298 mutations are enriched for likely functional mutations, including putative loss-of-function events. Recurrence of mutations suggested that these 'hotspot' sites were positively selected. Cancers with recurrent somatic HLA mutations were associated with upregulation of signatures of cytolytic activity characteristic of tumor infiltration by effector lymphocytes, supporting immune evasion by altered HLA function as a contributory mechanism in cancer.
<<<
翻译