独特的突变过程决定了MHC I类和II类突变在原发性和转移性瘤中的选择
Michael B Mumphrey1, Noshad Hosseini1, Abhijit Parolia2
1Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
Cell reports
|August 19, 2023
概括
癌细胞通过失去主要基因相容性复合体 (MHC) 表达而逃避免疫监测. 我们的研究揭示了多种癌症中常见的MHC基因突变,影响了免疫逃避和免疫疗法耐药性.
科学领域:
- 在瘤学瘤学.
- 免疫学 免疫学 免疫学
- 基因组学就是基因组学.
背景情况:
- 癌细胞可以通过减少主要组织相容性复合体 (MHC) 分子的表达来逃避免疫检测.
- 这种抗原呈现的破坏是免疫逃脱和对癌症免疫疗法的抵抗的关键机制.
研究的目的:
- 开发和应用一个个性化的基因组学算法,Hapster,对MHC基因内的体变异进行全面分析.
- 在初级和转移性瘤中创建一个大规模的MHC突变目录,并确定突变发生的模式.
主要方法:
- 开发了哈普斯特算法,用于准确调用MHC基因的体质突变.
- 分析了来自10,001个原发性和2,199个转移性瘤的基因组数据.
- 根据残留物影响确定MHC突变的功能分类.
主要成果:
- 在初级和转移性瘤中,MHC I 类基因经常发生突变,比 MHC II 类基因更为如此.
- 创建了1663个非同义突变的目录,揭示了癌症类型特定的突变热点.
- 对影响关键MHC功能部位的突变,包括B2M,结和T细胞接口,观察到显著的阳性选择.
结论:
- MHC基因突变是癌症的常见特征,有助于免疫逃避和免疫治疗耐药性.
- 哈普斯特提供了对MHC突变发生的宝贵见解,突出了特定的突变模式及其功能后果.
- 了解MHC突变对于开发更有效的癌症免疫疗法至关重要.
相关概念视频
Mismatch Repair
4.9K
Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...
4.9K
Cancers Originate from Somatic Mutations in a Single Cell
12.0K
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
12.0K
Mutations in Microorganisms
32
Mutations are heritable changes in an organism’s genome involving alterations in the base sequence of DNA or RNA. These changes can influence cellular processes and phenotypic traits, potentially transforming the unaltered wild type into a mutant form. Such changes, termed forward mutations, are pivotal in shaping the genetic diversity of organisms.RNA viruses exhibit the highest mutation rates due to the absence of robust proofreading mechanisms during genome replication. In contrast,...
32
Metastasis
5.6K
Metastasis is the spread of cancer cells from the original site to distant locations in the body. Cancer cells can spread via blood vessels (hematogenous) as well as lymph vessels in the body.
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
Epithelial-to-Mesenchymal Transition
The epithelial-to-mesenchymal transition or EMT is a developmental process commonly observed in wound healing, embryogenesis, and cancer metastasis. EMT is induced by transforming growth factor-beta (TGF-β) or receptor tyrosine kinase (RTK) ligands, which further...
5.6K
Adaptive Mechanisms in Cancer Cells
5.8K
Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
5.8K
Spontaneous and Induced Mutations
39
Spontaneous mutations arise infrequently during DNA replication due to errors in the process. A key factor behind these errors is tautomeric shifts in nitrogenous bases, where bases transition from keto to enol forms or amino to imino forms. This shift can alter base-pairing rules, leading to mutations. Additionally, reactive oxygen species (ROS) arising from aerobic metabolism can damage DNA, resulting in depurination (loss of a purine base) or depyrimidination (loss of a pyrimidine base).
39


