Pervasiveness of HLA allele-specific expression loss across tumor types.
Pervasiveness of HLA allele-specific expression loss across tumor types.
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DOI：
10.1186/s13073-023-01154-x
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发表时间：
2023-02-09
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
作者：
人类白细胞抗原 I 类 (HLA-I) 基因有效呈递突变肽片段对于免疫介导的癌细胞杀伤是必要的。根据最近的报道，患者 HLA-I 基因型可以影响癌症免疫治疗的疗效，并且 HLA-I 杂合性的体细胞丢失已被确定为免疫逃避的一个因素。虽然在不同肿瘤类型中也有 HLA-I 表达失调的报道，但 HLA-I 等位基因特异性表达丧失（即特定 HLA-I 等位基因的优先 RNA 表达丧失）在癌症中的作用尚未得到充分表征。在这里，我们使用 RNA 和全外显子组测序数据，使用我们的新方法 arcasHLA-quant 来量化癌症中的 HLA-I 等位基因特异性表达 (ASE)。我们发现，三个 HLA-I 基因中至少一个的 HLA-I ASE 丢失是 TCGA 肿瘤类型中的普遍现象。在胰腺腺癌中，肿瘤特异性 HLA-I ASE 丢失与总体生存率降低相关，特别是在基底样亚型中，我们通过激光捕获显微切割在独立队列中验证了这一发现。此外，我们通过回顾性分析表明 HLA-I ASE 丢失与转移性黑色素瘤免疫治疗效果不佳相关。总之，我们的结果强调了 HLA-I ASE 丢失的普遍性，并为其在癌症预后和免疫治疗中的临床意义提供了初步证据。 在线版本包含可在 10.1186/s13073-023-01154-x 获取的补充材料。
Efficient presentation of mutant peptide fragments by the human leukocyte antigen class I (HLA-I) genes is necessary for immune-mediated killing of cancer cells. According to recent reports, patient HLA-I genotypes can impact the efficacy of cancer immunotherapy, and the somatic loss of HLA-I heterozygosity has been established as a factor in immune evasion. While global deregulated expression of HLA-I has also been reported in different tumor types, the role of HLA-I allele-specific expression loss — that is, the preferential RNA expression loss of specific HLA-I alleles — has not been fully characterized in cancer. Here, we use RNA and whole-exome sequencing data to quantify HLA-I allele-specific expression (ASE) in cancer using our novel method arcasHLA-quant. We show that HLA-I ASE loss in at least one of the three HLA-I genes is a pervasive phenomenon across TCGA tumor types. In pancreatic adenocarcinoma, tumor-specific HLA-I ASE loss is associated with decreased overall survival specifically in the basal-like subtype, a finding that we validated in an independent cohort through laser-capture microdissection. Additionally, we show that HLA-I ASE loss is associated with poor immunotherapy outcomes in metastatic melanoma through retrospective analyses. Together, our results highlight the prevalence of HLA-I ASE loss and provide initial evidence of its clinical significance in cancer prognosis and immunotherapy treatment. The online version contains supplementary material available at 10.1186/s13073-023-01154-x.
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DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
影响因子：
64.5
作者：
McGranahan N;Rosenthal R;Hiley CT;Rowan AJ;Watkins TBK;Wilson GA;Birkbak NJ;Veeriah S;Van Loo P;Herrero J;Swanton C;TRACERx Consortium
通讯作者：
TRACERx Consortium
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
4.6
作者：
Bonneville R;Krook MA;Kautto EA;Miya J;Wing MR;Chen HZ;Reeser JW;Yu L;Roychowdhury S
通讯作者：
Roychowdhury S
影响因子：
7.3
作者：
Johansson T;Yohannes DA;Koskela S;Partanen J;Saavalainen P
通讯作者：
Saavalainen P