Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer.
Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer.
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综合分析揭示 HLA-I LOH 在三阴性乳腺癌中的预后价值
DOI：
10.1136/jitc-2021-003371
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发表时间：
2021-10
影响因子：
10.9
通讯作者：
Shao ZM
中科院分区：
文献类型：
--
作者：
Zhou YF;Xiao Y;Jin X;Di GH;Jiang YZ;Shao ZM
三阴性乳腺癌（tnbc），特别是那些非免疫炎症性肿瘤，预后差，治疗有限。人白细胞抗原(HLA)- 1不仅有助于抗肿瘤免疫应答和肿瘤微环境的表型，而且是免疫治疗后预后的负面预测因子。然而，HLA功能状态在tnbc中的重要性仍然知之甚少。方法利用最大的tnbc原始多组学数据集，从HLA-Ⅰ同质性和杂合性损失（LOH）的角度系统表征tnbc的HLA-Ⅰ状态。测定hla - 1水平对预后的意义。为了解释HLA-Ⅰ状态的预后价值的潜在机制，我们测量了突变特征、拷贝数改变、新抗原和肿瘤内异质性。进一步分析HLA-Ⅰ功能状态与肿瘤免疫微环境的相关性。结果hla - 1的LOH和均匀性分别占tnbc的18%和21%。hla - 1 LOH取代hla - 1同质性是tnbc的独立预后生物标志物。特别是对于非免疫炎症性肿瘤患者，hla - 1 LOH比hla - 1非LOH的预后更差。此外，综合基因组学和转录组学分析表明，hla - 1 LOH伴随着突变特征3和同源重组缺陷评分的上调，这意味着DNA双链断裂修复失败。此外，hla - 1 LOH比hla - 1 non-LOH具有更高的突变和新抗原载量以及更多的亚克隆。这些结果表明，虽然DNA双链断裂修复失败的hla - 1 LOH肿瘤容易产生新抗原，但其有限的抗原呈递能力最终导致了较差的免疫选择压力。结论本研究阐明了hla - 1功能状态的基因组图谱，并强调了hla - 1 LOH在tnbc中的预后意义。对于tnbc中的“冷”肿瘤，hla - 1 LOH比hla - 1 non-LOH的预后更差。
Background Triple-negative breast cancers (TNBCs), especially those non-immune-inflamed tumors, have a poor prognosis and limited therapies. Human leukocyte antigen (HLA)-I not only contributes to antitumor immune response and the phenotype of the tumor microenvironment, but also is a negative predictor of outcomes after immunotherapy. However, the importance of HLA functional status in TNBCs remains poorly understood. Methods Using the largest original multiomics datasets on TNBCs, we systematically characterized the HLA-Ⅰ status of TNBCs from the perspective of HLA-Ⅰ homogeneity and loss of heterozygosity (LOH). The prognostic significance of HLA-I status was measured. To explain the potential mechanism of prognostic value in HLA-Ⅰ status, the mutational signature, copy number alteration, neoantigen and intratumoral heterogeneity were measured. Furthermore, the correlation between HLA-Ⅰ functional status and the tumor immune microenvironment was analyzed. Results LOH and homogeneity in HLA-I accounted for 18% and 21% of TNBCs, respectively. HLA-I LOH instead of HLA-I homogeneity was an independent prognostic biomarker in TNBCs. In particular, for patients with non-immune-inflamed tumors, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH. Furthermore, integrated genomic and transcriptomic analysis showed that HLA-I LOH was accompanied by upregulated scores of mutational signature 3 and homologous recombination deficiency scores, which implied the failure of DNA double-strand break repair. Moreover, HLA-I LOH had higher mutation and neoantigen loads and more subclones than HLA-I non-LOH. These results indicated that although HLA-I LOH tumors with failure of DNA double-strand break repair were prone to produce neoantigens, their limited capacity for antigen presentation finally contributed to poor immune selection pressure. Conclusion Our study illustrates the genomic landscape of HLA-I functional status and stresses the prognostic significance of HLA-I LOH in TNBCs. For “cold” tumors in TNBCs, HLA-I LOH indicated a worse prognosis than HLA-I non-LOH.
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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
DOI：
10.4049/jimmunol.1700893
发表时间：
2017-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Jurtz V;Paul S;Andreatta M;Marcatili P;Peters B;Nielsen M
通讯作者：
Nielsen M
DOI：
10.4049/jimmunol.1302101
发表时间：
2013-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Paul S;Weiskopf D;Angelo MA;Sidney J;Peters B;Sette A
通讯作者：
Sette A
三阴性乳腺癌的基因组和转录组景观：亚型和治疗策略
影响因子：
50.3
作者：
Jiang, Yi-Zhou;Ma, Ding;Shao, Zhi-Ming
通讯作者：
Shao, Zhi-Ming
影响因子：
64.8
作者：
Nik-Zainal S;Davies H;Staaf J;Ramakrishna M;Glodzik D;Zou X;Martincorena I;Alexandrov LB;Martin S;Wedge DC;Van Loo P;Ju YS;Smid M;Brinkman AB;Morganella S;Aure MR;Lingjærde OC;Langerød A;Ringnér M;Ahn SM;Boyault S;Brock JE;Broeks A;Butler A;Desmedt C;Dirix L;Dronov S;Fatima A;Foekens JA;Gerstung M;Hooijer GK;Jang SJ;Jones DR;Kim HY;King TA;Krishnamurthy S;Lee HJ;Lee JY;Li Y;McLaren S;Menzies A;Mustonen V;O'Meara S;Pauporté I;Pivot X;Purdie CA;Raine K;Ramakrishnan K;Rodríguez-González FG;Romieu G;Sieuwerts AM;Simpson PT;Shepherd R;Stebbings L;Stefansson OA;Teague J;Tommasi S;Treilleux I;Van den Eynden GG;Vermeulen P;Vincent-Salomon A;Yates L;Caldas C;van't Veer L;Tutt A;Knappskog S;Tan BK;Jonkers J;Borg Å;Ueno NT;Sotiriou C;Viari A;Futreal PA;Campbell PJ;Span PN;Van Laere S;Lakhani SR;Eyfjord JE;Thompson AM;Birney E;Stunnenberg HG;van de Vijver MJ;Martens JW;Børresen-Dale AL;Richardson AL;Kong G;Thomas G;Stratton MR
通讯作者：
Stratton MR