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Integrated analysis reveals prognostic value of HLA-I LOH in triple-negative breast cancer.

AbstractBACKGROUND:
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.
AuthorsYi-Fan Zhou, Yi Xiao, Xi Jin, Gen-Hong Di, Yi-Zhou Jiang, Zhi-Ming Shao
JournalJournal for immunotherapy of cancer (J Immunother Cancer) Vol. 9 Issue 10 (10 2021) ISSN: 2051-1426 [Electronic] England
PMID34615706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Chemical References
  • HLA Antigens
Topics
  • Female
  • HLA Antigens (genetics)
  • Humans
  • Loss of Heterozygosity (genetics)
  • Prognosis
  • Survival Analysis
  • Triple Negative Breast Neoplasms (genetics, mortality)

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