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Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients.

ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nucleic acids and highly diverse clinical manifestations. To assess its molecular heterogeneity, we longitudinally profiled the blood transcriptome of 158 pediatric patients. Using mixed models accounting for repeated measurements, demographics, treatment, disease activity (DA), and nephritis class, we confirmed a prevalent IFN signature and identified a plasmablast signature as the most robust biomarker of DA. We detected gradual enrichment of neutrophil transcripts during progression to active nephritis and distinct signatures in response to treatment in different nephritis subclasses. Importantly, personalized immunomonitoring uncovered individual correlates of disease activity that enabled patient stratification into seven groups, supported by patient genotypes. Our study uncovers the molecular heterogeneity of SLE and provides an explanation for the failure of clinical trials. This approach may improve trial design and implementation of tailored therapies in genetically and clinically complex autoimmune diseases. PAPERCLIP.

SUBMITTER: Banchereau R

PROVIDER: S-EPMC5426482 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients.

Banchereau Romain R Hong Seunghee S Cantarel Brandi B Baldwin Nicole N Baisch Jeanine J Edens Michelle M Cepika Alma-Martina AM Acs Peter P Turner Jacob J Anguiano Esperanza E Vinod Parvathi P Kahn Shaheen S Obermoser Gerlinde G Blankenship Derek D Wakeland Edward E Nassi Lorien L Gotte Alisa A Punaro Marilynn M Liu Yong-Jun YJ Banchereau Jacques J Rossello-Urgell Jose J Wright Tracey T Pascual Virginia V

Cell 20160331 3

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nucleic acids and highly diverse clinical manifestations. To assess its molecular heterogeneity, we longitudinally profiled the blood transcriptome of 158 pediatric patients. Using mixed models accounting for repeated measurements, demographics, treatment, disease activity (DA), and nephritis class, we confirmed a prevalent IFN signature and identified a plasmablast signature as the most robust biom ...[more]

PMID: 27040498

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Project description:BackgroundPrecision medicine incorporating genetic profiling is becoming a standard of care in medical oncology. However, in the field of radiation oncology there is limited use of genetic profiling and the impact of germline genetic biomarkers on radiosensitivity, radioresistance, or patient outcomes after radiation therapy is poorly understood. In HNSCC, the toxicity associated with treatment can cause delays or early cessation which has been associated with worse outcomes. Identifying potential biomarkers which can help predict toxicity, as well as response to treatment, is of significant interest.MethodsPatients with HNSCC who received RT and underwent next generation sequencing of somatic tumor samples, transcriptome RNA-seq with matched normal tissue samples were included. Patients were then grouped by propensity towards increased late vs. early toxicity (Group A) and those without (Group B), assessed by CTCAE v5.0. The groups were then analyzed for association of specific germline variants with toxicity and clinical outcomes.ResultsIn this study we analyzed 37 patients for correlation between germline variants and toxicity. We observed that TSC2, HLA-A, TET2, GEN1, NCOR2 and other germline variants were significantly associated with long term toxicities. 34 HNSCC patients treated with curative intent were evaluated for clinical outcomes. Group A had significantly improved overall survival as well as improved rates of locoregional recurrence and metastatic disease. Specific variants associated with improved clinical outcomes included TSC2, FANCD2, and PPP1R15A, while the HLA-A and GEN1 variants were not correlated with survival or recurrence. A group of five HLA-DMA/HLA-DMB variants was only found in Group B and was associated with a higher risk of locoregional recurrence.ConclusionsThis study indicates that germline genetic biomarkers may have utility in predicting toxicity and outcomes after radiation therapy and deserve further investigation in precision radiation medicine approaches.

Dataset Information

Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients.

Publications

Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients.

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