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Blood transcriptional signatures of asymptomatic FDG-PET/CT-defined Subclinical TB lesions and their prediction of future TB progression

ABSTRACT: Diagnostic tests for tuberculosis (TB) infection poorly predict future incident disease risk. We investigated a cohort of asymptomatic HIV-uninfected household contacts of TB in South Africa in which baseline lung lesions indicative of Subclinical TB identified by [18F]-fluoro-2-deoxy-D-glucose (FDG)-positron emission/computed tomography (PET/CT) had high predictive value for future TB over 5 years. RNA-sequencing analysis of whole blood samples at baseline PET/CT, 5-15m PET/CT2, and the TB diagnosis of incident TB revealed persistent enrichment of neutrophil and monocyte transcriptional modules in those with Subclinical TB and worsening and discrete lung abnormalities, while expression of a core set of type I IFN genes related to FDG-avid lymph nodes. Leveraging multiple machine learning algorithms, we derived gene signatures of various PET/CT lesion Subclinical phenotypesTB, future lesion worsening and TB diagnosis. prevalent and incident TB. Validating signatures in two independent cohorts against TB progression within 6,12,18 and fup to 24-29-months, confirmed gave AUC of 0.75-0.95 and 0.77-0.87 with performance above optimal sensitivity and wminimum specificity for the WHO target product profile for TB progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240463 | GEO | 2025/08/09

REPOSITORIES: GEO

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Project description:The feasibility of longitudinal metastatic biopsies for gene expression profiling in breast cancer is unexplored. Dynamic changes in gene expression can potentially predict efficacy of targeted cancer drugs. Patients enrolled in a phase III trial of metastatic breast cancer with sunitinib combined with docetaxel (SU+DOC) versus docetaxel alone (DOC) were offered to participate in a translational substudy comprising longitudinal fine needle aspiration biopsies (FNAB) and positron emission imaging before (T1) and two weeks after start of treatment (T2). Aspirated tumor material was used for microarray analysis, and treatment-induced changes (T2 versus T1) in gene expression and standardized uptake values were investigated. Twenty-one patients were included in the docetaxel ± sunitinib trial at Karolinska and 18 of them agreed to participate in the substudy. Of the 18 women enrolled, 8 were randomly assigned to SU+DOC and 10 to DOC. Metastatic FNAB were carried out in 17 of the 18 patients at both time points with no complications reported. Representative tumor material, sufficient for RNA extraction was obtained in 15 patients at T1 and 14 patients at T2. Matched samples both at T1 and T2 were obtained for 14 subjects, 7 in each arm. The main objective was to determine whether gene expression profiling is feasible using sequential, intra-patient FNAB. Secondary objectives were to identify potential biomarkers of early response by gene expression and/or functional imaging and to explore drug action in vivo by changes in gene expression. A Karolinska substudy of the docetaxel ± sunitinib phase III clinical trial utilising sequential metastatic fine needle aspiration biopsies (FNAB) and 18-F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography (FDG PET/CT). In brief, the randomized docetaxel ± sunitinib trial compared sunitinib combined with docetaxel (SU+DOC) versus docetaxel alone (DOC), as first line therapy in patients with HER2 negative metastatic breast cancer. Patients in the exploratory substudy were subjected to baseline FDG PET/CT assessment, followed by FNAB of one tumor lesion prior to start of treatment (Time point T1). FDG PET/CT and FNAB were repeated at Day 14 ± 1 (Time point T2) when sunitinib has achieved steady state.

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Blood transcriptional signatures of asymptomatic FDG-PET/CT-defined Subclinical TB lesions and their prediction of future TB progression

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