Prognosis stratification and personalized treatment in bladder cancer through a robust immune gene pair‐based signature

To the Editor: Numerous prognostic signatures to bladder cancer (BCa) have been reported, but many of them limited to either nonmuscle-invasive (NMIBC) or muscle-invasive BCa (MIBC), and inherent technical biases across platforms impeded clinical application. As cancer immunity plays a critical role in tumor progression,1 we collected 1235 BCa patients from nine independent cohorts across different platforms (Tables S1 and S2) and developed a prognostic signature based on 29 immune-related gene pairs (IRGPs; Table S3). The entireworkflow is depicted in Figure S1, and technical details listed in Supporting Materials and Methods. We calculated an index (IRGPI, https://github.com/ xlucpu/BCaller), which acts as an independent prognostic factor after adjusting other clinicopathological features in metatraining, metatesting, validation 1 and 2 datasets (HR range: 1.55–3.21, all p < .05; Figure 1A–E, Figure S2, Tables S4 and S5), and remained highly prognostic for both NMIBCs and MIBCs (Figure 1E). Using dataset-specific median cutoff, IRGPI stratified patients into low(LRisk) and high-risk (HRisk) groups (HR range: 2.30–6.13, all p< .001; Figure 1F–I) with significant restricted mean survival time ratio (RMS range: 0.42–0.71, all p ≤ .001; Table S6). Using the cross-platform cutoff of 1.195, HRisk groups consistently showed poorer outcome than matched LRisk groups (all p < .001; Figure S3). Functional analyses revealed immune cell-related pathways were highly enriched for genes within IRGPs (Figure S4A); LRisk showed a higher abundance of lymphocytes and dendritic cells, whereas HRisk enriched macrophages (Figure 1J). Additionally, poor outcome and immune suppression-related pathways were significantly activated in HRisk groups (Figure 1K, Figure S4B–E), which is concordant with previous literatures.2–4 We then investigated the genomic variation and molecular subtype between risk groups. We found HRisk group

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