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Purpose <p>The radiosensitivity index (RSI) is a transcriptomic predictor of intrinsic radiosensitivity. The longitudinal behavior of the RSI in glioma and its variation across intratumoral cellular states have been unknown. We investigated RSI dynamics between matched primary and recurrent gliomas and examined RSI heterogeneity at single-cell resolution.</p> Methods <p>The RSI was calculated using the Eschrich 10-gene model in 214 matched primary–recurrent glioma pairs from the GLASS Consortium (bulk RNA-seq) and in 6,863 malignant cells from 28 IDH-wildtype glioblastomas profiled by Smart-seq2. Longitudinal changes were assessed by Wilcoxon’s signed-rank test. A survival analysis used Kaplan–Meier and Cox regression. Cell state-specific RSI differences were evaluated by the Kruskal–Wallis test with Bonferroni-corrected pairwise comparisons.</p> Results <p>The bulk RSI showed no significant change between primary and recurrent tumors (ΔRSI = + 0.009 ± 0.096, <i>p</i> = 0.17), with a strong primary–recurrent correlation (<i>r</i> = 0.65, <i>p</i> &lt; 0.001). We observed a marginal RSI increase in the IDH-wildtype tumors (ΔRSI = + 0.019, <i>p</i> = 0.042). The Kaplan–Meier analysis suggested shorter survival in RSI-increasing tumors (median 31 vs. 47 months, log-rank <i>p</i> = 0.040), but the RSI change was not independent in multivariable Cox regression (HR = 0.83, <i>p</i> = 0.82). At single-cell resolution, neural progenitor cell (NPC)-like cells exhibited the lowest RSI (Kruskal–Wallis <i>p</i> = 3.0 × 10⁻⁵), though effect sizes were small (rank-biserial <i>r</i> = 0.06–0.09).</p> Conclusion <p>The bulk RSI remains stable across glioma progression, and the RSI change does not independently predict survival. The single-cell analysis revealed significant but biologically modest RSI variation across cellular states, suggesting limited resolution of the RSI signature at the single-cell level.</p>

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Radiosensitivity index stability across glioma progression: a longitudinal bulk and single-cell analysis

  • 期刊论文

  • 发表日期：

    2026年4月15日

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  • Hisashi Nakano,
  • Takehiro Shiinoki

摘要

Purpose

The radiosensitivity index (RSI) is a transcriptomic predictor of intrinsic radiosensitivity. The longitudinal behavior of the RSI in glioma and its variation across intratumoral cellular states have been unknown. We investigated RSI dynamics between matched primary and recurrent gliomas and examined RSI heterogeneity at single-cell resolution.

Methods

The RSI was calculated using the Eschrich 10-gene model in 214 matched primary–recurrent glioma pairs from the GLASS Consortium (bulk RNA-seq) and in 6,863 malignant cells from 28 IDH-wildtype glioblastomas profiled by Smart-seq2. Longitudinal changes were assessed by Wilcoxon’s signed-rank test. A survival analysis used Kaplan–Meier and Cox regression. Cell state-specific RSI differences were evaluated by the Kruskal–Wallis test with Bonferroni-corrected pairwise comparisons.

Results

The bulk RSI showed no significant change between primary and recurrent tumors (ΔRSI = + 0.009 ± 0.096, p = 0.17), with a strong primary–recurrent correlation (r = 0.65, p < 0.001). We observed a marginal RSI increase in the IDH-wildtype tumors (ΔRSI = + 0.019, p = 0.042). The Kaplan–Meier analysis suggested shorter survival in RSI-increasing tumors (median 31 vs. 47 months, log-rank p = 0.040), but the RSI change was not independent in multivariable Cox regression (HR = 0.83, p = 0.82). At single-cell resolution, neural progenitor cell (NPC)-like cells exhibited the lowest RSI (Kruskal–Wallis p = 3.0 × 10⁻⁵), though effect sizes were small (rank-biserial r = 0.06–0.09).

Conclusion

The bulk RSI remains stable across glioma progression, and the RSI change does not independently predict survival. The single-cell analysis revealed significant but biologically modest RSI variation across cellular states, suggesting limited resolution of the RSI signature at the single-cell level.