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Development and validation of a prognostic gene expression signature for lower-grade glioma following surgery and adjuvant radiotherapy

      Highlights

      • The timing and benefit of adjuvant radiation for lower-grade glioma (WHO grade II–III) are not well established.
      • A prognostic signature constructed from the expression of 5 genes was validated in patients with lower-grade glioma in two unrelated genomics consortia.
      • This signature was significantly associated with progression-free survival and overall survival, independent of relevant covariates, and may also be predictive of response to radiation treatment.

      Abstract

      Background and purpose

      Standard of care for lower-grade glioma (LGG) is maximal safe resection and risk-adaptive adjuvant therapy. While patients who benefit the most from adjuvant chemotherapy have been elucidated in prospective randomized studies, comparable insights for adjuvant radiotherapy (RT) are lacking. We sought to identify and validate patterns of gene expression that are associated with differential outcomes among LGG patients treated by RT from two large genomics databases.

      Materials and methods

      Patients from The Cancer Genome Atlas (TCGA) with LGG (WHO grade II–III glioma) treated by surgery and adjuvant RT were randomized 1:1 to a discovery cohort or an internal validation cohort. Using the discovery cohort only, associations between tumor RNA-seq expression and progression-free survival (PFS) as well as overall survival (OS) were evaluated with adjustment for clinicopathologic covariates. A Genomic Risk Score (GRS) was then constructed from the expression levels of top genes also screened for involvement in glioma carcinogenesis. The prognostic value of GRS was further assessed in the internal validation cohort of TCGA and a second distinct database, compiled by the Chinese Glioma Genome Association (CGGA).

      Results

      From TCGA, 289 patients with LGG received adjuvant RT alone (38 grade II, 30 grade III) or chemoradiotherapy (CRT) (51 grade II, 170 grade III) between 2009 and 2015. From CGGA, 178 patients with LGG received adjuvant RT alone (40 grade II, 13 grade III) or CRT (41 grade II, 84 grade III) between 2004 and 2016. The genes comprising GRS are involved in MAP kinase activity, T cell chemotaxis, and cell cycle transition: MAP3K15, MAPK10, CCL3, CCL4, and ADAMTS1. High GRS, defined as having a GRS in the top third, was significantly associated with poorer outcomes independent of age, sex, glioma histology, WHO grade, IDH mutation, 1p/19q co-deletion, and chemotherapy status in the discovery cohort (PFS HR 1.61, 95% CI 1.10–2.36, P = 0.014; OS HR 2.74, 95% CI 1.68–4.47, P < 0.001). These findings were replicated in the internal validation cohort (PFS HR 1.58, 95% CI 1.05–2.37, P = 0.027; OS HR 1.84, 95% CI 1.13–3.00, P = 0.015) and the CGGA external validation cohort (OS HR 1.72, 95% CI 1.27–2.34, P < 0.001). Association between GRS and outcomes was observed only among patients who underwent RT, in both TCGA and CGGA.

      Conclusion

      This study successfully identified an expression signature of five genes that stratified outcomes among LGG patients who received adjuvant RT, with two rounds of validation leveraging independent genomics databases. Expression levels of the highlighted genes were associated with PFS and OS only among patients whose treatment included RT, but not among those with omission of RT, suggesting that expression of these genes may be predictive of radiation treatment response. While additional prospective studies are warranted, interrogation of these genes may be considered in the multidisciplinary management of LGG.

      Keywords

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      1. Two Studies for patients with high risk prostate cancer testing less intense treatment for patients with a low gene risk score and testing a more intense treatment for patients with a high gene risk score. The PREDICT-RT Trial https://clinicaltrials.gov/ct2/show/NCT04513717.