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Characterization and prognostic significance of alternative splicing events in lower-grade diffuse gliomas.

ABSTRACT: Alternative splicing (AS) is assumed to play important roles in the progression and prognosis of cancer. Currently, the comprehensive analysis and clinical relevance of AS in lower-grade diffuse gliomas have not been systematically addressed. Here, we gathered alternative splicing data of lower-grade diffuse gliomas from SpliceSeq. Based on the Percent Spliced In (PSI) values of 515 lower-grade diffuse glioma patients from the Cancer Genome Atlas (TCGA), we performed subtype-differential AS analysis and consensus clustering to determine robust clusters of patients. A total of 48 050 AS events in 10 787 genes in lower-grade diffuse gliomas were profiled. Subtype-differential splicing analysis and functional annotation revealed that spliced genes were significantly enriched in numerous cancer-related biological phenotypes and signalling pathways. Consensus clustering using AS events identified three robust clusters of patients with distinguished pathological and prognostic features. Moreover, each cluster was also associated with distinct genomic alterations. Finally, we developed and validated an AS-related signature with Cox proportional hazards model. The signature, significantly associated with clinical and molecular features, could serve as an independent prognostic factor for lower-grade diffuse gliomas. Thus, our results indicated that AS events could discriminate molecular subtypes and have prognostic impact in lower-grade diffuse gliomas.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC7701518 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Characterization and prognostic significance of alternative splicing events in lower-grade diffuse gliomas.

Zhao Zheng Z Li Guan-Zhang GZ Liu Yu-Qing YQ Huang Ruo-Yu RY Wang Kuan-Yu KY Jiang Hao-Yu HY Li Ren-Peng RP Chai Rui-Chao RC Zhang Chuan-Bao CB Wu Fan F

Journal of cellular and molecular medicine 20201002 22

Alternative splicing (AS) is assumed to play important roles in the progression and prognosis of cancer. Currently, the comprehensive analysis and clinical relevance of AS in lower-grade diffuse gliomas have not been systematically addressed. Here, we gathered alternative splicing data of lower-grade diffuse gliomas from SpliceSeq. Based on the Percent Spliced In (PSI) values of 515 lower-grade diffuse glioma patients from the Cancer Genome Atlas (TCGA), we performed subtype-differential AS anal ...[more]

PMID: 33006444

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Project description:BackgroundWhile molecular insights to diffuse lower-grade glioma (dLGG) have improved the basis for prognostication, most established clinical prognostic factors come from the pre-molecular era. For instance, WHO grade as a predictor for survival in dLGG with isocitrate dehydrogenase (IDH) mutation has recently been questioned. We studied the prognostic role of WHO grade in molecularly defined subgroups and evaluated earlier used prognostic factors in the current molecular setting.Material and methodsA total of 253 adults with morphological dLGG, consecutively included between 2007 and 2018, were assessed. IDH mutations, codeletion of chromosomal arms 1p/19q, and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions were analyzed.ResultsThere was no survival benefit for patients with WHO grade 2 over grade 3 IDH-mut dLGG after exclusion of tumors with known CDKN2A/B homozygous deletion (n=157) (log-rank p=0.97). This was true also after stratification for oncological postoperative treatment and when astrocytomas and oligodendrogliomas were analyzed separately. In IDH-mut astrocytomas, residual tumor volume after surgery was an independent prognostic factor for survival (HR 1.02; 95% CI 1.01-1.03; p=0.003), but not in oligodendrogliomas (HR 1.02; 95% CI 1.00-1.03; p=0.15). Preoperative tumor size was an independent predictor in both astrocytomas (HR 1.03; 95% CI 1.00-1.05; p=0.02) and oligodendrogliomas (HR 1.05; 95% CI 1.01-1.09; p=0.01). Age was not a significant prognostic factor in multivariable analyses (astrocytomas p=0.64, oligodendrogliomas p=0.08).ConclusionOur findings suggest that WHO grade is not a robust prognostic factor in molecularly well-defined dLGG. Preoperative tumor size remained a prognostic factor in both IDH-mut astrocytomas and oligodendrogliomas in our cohort, whereas residual tumor volume predicted prognosis in IDH-mut astrocytomas only. The age cutoffs for determining high risk in patients with IDH-mut dLGG from the pre-molecular era are not supported by our results.

Project description:BackgroundRecently, the Therapy-Disability-Neurology (TDN) was introduced as a multidimensional reporting system to detect adverse events in neurosurgery. The aim of this study was to compare the novel TDN score with the Landriel-Ibanez classification (LIC) grade in a large cohort of patients with diffuse lower-grade glioma (dLGG). Since the TDN score lacks validation against patient-reported outcomes, we described health-related quality of life (HRQoL) change in relation to TDN scores in a subset of patients.MethodsWe screened adult patients with a surgically treated dLGG World Health Organization (WHO) grade 2 and 3 between 2010 and 2020. Up until 2017, it consists of a retrospective cohort (n = 158). From 2017 and onwards, HRQoL was registered using EuroQoL-5-dimension, three levels of response (EQ-5D 3L) questionnaire at baseline and 3 months follow-up, in a prospectively recruited cohort (n = 102). Both the LIC grade and TDN score were used to classify adverse events.ResultsIn total, 231 patients were included. In 110/231 (47.6%) of the surgical procedures, a postoperative complication was registered. When comparing the TDN score to LIC grades, only a minor shift towards complications of higher order could be observed. EQ-5D 3L was reported for 45 patients. Patients with complications related to surgery had pre- to postoperative changes in EQ-5D 3L index values (n = 27; mean 0.03, 95% CI -0.06 to 0.11) that were comparable to patients without complications (n = 18; mean -0.06, 95% CI -0.21 to 0.08). In contrast, patients with new-onset neurological deficit had a deterioration in HRQoL at follow-up, with a mean change in the EQ-5D 3L index value of 0.11 (n = 13, 95% CI 0.0 to 0.22) compared to -0.06 (n = 32, 95% CI -0.15 to 0.03) for all other patients.ConclusionsIn patients with dLGG, TDN scores compared to the standard LIC tend to capture more adverse events of higher order. There was no clear relation between TDN severity and HRQoL. However, new-onset neurological deficit caused impairment in HRQoL. For the TDN score to better align with patient-reported outcomes, more emphasis on neurological deficit and function should be considered.

Project description:BackgroundDiffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.MethodsWe performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.ResultsUnsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.ConclusionsThe integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

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Characterization and prognostic significance of alternative splicing events in lower-grade diffuse gliomas.

Publications

Characterization and prognostic significance of alternative splicing events in lower-grade diffuse gliomas.

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