ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis
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Citations
CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011.
The epidemiology of glioma in adults: a "state of the science" review.
Whole-genome landscapes of major melanoma subtypes
Epidemiologic and Molecular Prognostic Review of Glioblastoma
Mutational landscape and clonal architecture in grade II and III gliomas
References
Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype
Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.
TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal
Adjuvant Procarbazine, Lomustine, and Vincristine Chemotherapy in Newly Diagnosed Anaplastic Oligodendroglioma: Long-Term Follow-Up of EORTC Brain Tumor Group Study 26951
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Frequently Asked Questions (15)
Q2. How did the authors assess ATRX expression in a subset of the NOA-04 trial?
Using immunohistochemistry to assess ATRX expression in a subset of the NOA-04 trial patient population, the authors detected ATRX loss in approximately 40% of AA and 25% of mixed AOA.
Q3. What was the t test used to compare the mean age of the two groups?
One-way ANOVA was employed to compare mean age between different groups followed by a pairwise t test comparison with Bonferroni correction.
Q4. What is the way to evaluate the prognostic value of ATRX status?
Given the superior clinical course of oligodendroglial tumors, it seems to be important to evaluate the prognostic value of ATRX status only in astrocytic tumors as the authors did here.
Q5. How many patients were available for the NOA-04 biomarker cohort?
The present NOA-04 biomarker cohort comprised 133 of the 274 patients of the NOA-04 intention-to-treat (ITT) population for which unstained paraffin slides were available.
Q6. What is the prevalence of ATRX deficiency in IDH mutants?
While two studies reported a ~ 70% prevalence of ATRX deficiency in IDH mutant, 1p/19qWiestler et al. ‐11‐ intact tumors [8, 9], another study reported a < 50% prevalence [15].
Q7. What is the significance of the ATRX loss in the NOA-04 trial?
The high prevalence of ATRX loss in this tumor subset, as reported by others, argues for ATRX deficiency as a class-defining feature.
Q8. How many patients were IDH wild type?
The authors grouped the 133 NOA-04 samples accordingly, resulting in 40 patients with ATRX loss, 40 patients with 1p/19q co-deletion, 17 patients with IDH mutation onlyWiestler et al. ‐12‐ and 31 patients who were IDH wild type.
Q9. What is the way to classify mixed gliomas?
ATRX in conjunction with 1p/19q status may help to unequivocally classify mixed gliomas, whose diagnoses are subject to relevant inter-observer variation, as either astrocytic or oligodendroglial.
Q10. What was the prognostic value of reference histology?
Upon incorporation of both ATRX and 1p/19q status into the model (Table 3b), the prognostic value of reference histology was no longer significant, while both ATRX loss and 1p/19q co-deletion were associated with TTF.
Q11. What was the primary endpoint of the NOA-04 trial?
In a univariate Cox regression model, reference histology was significantly associated with time to treatment failure (TTF), the primary endpoint of the NOA-04 trial (Table 3a).
Q12. What is the significance of ATRX status in pediatric gliomas?
To this extent, ATRX status is important as it both helps to re-classify mixed oligoastrocytic tumors and defines a subgroup of astrocytic tumors with a superior clinical course.
Q13. What was the consensus of the panel review of the NOA-04 trial?
A retrospective panel review of 150 patients from the EORTC 26951 trial, which did not impose such a restrictive central histology, confirmed on consensus only 8% of the local AOA diagnoses [12].
Q14. What is the recent discovery of ATRX in gliomas?
ATRX mutation and loss of expression, which has just recently been discovered in gliomas [7], might further refine this classification.
Q15. What is the association between ATRX loss and TTF?
Patients with tumors with ATRX loss had a longer time to treatment failure (median TTF 55.6 months [95% CI 45.1 months – to not reached], n = 40) than patients with IDH mutant tumors with ATRX expression (median TTF 31.8 months [95% CI 2.8 months – to not reached], n = 9, p = 0.0168, log rank test; Fig. 3e).