J Korean Med Sci.  2016 Aug;31(8):1208-1214. 10.3346/jkms.2016.31.8.1208.

Immunohistochemical Analysis of ATRX, IDH1 and p53 in Glioblastoma and Their Correlations with Patient Survival

• Chaurasia
• Park SH
• Seo JW
• Park CK

• KMID: 2373747
• DOI: http://doi.org/10.3346/jkms.2016.31.8.1208

Abstract

Glioblastoma (GBM) can be classified into molecular subgroups, on the basis of biomarker expression. Here, we classified our cohort of 163 adult GBMs into molecular subgroups according to the expression of proteins encoded by genes of alpha thalassemia/mental retardation syndrome X-linked (ATRX), isocitrate dehydrogenase (IDH) and TP53. We focused on the survival rate of molecular subgroups, depending on each and various combination of these biomarkers. ATRX, IDH1 and p53 protein expression were evaluated immunohistochemically and Kaplan-Meier analysis were carried out in each group. A total of 15.3% of enrolled GBMs demonstrated loss of ATRX expression (ATRX-), 10.4% expressed an aberrant IDH1 R132H protein (IDH1+), and 48.4% exhibited p53 overexpression (p53+). Survival differences were statistically significant when single protein expression or different combinations of expression of these proteins were analyzed. In conclusion, in the case of single protein expression, the patients with each IDH1+, or ATRX-, or p53- GBMs showed better survival than patients with counterparts protein expressed GBMs. In the case of double protein pairs, the patients with ATRX-/p53-, ATRX-/IDH1+, and IDH1+/p53- GBMs revealed better survival than the patients with GBMs with the remained pairs. In the case of triple protein combinations, the patients with ATRX-/p53-/IDH+ showed statistically significant survival gain than the patients with remained combination of proteins-expression status. Therefore, these three biomarkers, individually and as a combination, can stratify GBMs into prognostically relevant subgroups and have strong prognostic values in adult GBMs.

Keyword

Glioblastoma; ATRX; p53; Isocitrate Dehydrogenase; Mutation; Overall Survival; Progression Free Survival

MeSH Terms

Adult
Aged
Biomarkers, Tumor/metabolism
Brain Neoplasms/*diagnosis/metabolism/mortality
DNA Helicases/*metabolism
Disease-Free Survival
Glioblastoma/*diagnosis/metabolism/mortality
Humans
Immunohistochemistry
Isocitrate Dehydrogenase/*metabolism
Kaplan-Meier Estimate
Middle Aged
Nuclear Proteins/*metabolism
Retrospective Studies
Tumor Suppressor Protein p53/genetics/*metabolism
Young Adult
Biomarkers, Tumor
DNA Helicases
Isocitrate Dehydrogenase
Nuclear Proteins
Tumor Suppressor Protein p53

Figure

• 

  Fig. 1 The figures show representative pictures of one of GBMs and aberrant protein expression, that is, ATRX-/p53+/IDH1+, which are the least common combination of protein status, comprising 1.8% of our studied cohort. (A) H & E. (B) ATRX. (C) p53. (D) IDH1, (A-D) × 200.

• 

  Fig. 2 Kaplan-Meier plots for GBM patient survival by ATRX, IDH and p53 protein expressions status. (A, B) The better survival (OS and PFS) is found in the patients with GBMs with positive IDH1 than the patients with lack of IDH1. (C, D) The better survival (OS and PFS) is noted in the patient with loss of ATRX expression than the patients with preserved ATRX expression. (E, F) The better survival with GBMs with lack of p53 overexpression has better PFS than the patients with GBMs with p53 overexpression, but OS is not statistically significant difference between the patients with p53 positive and negative GBMs. (G, H) Younger age patients (≤ 45 years old) have statistically significant better survival than the older GBM patients (> 45 years old).

• 

  Fig. 3 Kaplan-Meier plots for GBM patient survival by combined two and three gene immunohistochemical status. (A) Among ATRX/IDH1 combination subgroups, the highest median OS of 42.7 months is found in the patients with ATRX-/IDH1+ status. (B) Among ATRX/p53 combination subgroups, the highest median OS of 39.9 months is found in the patients with ATRX-/p53- status. (C) Among IDH1/p53 combination subgroups, the highest median OS of 33.4 months is found in the patients with IDH+/p53- status. (D) The highest median OS of 47.9 months is found in patients with ATRX-/p53-/IDH+ status among three protein combination subgroups.

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