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Is CMV a target in pediatric glioblastoma? Expression of CMV proteins, pp65 and IE1-72 and CMV nucleic acids in a cohort of pediatric glioblastoma patients.

Wakefield A, Pignata A, Ghazi A, Ashoori A, Hegde M, Landi D, Gray T, Scheurer ME, Chintagumpala M, Adesina A, Gottschalk S, Hicks J, Powell SZ, Ahmed N - J. Neurooncol. (2015)

Bottom Line: While the 5-year overall survival is better in pediatric than in adult patients diagnosed with glioblastoma (GBM), outcomes in children remain very poor.Indeed, CMV is emerging as a potential glioma-associated target for anti-CMV agents and cellular therapeutics.ISH positive samples showed high concordance with being pp65 or IE1-72 positive.

View Article: PubMed Central - PubMed

Affiliation: Texas Children's Hospital, Houston Methodist Hospital, Center for Cell and Gene Therapy, Baylor College of Medicine, 1102 Bates Street MC 3-3320, Houston, TX, 77030, USA.

ABSTRACT
While the 5-year overall survival is better in pediatric than in adult patients diagnosed with glioblastoma (GBM), outcomes in children remain very poor. Understanding the mechanisms of tumorigenesis and tumor propagation can identify therapeutic targets to improve these outcomes. Human cytomegalovirus (CMV) proteins and nucleic acids are present in the majority of adult GBM. Indeed, CMV is emerging as a potential glioma-associated target for anti-CMV agents and cellular therapeutics. Furthermore, CMV appears to contribute to GBM's malignant phenotype, although its role in tumorigenesis is less certain. In this cohort of 25 serially diagnosed pediatric GBMs, the largest described cohort to date, we used immunohistochemical staining and in situ hybridization to show the presence of CMV antigens pp65 and IE1-72 as well as CMV nucleic acids, respectively. Our cohort indicated either CMV antigen pp65 or IE1-72 was present in approximately 67 % of pediatric GBM samples. The majority of samples stained positive for either CMV antigen showing a cytoplasmic pattern in 25-50 % of cells within the sample at a moderate intensity, while a few samples showed nuclear staining and higher grade/intensity. Of 16 samples where in situ hybridization was performed, 13 (81 %) showed specific staining using a CMV genome specific probe cocktail. ISH positive samples showed high concordance with being pp65 or IE1-72 positive. These findings, paired with the association of CMV expression with poor prognosis and overall survival, indicate the need to further investigate how these antigens are promoting tumor growth and preventing cell death. Also, the expression of these antigens in a majority of tumor tissues should be considered for immunotherapeutic targets in cases of pediatric GBM.

No MeSH data available.


Related in: MedlinePlus

Venn diagram corroborating pp65 and IE1 detection using IHC with CMV genome specific ISH. Of a total of 16 GBMs examined using ISH, 13 were positive for CMV and 3 were negative. Eleven of 13 samples showed concomitant ISH and IE1-72 (n = 10) positivity or concomitant ISH and pp65 positivity (n = 7). Six out of 13 samples were triple ISH, IE1-72 and pp65 positive
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Fig5: Venn diagram corroborating pp65 and IE1 detection using IHC with CMV genome specific ISH. Of a total of 16 GBMs examined using ISH, 13 were positive for CMV and 3 were negative. Eleven of 13 samples showed concomitant ISH and IE1-72 (n = 10) positivity or concomitant ISH and pp65 positivity (n = 7). Six out of 13 samples were triple ISH, IE1-72 and pp65 positive

Mentions: To confirm the presence of CMV in GBMs, we performed ISH analysis using a human CMV DNA probe cocktail. Sixteen samples of the cohort of 25 were available for testing. Thirteen out of 16 GBMs were positive for the CMV genome (Fig. 4), confirming that CMV is detectable in the majority of primary GBM samples. The staining pattern was strictly nuclear for positive samples and was uniformly expressed in the majority of nuclei examined. In 11 out of 13 positive samples concomitant IE1-72 (n = 10) or pp65 (n = 7) were detected. Six out of 13 samples were triple positive for CMV nucleic acid using ISH, IE1-72 and pp65 using IHC and 3 out of 13 were triple negative for all (Fig. 5). These results confirm results for our group and those from others demonstrating a high degree of correlation between CMV nucleic acid detection and the presence of the CMV immunodominant proteins pp65 and IE1-72.Fig. 4


Is CMV a target in pediatric glioblastoma? Expression of CMV proteins, pp65 and IE1-72 and CMV nucleic acids in a cohort of pediatric glioblastoma patients.

Wakefield A, Pignata A, Ghazi A, Ashoori A, Hegde M, Landi D, Gray T, Scheurer ME, Chintagumpala M, Adesina A, Gottschalk S, Hicks J, Powell SZ, Ahmed N - J. Neurooncol. (2015)

Venn diagram corroborating pp65 and IE1 detection using IHC with CMV genome specific ISH. Of a total of 16 GBMs examined using ISH, 13 were positive for CMV and 3 were negative. Eleven of 13 samples showed concomitant ISH and IE1-72 (n = 10) positivity or concomitant ISH and pp65 positivity (n = 7). Six out of 13 samples were triple ISH, IE1-72 and pp65 positive
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4612329&req=5

Fig5: Venn diagram corroborating pp65 and IE1 detection using IHC with CMV genome specific ISH. Of a total of 16 GBMs examined using ISH, 13 were positive for CMV and 3 were negative. Eleven of 13 samples showed concomitant ISH and IE1-72 (n = 10) positivity or concomitant ISH and pp65 positivity (n = 7). Six out of 13 samples were triple ISH, IE1-72 and pp65 positive
Mentions: To confirm the presence of CMV in GBMs, we performed ISH analysis using a human CMV DNA probe cocktail. Sixteen samples of the cohort of 25 were available for testing. Thirteen out of 16 GBMs were positive for the CMV genome (Fig. 4), confirming that CMV is detectable in the majority of primary GBM samples. The staining pattern was strictly nuclear for positive samples and was uniformly expressed in the majority of nuclei examined. In 11 out of 13 positive samples concomitant IE1-72 (n = 10) or pp65 (n = 7) were detected. Six out of 13 samples were triple positive for CMV nucleic acid using ISH, IE1-72 and pp65 using IHC and 3 out of 13 were triple negative for all (Fig. 5). These results confirm results for our group and those from others demonstrating a high degree of correlation between CMV nucleic acid detection and the presence of the CMV immunodominant proteins pp65 and IE1-72.Fig. 4

Bottom Line: While the 5-year overall survival is better in pediatric than in adult patients diagnosed with glioblastoma (GBM), outcomes in children remain very poor.Indeed, CMV is emerging as a potential glioma-associated target for anti-CMV agents and cellular therapeutics.ISH positive samples showed high concordance with being pp65 or IE1-72 positive.

View Article: PubMed Central - PubMed

Affiliation: Texas Children's Hospital, Houston Methodist Hospital, Center for Cell and Gene Therapy, Baylor College of Medicine, 1102 Bates Street MC 3-3320, Houston, TX, 77030, USA.

ABSTRACT
While the 5-year overall survival is better in pediatric than in adult patients diagnosed with glioblastoma (GBM), outcomes in children remain very poor. Understanding the mechanisms of tumorigenesis and tumor propagation can identify therapeutic targets to improve these outcomes. Human cytomegalovirus (CMV) proteins and nucleic acids are present in the majority of adult GBM. Indeed, CMV is emerging as a potential glioma-associated target for anti-CMV agents and cellular therapeutics. Furthermore, CMV appears to contribute to GBM's malignant phenotype, although its role in tumorigenesis is less certain. In this cohort of 25 serially diagnosed pediatric GBMs, the largest described cohort to date, we used immunohistochemical staining and in situ hybridization to show the presence of CMV antigens pp65 and IE1-72 as well as CMV nucleic acids, respectively. Our cohort indicated either CMV antigen pp65 or IE1-72 was present in approximately 67 % of pediatric GBM samples. The majority of samples stained positive for either CMV antigen showing a cytoplasmic pattern in 25-50 % of cells within the sample at a moderate intensity, while a few samples showed nuclear staining and higher grade/intensity. Of 16 samples where in situ hybridization was performed, 13 (81 %) showed specific staining using a CMV genome specific probe cocktail. ISH positive samples showed high concordance with being pp65 or IE1-72 positive. These findings, paired with the association of CMV expression with poor prognosis and overall survival, indicate the need to further investigate how these antigens are promoting tumor growth and preventing cell death. Also, the expression of these antigens in a majority of tumor tissues should be considered for immunotherapeutic targets in cases of pediatric GBM.

No MeSH data available.


Related in: MedlinePlus