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Expression of the neuron-specific protein CHD5 is an independent marker of outcome in neuroblastoma.

Garcia I, Mayol G, Rodríguez E, Suñol M, Gershon TR, Ríos J, Cheung NK, Kieran MW, George RE, Perez-Atayde AR, Casala C, Galván P, de Torres C, Mora J, Lavarino C - Mol. Cancer (2010)

Bottom Line: Within NTs, CHD5 immunoreactivity was found restricted to differentiating neuroblasts and ganglion-like cells, and absent in undifferentiated neuroblasts and stromal Schwann cells.Correlation between protein and mRNA levels was found, suggesting transcriptional regulation of CHD5.Re-establishment of CHD5 expression induced by chemotherapy could be a surrogate marker of treatment response.

View Article: PubMed Central - HTML - PubMed

Affiliation: Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.

ABSTRACT

Background: The chromodomain, helicase DNA-binding protein 5 (CHD5) is a potential tumor suppressor gene located on chromosome 1p36, a region recurrently deleted in high risk neuroblastoma (NB). Previous data have shown that CHD5 mRNA is present in normal neural tissues and in low risk NB, nevertheless, the distribution of CHD5 protein has not been explored. The aim of this study was to investigate CHD5 protein expression as an immunohistochemical marker of outcome in NB. With this purpose, CHD5 protein expression was analyzed in normal neural tissues and neuroblastic tumors (NTs). CHD5 gene and protein expression was reexamined after induction chemotherapy in a subset of high risk tumors to identify potential changes reflecting tumor response.

Results: We provide evidence that CHD5 is a neuron-specific protein, absent in glial cells, with diverse expression amongst neuron types. Within NTs, CHD5 immunoreactivity was found restricted to differentiating neuroblasts and ganglion-like cells, and absent in undifferentiated neuroblasts and stromal Schwann cells. Correlation between protein and mRNA levels was found, suggesting transcriptional regulation of CHD5. An immunohistochemical analysis of 90 primary NTs highlighted a strong association of CHD5 expression with favorable prognostic variables (age at diagnosis <12 months, low clinical stage, and favorable histology; P < 0.001 for all), overall survival (OS) (P < 0.001) and event-free survival (EFS) (P < 0.001). Multivariate analysis showed that CHD5 prognostic value is independent of other clinical and biologically relevant parameters, and could therefore represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. The prognostic value of CHD5 was confirmed in an independent, blinded set of 32 NB tumors (P < 0.001).Reactivation of CHD5 expression after induction chemotherapy was observed mainly in those high risk tumors with induced tumor cell differentiation features. Remarkably, these NB tumors showed good clinical response and prolonged patient survival.

Conclusions: The neuron-specific protein CHD5 may represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. Re-establishment of CHD5 expression induced by chemotherapy could be a surrogate marker of treatment response.

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CHD5 protein expression in neuroblastic tumors. CHD5 immunostaining in (A) stage 4 undifferentiated NB (400x); (B) loco-regional differentiating NB (400x); (C) stage 3, MYCN amplified, undifferentiated NB (400x); (D) Ganglioneuroblastoma (100x); (E) stage 4 (200x) and (F) stage 4s primary tumor (200x) with bone marrow neuroblast aggregates (G-H), respectively (400x).
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Figure 2: CHD5 protein expression in neuroblastic tumors. CHD5 immunostaining in (A) stage 4 undifferentiated NB (400x); (B) loco-regional differentiating NB (400x); (C) stage 3, MYCN amplified, undifferentiated NB (400x); (D) Ganglioneuroblastoma (100x); (E) stage 4 (200x) and (F) stage 4s primary tumor (200x) with bone marrow neuroblast aggregates (G-H), respectively (400x).

Mentions: Stage 4 NB cases, all histologically undifferentiated high risk NB, appeared predominantly (20/24) negative or with <25% neuroblastic cells with faint CHD5 nuclear reactivity (Figure 2A and 2E; Table 1, Additional file 1). Only 3/24 undifferentiated NB tumors exhibited weak nuclear reactivity in 25-75% of cells, and one had intense nuclear staining in >75% of tumor cells. In contrast, stage 4s NB, histologically undifferentiated low risk tumors, showed consistently (8/8) very intense CHD5 nuclear positivity in >75%, generally >90% of the neuroblasts (Figure 2F, Table 1, Additional file 1). This clinically low risk NB is, nevertheless, a highly proliferative metastatic tumor. Thus, for 2 stage 4s NB tumors, CHD5 expression was also evaluated in the liver and bone marrow metastases. Intense CHD5 immunopositivity, equivalent to the primary tumor, was observed in >75% neuroblasts disseminated in the liver. Intriguingly, bone marrow neuroblastic aggregates, identified using an antibody against the ganglioside GD2 ubiquitously expressed in NB (data not shown), lacked CHD5 immunoreactivity (Figure 2H), similar to stage 4 bone marrow smears (Figure 2G).


Expression of the neuron-specific protein CHD5 is an independent marker of outcome in neuroblastoma.

Garcia I, Mayol G, Rodríguez E, Suñol M, Gershon TR, Ríos J, Cheung NK, Kieran MW, George RE, Perez-Atayde AR, Casala C, Galván P, de Torres C, Mora J, Lavarino C - Mol. Cancer (2010)

CHD5 protein expression in neuroblastic tumors. CHD5 immunostaining in (A) stage 4 undifferentiated NB (400x); (B) loco-regional differentiating NB (400x); (C) stage 3, MYCN amplified, undifferentiated NB (400x); (D) Ganglioneuroblastoma (100x); (E) stage 4 (200x) and (F) stage 4s primary tumor (200x) with bone marrow neuroblast aggregates (G-H), respectively (400x).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992029&req=5

Figure 2: CHD5 protein expression in neuroblastic tumors. CHD5 immunostaining in (A) stage 4 undifferentiated NB (400x); (B) loco-regional differentiating NB (400x); (C) stage 3, MYCN amplified, undifferentiated NB (400x); (D) Ganglioneuroblastoma (100x); (E) stage 4 (200x) and (F) stage 4s primary tumor (200x) with bone marrow neuroblast aggregates (G-H), respectively (400x).
Mentions: Stage 4 NB cases, all histologically undifferentiated high risk NB, appeared predominantly (20/24) negative or with <25% neuroblastic cells with faint CHD5 nuclear reactivity (Figure 2A and 2E; Table 1, Additional file 1). Only 3/24 undifferentiated NB tumors exhibited weak nuclear reactivity in 25-75% of cells, and one had intense nuclear staining in >75% of tumor cells. In contrast, stage 4s NB, histologically undifferentiated low risk tumors, showed consistently (8/8) very intense CHD5 nuclear positivity in >75%, generally >90% of the neuroblasts (Figure 2F, Table 1, Additional file 1). This clinically low risk NB is, nevertheless, a highly proliferative metastatic tumor. Thus, for 2 stage 4s NB tumors, CHD5 expression was also evaluated in the liver and bone marrow metastases. Intense CHD5 immunopositivity, equivalent to the primary tumor, was observed in >75% neuroblasts disseminated in the liver. Intriguingly, bone marrow neuroblastic aggregates, identified using an antibody against the ganglioside GD2 ubiquitously expressed in NB (data not shown), lacked CHD5 immunoreactivity (Figure 2H), similar to stage 4 bone marrow smears (Figure 2G).

Bottom Line: Within NTs, CHD5 immunoreactivity was found restricted to differentiating neuroblasts and ganglion-like cells, and absent in undifferentiated neuroblasts and stromal Schwann cells.Correlation between protein and mRNA levels was found, suggesting transcriptional regulation of CHD5.Re-establishment of CHD5 expression induced by chemotherapy could be a surrogate marker of treatment response.

View Article: PubMed Central - HTML - PubMed

Affiliation: Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Fundación Sant Joan de Déu, Barcelona, Spain.

ABSTRACT

Background: The chromodomain, helicase DNA-binding protein 5 (CHD5) is a potential tumor suppressor gene located on chromosome 1p36, a region recurrently deleted in high risk neuroblastoma (NB). Previous data have shown that CHD5 mRNA is present in normal neural tissues and in low risk NB, nevertheless, the distribution of CHD5 protein has not been explored. The aim of this study was to investigate CHD5 protein expression as an immunohistochemical marker of outcome in NB. With this purpose, CHD5 protein expression was analyzed in normal neural tissues and neuroblastic tumors (NTs). CHD5 gene and protein expression was reexamined after induction chemotherapy in a subset of high risk tumors to identify potential changes reflecting tumor response.

Results: We provide evidence that CHD5 is a neuron-specific protein, absent in glial cells, with diverse expression amongst neuron types. Within NTs, CHD5 immunoreactivity was found restricted to differentiating neuroblasts and ganglion-like cells, and absent in undifferentiated neuroblasts and stromal Schwann cells. Correlation between protein and mRNA levels was found, suggesting transcriptional regulation of CHD5. An immunohistochemical analysis of 90 primary NTs highlighted a strong association of CHD5 expression with favorable prognostic variables (age at diagnosis <12 months, low clinical stage, and favorable histology; P < 0.001 for all), overall survival (OS) (P < 0.001) and event-free survival (EFS) (P < 0.001). Multivariate analysis showed that CHD5 prognostic value is independent of other clinical and biologically relevant parameters, and could therefore represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. The prognostic value of CHD5 was confirmed in an independent, blinded set of 32 NB tumors (P < 0.001).Reactivation of CHD5 expression after induction chemotherapy was observed mainly in those high risk tumors with induced tumor cell differentiation features. Remarkably, these NB tumors showed good clinical response and prolonged patient survival.

Conclusions: The neuron-specific protein CHD5 may represent a marker of outcome in NB that can be tested by conventional immunohistochemistry. Re-establishment of CHD5 expression induced by chemotherapy could be a surrogate marker of treatment response.

Show MeSH
Related in: MedlinePlus