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Clinicopathological significance and potential drug target of p15INK4B in multiple myeloma.

Li J, Bi L, Lin Y, Lu Z, Hou G - Drug Des Devel Ther (2014)

Bottom Line: However, there is a lack of systematic analysis of p15 epigenetic modification such as methylation in MM from different studies that can provide more powerful estimation of an effect.In addition, the frequency of p15(INK4B) methylation was significantly higher in patients with MM than in those with asymptomatic monoclonal gammopathy of undetermined significance.These results suggest that silencing of p15(INK4B) gene expression by epigenetic modification such as promoter hypermethylation plays a role not only in the initiation of MM but also in plasma cell malignant transformation, disease progression, and development.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People's Republic of China.

ABSTRACT
Multiple myeloma (MM) is a clonal malignancy characterized by the proliferation of malignant plasma cells in the bone marrow and the production of monoclonal immunoglobulin. In addition to genetic changes, gene hypermethylation is an alternative mechanism of tumor suppressor gene inactivation in MM. The cyclin-dependent kinase inhibitor 1 (CDKN2B or p15(INK4B) ) gene lies adjacent to the tumor suppressor gene, cyclin-dependent kinase inhibitor 2 (CDKN2A), and is frequently mutated and deleted in a wide variety of tumors, including MM. However, there is a lack of systematic analysis of p15 epigenetic modification such as methylation in MM from different studies that can provide more powerful estimation of an effect. In this study, we have systematically reviewed the studies of p15(INK4B) promoter methylation in MM and quantified the association between p15(INK4B) promoter methylation and MM using meta-analysis methods. We observed that the frequency of p15(INK4B) methylation is significantly higher in MM patients than in normal healthy controls. The pooled odds ratio (OR) from ten studies including 394 MM and 99 normal individuals is 0.08, while confidence interval (CI) is 0.03-0.21 (P<0.00001). This indicates that p15(INK4B) inactivation through methylation plays an important role in the pathogenesis of MM. In addition, the frequency of p15(INK4B) methylation was significantly higher in patients with MM than in those with asymptomatic monoclonal gammopathy of undetermined significance. The pooled OR from four studies is 0.40, 95% CI =0.21-0.78 (P=0.007). These results suggest that silencing of p15(INK4B) gene expression by epigenetic modification such as promoter hypermethylation plays a role not only in the initiation of MM but also in plasma cell malignant transformation, disease progression, and development.

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p15 methylation in MGUS.Notes: Three of the included studies investigated p15INK4B methylation status between 63 multiple myeloma patients and 19 normal individuals. The combined odds ratio was 0.30 (95% CI: 0.05–1.72; Z=1.35; P=0.18).Abbreviations: MGUS, monoclonal gammopathy of undetermined significance; CI, confidence interval.
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f2-dddt-8-2129: p15 methylation in MGUS.Notes: Three of the included studies investigated p15INK4B methylation status between 63 multiple myeloma patients and 19 normal individuals. The combined odds ratio was 0.30 (95% CI: 0.05–1.72; Z=1.35; P=0.18).Abbreviations: MGUS, monoclonal gammopathy of undetermined significance; CI, confidence interval.

Mentions: We observed that p15INK4B methylation is higher in MGUS than in normal individual controls, but it did not reach significant difference. The pooled ORs from three studies including 63 patients with MGUS and 19 healthy individuals are shown in Figure 2 (OR=0.30, 95% CI=0.05–1.72, P=0.18). These findings indicate that although MGUS is considered as a premalignant condition, p15INK4B gene methylation is not the only one determinant factor for its potential malignancy. We excluded the other two studies that showed that p15INK4B methylation in MGUS is 1.8%21 and 6.5%,22 because no healthy individual controls were available.


Clinicopathological significance and potential drug target of p15INK4B in multiple myeloma.

Li J, Bi L, Lin Y, Lu Z, Hou G - Drug Des Devel Ther (2014)

p15 methylation in MGUS.Notes: Three of the included studies investigated p15INK4B methylation status between 63 multiple myeloma patients and 19 normal individuals. The combined odds ratio was 0.30 (95% CI: 0.05–1.72; Z=1.35; P=0.18).Abbreviations: MGUS, monoclonal gammopathy of undetermined significance; CI, confidence interval.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222634&req=5

f2-dddt-8-2129: p15 methylation in MGUS.Notes: Three of the included studies investigated p15INK4B methylation status between 63 multiple myeloma patients and 19 normal individuals. The combined odds ratio was 0.30 (95% CI: 0.05–1.72; Z=1.35; P=0.18).Abbreviations: MGUS, monoclonal gammopathy of undetermined significance; CI, confidence interval.
Mentions: We observed that p15INK4B methylation is higher in MGUS than in normal individual controls, but it did not reach significant difference. The pooled ORs from three studies including 63 patients with MGUS and 19 healthy individuals are shown in Figure 2 (OR=0.30, 95% CI=0.05–1.72, P=0.18). These findings indicate that although MGUS is considered as a premalignant condition, p15INK4B gene methylation is not the only one determinant factor for its potential malignancy. We excluded the other two studies that showed that p15INK4B methylation in MGUS is 1.8%21 and 6.5%,22 because no healthy individual controls were available.

Bottom Line: However, there is a lack of systematic analysis of p15 epigenetic modification such as methylation in MM from different studies that can provide more powerful estimation of an effect.In addition, the frequency of p15(INK4B) methylation was significantly higher in patients with MM than in those with asymptomatic monoclonal gammopathy of undetermined significance.These results suggest that silencing of p15(INK4B) gene expression by epigenetic modification such as promoter hypermethylation plays a role not only in the initiation of MM but also in plasma cell malignant transformation, disease progression, and development.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology and Oncology, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People's Republic of China.

ABSTRACT
Multiple myeloma (MM) is a clonal malignancy characterized by the proliferation of malignant plasma cells in the bone marrow and the production of monoclonal immunoglobulin. In addition to genetic changes, gene hypermethylation is an alternative mechanism of tumor suppressor gene inactivation in MM. The cyclin-dependent kinase inhibitor 1 (CDKN2B or p15(INK4B) ) gene lies adjacent to the tumor suppressor gene, cyclin-dependent kinase inhibitor 2 (CDKN2A), and is frequently mutated and deleted in a wide variety of tumors, including MM. However, there is a lack of systematic analysis of p15 epigenetic modification such as methylation in MM from different studies that can provide more powerful estimation of an effect. In this study, we have systematically reviewed the studies of p15(INK4B) promoter methylation in MM and quantified the association between p15(INK4B) promoter methylation and MM using meta-analysis methods. We observed that the frequency of p15(INK4B) methylation is significantly higher in MM patients than in normal healthy controls. The pooled odds ratio (OR) from ten studies including 394 MM and 99 normal individuals is 0.08, while confidence interval (CI) is 0.03-0.21 (P<0.00001). This indicates that p15(INK4B) inactivation through methylation plays an important role in the pathogenesis of MM. In addition, the frequency of p15(INK4B) methylation was significantly higher in patients with MM than in those with asymptomatic monoclonal gammopathy of undetermined significance. The pooled OR from four studies is 0.40, 95% CI =0.21-0.78 (P=0.007). These results suggest that silencing of p15(INK4B) gene expression by epigenetic modification such as promoter hypermethylation plays a role not only in the initiation of MM but also in plasma cell malignant transformation, disease progression, and development.

Show MeSH
Related in: MedlinePlus