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Cumulative Epigenetic Abnormalities in Host Genes with Viral and Microbial Infection during Initiation and Progression of Malignant Lymphoma/Leukemia.

Oka T, Sato H, Ouchida M, Utsunomiya A, Yoshino T - Cancers (Basel) (2011)

Bottom Line: Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles.Tumor suppressor genes become frequent targets of aberrant hypermethylation in the course of gene-silencing due to the increased and deregulated DNA methyltransferases (DNMTs).The purpose of this article is to review the current status of knowledge about the contribution of cumulative epigenetic abnormalities of the host genes after microbial and virus infection to the crisis and progression of malignant lymphoma/leukemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. oka@md.okayama-u.ac.jp.

ABSTRACT
Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles. Aberrant promoter hypermethylation is a prevalent phenomenon in human cancers as well as malignant lymphoma/leukemia. Tumor suppressor genes become frequent targets of aberrant hypermethylation in the course of gene-silencing due to the increased and deregulated DNA methyltransferases (DNMTs). The purpose of this article is to review the current status of knowledge about the contribution of cumulative epigenetic abnormalities of the host genes after microbial and virus infection to the crisis and progression of malignant lymphoma/leukemia. In addition, the relevance of this knowledge to malignant lymphoma/leukemia assessment, prevention and early detection will be discussed.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of development and progression of gastric lymphoma in terms of specific gene methylation. Genes associated with orange arrows indicate significant increase of methylation frequency from arrow start point status to end point status. On the other hand, genes associated with green arrow show statistically significant decrease of methylation frequency from start-point to end-point status (p < 0.05). Left panel: schematic illustration of H. pylori (-) L-MALT-related diseases in terms of CpG hypermethylation; right panel: schematic illustration of H. pylori (+) L-MALT related diseases in terms of CpG hypermethylation.
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f2-cancers-03-00568: Schematic illustration of development and progression of gastric lymphoma in terms of specific gene methylation. Genes associated with orange arrows indicate significant increase of methylation frequency from arrow start point status to end point status. On the other hand, genes associated with green arrow show statistically significant decrease of methylation frequency from start-point to end-point status (p < 0.05). Left panel: schematic illustration of H. pylori (-) L-MALT-related diseases in terms of CpG hypermethylation; right panel: schematic illustration of H. pylori (+) L-MALT related diseases in terms of CpG hypermethylation.

Mentions: MALT lymphoma, a common low-grade B-cell lymphoma arising from a background of chronic inflammatory diseases at a number of mucosal sites, was first described by Isaacson and Wright in 1983 [30]. MALT lymphomas originating in the stomach are causatively linked to Helicobacter pylori infection, and eradication of the bacterium with antibiotics leads to long-term complete remission of the lymphoma in about 70% of patients [31]. Additional evidence links Campylobacter jejuni [32], Chlamydia psittaci [33], Borrelia burgdorferi [34], and hepatitis C virus [35,36] infection with MALT lymphoma of the small intestine, ocular adnexa, skin and splenic marginal zone, respectively. These organs are normally devoid of organized lymphoid tissue and lymphoma. MALT lymphomas arise from these sites as a result of chronic inflammatory or autoimmune disorders, such as H. pylori-associated chronic gastritis, lymphoepithelial sialoadenitis, Sjogren syndrome and Hashimoto thyroiditis [37,38]. The common karyotypic alterations that characterize MALT lymphoma include the trisomies of 3 and 18 [39,40] and the translocations t(11;18)(q21;q21) [41,42], t(1;14)(p22;q32) [43,44], t(14;18)(q32;q21) [39,45], and t(3;14)(p14.1;q32) [46,47], which commonly activate the NF-κB pathway. The most common translocation is t(11;18)(q21;q21), which results from the fusion of the API2 (apoptosis inhibitor 2) and the MALT1 (MALT lymphoma-associated translocation) genes [48,49]. Clonal identities of the immunoglobulin heavy chains between low-grade MALT lymphomas and coexisting diffuse large B-cell lymphoma (DLBCL) have been found in a considerable number of patients, indicating that low-grade MALT lymphoma progresses to high-grade malignancy composed of large-sized lymphoma (high grade MALT lymphoma) [50,51]. The detailed molecular mechanism of the progression to high-grade lymphoma has not been elucidated. Recently, we have demonstrated the average number of methylated genes was significantly greater in gastric lymphomas with H. pylori infection as compared to normal controls (p < 0.001). Concordant promoter hypermethylation of multiple genes, i.e., the CpG island methylator phenotype (CIMP), was observed in 93.3% (14/15) of DLBCL, 100% (5/5) of high-grade MALT lymphomas, and 61.9% (13/21) of MALT lymphomas, in contrast, CIMP was not found in the healthy control group (0%) [52]. The average number of methylated genes and the CIMP incidence significantly increased with H. pylori infection. Furthermore, aberrant CpG methylation of specific genes, such as P16, MGMT, DAPK, KIP2, H-cadherin (HCAD) and MINT31, was consistently associated with H. pylori infection and lost after eradication therapy (Figure 1 and 2) [52]. These findings strongly suggest that H. pylori infection causes the aberrant DNA hypermethylation of specific genes and induces CIMP, which is an important epigenetic mechanism for the development and progression of gastric MALT lymphoma. Additionally, these findings provide new sensitive epigenetic markers to detect early stage MALT lymphoma and progression status of the diseases, knowledge of the epigenetic changes that occur in the genome of host and H. pylori should provide us with markers for following cancer progression, as well as new tools for cancer therapy. In several studies, aberrant DNA hypermethylation in gastric biopsies from H. pylori-positive patients has been shown to correlate with higher risk of gastric cancer [53,54]. Aberrant DNA hypermethylation is frequently associated with chronic inflammation, as observed in non-cancerous adjacent tissues of patients with inflammation-associated cancers, which should be further investigated in the context of H. pylori infection.


Cumulative Epigenetic Abnormalities in Host Genes with Viral and Microbial Infection during Initiation and Progression of Malignant Lymphoma/Leukemia.

Oka T, Sato H, Ouchida M, Utsunomiya A, Yoshino T - Cancers (Basel) (2011)

Schematic illustration of development and progression of gastric lymphoma in terms of specific gene methylation. Genes associated with orange arrows indicate significant increase of methylation frequency from arrow start point status to end point status. On the other hand, genes associated with green arrow show statistically significant decrease of methylation frequency from start-point to end-point status (p < 0.05). Left panel: schematic illustration of H. pylori (-) L-MALT-related diseases in terms of CpG hypermethylation; right panel: schematic illustration of H. pylori (+) L-MALT related diseases in terms of CpG hypermethylation.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756377&req=5

f2-cancers-03-00568: Schematic illustration of development and progression of gastric lymphoma in terms of specific gene methylation. Genes associated with orange arrows indicate significant increase of methylation frequency from arrow start point status to end point status. On the other hand, genes associated with green arrow show statistically significant decrease of methylation frequency from start-point to end-point status (p < 0.05). Left panel: schematic illustration of H. pylori (-) L-MALT-related diseases in terms of CpG hypermethylation; right panel: schematic illustration of H. pylori (+) L-MALT related diseases in terms of CpG hypermethylation.
Mentions: MALT lymphoma, a common low-grade B-cell lymphoma arising from a background of chronic inflammatory diseases at a number of mucosal sites, was first described by Isaacson and Wright in 1983 [30]. MALT lymphomas originating in the stomach are causatively linked to Helicobacter pylori infection, and eradication of the bacterium with antibiotics leads to long-term complete remission of the lymphoma in about 70% of patients [31]. Additional evidence links Campylobacter jejuni [32], Chlamydia psittaci [33], Borrelia burgdorferi [34], and hepatitis C virus [35,36] infection with MALT lymphoma of the small intestine, ocular adnexa, skin and splenic marginal zone, respectively. These organs are normally devoid of organized lymphoid tissue and lymphoma. MALT lymphomas arise from these sites as a result of chronic inflammatory or autoimmune disorders, such as H. pylori-associated chronic gastritis, lymphoepithelial sialoadenitis, Sjogren syndrome and Hashimoto thyroiditis [37,38]. The common karyotypic alterations that characterize MALT lymphoma include the trisomies of 3 and 18 [39,40] and the translocations t(11;18)(q21;q21) [41,42], t(1;14)(p22;q32) [43,44], t(14;18)(q32;q21) [39,45], and t(3;14)(p14.1;q32) [46,47], which commonly activate the NF-κB pathway. The most common translocation is t(11;18)(q21;q21), which results from the fusion of the API2 (apoptosis inhibitor 2) and the MALT1 (MALT lymphoma-associated translocation) genes [48,49]. Clonal identities of the immunoglobulin heavy chains between low-grade MALT lymphomas and coexisting diffuse large B-cell lymphoma (DLBCL) have been found in a considerable number of patients, indicating that low-grade MALT lymphoma progresses to high-grade malignancy composed of large-sized lymphoma (high grade MALT lymphoma) [50,51]. The detailed molecular mechanism of the progression to high-grade lymphoma has not been elucidated. Recently, we have demonstrated the average number of methylated genes was significantly greater in gastric lymphomas with H. pylori infection as compared to normal controls (p < 0.001). Concordant promoter hypermethylation of multiple genes, i.e., the CpG island methylator phenotype (CIMP), was observed in 93.3% (14/15) of DLBCL, 100% (5/5) of high-grade MALT lymphomas, and 61.9% (13/21) of MALT lymphomas, in contrast, CIMP was not found in the healthy control group (0%) [52]. The average number of methylated genes and the CIMP incidence significantly increased with H. pylori infection. Furthermore, aberrant CpG methylation of specific genes, such as P16, MGMT, DAPK, KIP2, H-cadherin (HCAD) and MINT31, was consistently associated with H. pylori infection and lost after eradication therapy (Figure 1 and 2) [52]. These findings strongly suggest that H. pylori infection causes the aberrant DNA hypermethylation of specific genes and induces CIMP, which is an important epigenetic mechanism for the development and progression of gastric MALT lymphoma. Additionally, these findings provide new sensitive epigenetic markers to detect early stage MALT lymphoma and progression status of the diseases, knowledge of the epigenetic changes that occur in the genome of host and H. pylori should provide us with markers for following cancer progression, as well as new tools for cancer therapy. In several studies, aberrant DNA hypermethylation in gastric biopsies from H. pylori-positive patients has been shown to correlate with higher risk of gastric cancer [53,54]. Aberrant DNA hypermethylation is frequently associated with chronic inflammation, as observed in non-cancerous adjacent tissues of patients with inflammation-associated cancers, which should be further investigated in the context of H. pylori infection.

Bottom Line: Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles.Tumor suppressor genes become frequent targets of aberrant hypermethylation in the course of gene-silencing due to the increased and deregulated DNA methyltransferases (DNMTs).The purpose of this article is to review the current status of knowledge about the contribution of cumulative epigenetic abnormalities of the host genes after microbial and virus infection to the crisis and progression of malignant lymphoma/leukemia.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. oka@md.okayama-u.ac.jp.

ABSTRACT
Although cancers have been thought to be predominantly driven by acquired genetic changes, it is becoming clear that microenvironment-mediated epigenetic alterations play important roles. Aberrant promoter hypermethylation is a prevalent phenomenon in human cancers as well as malignant lymphoma/leukemia. Tumor suppressor genes become frequent targets of aberrant hypermethylation in the course of gene-silencing due to the increased and deregulated DNA methyltransferases (DNMTs). The purpose of this article is to review the current status of knowledge about the contribution of cumulative epigenetic abnormalities of the host genes after microbial and virus infection to the crisis and progression of malignant lymphoma/leukemia. In addition, the relevance of this knowledge to malignant lymphoma/leukemia assessment, prevention and early detection will be discussed.

No MeSH data available.


Related in: MedlinePlus