p16/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis

Takino, Hisashi; Okabe, Mitsukuni; Li, Chunmei; Ohshima, Koichi; Yoshino, Tadashi; Nakamura, Shigeo; Ueda, Ryuzo; Eimoto, Tadaaki; Inagaki, Hiroshi

doi:10.1038/modpathol.3800400

Cited by 15 publications

(9 citation statements)

References 38 publications

(52 reference statements)

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“…Recently, p16 gene methylation was detected in 60% of MALT lymphoma cases, and it was also suggested that p16 methylation is not associated with tumor progression, but may be an early event in MALT lymphomagenesis. 49 In addition, mutations in the FAS gene were also found at a high frequency (60%) in MALT lymphoma. 50 FAS is a mediator of cell death in the germinal center B cells, which suggests that its inactivation may be involved in the pathogenesis of MALT lymphoma.…”

Section: Molecular Genetics Of Mucosa-associated Lymphoid Tissue Lympmentioning

confidence: 99%

Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

2006

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At least three recurrent chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), involving the API2-MALT1 fusion protein, BCL10 and MALT1, have been implicated in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma. Several lines of evidence indicated that both BCL10 and MALT1 are required for nuclear factor kappa B (NF-jB) activation by antigen receptor stimulation in lymphocytes, and API2-MALT1 can bypass this BCL10/MALT1 signaling pathway. Nuclear factor kappa B activation may contribute to antiapoptotic effect through NF-jB-mediated upregulation of apoptotic inhibitor genes. We recently demonstrated that API2-MALT1 can induce transactivation of the API2 gene through NF-jB activation, thus highlighting a positive feedback-loop mechanism of self-activation by upregulating its own expression in t(11;18) MALT lymphomas. We also demonstrated that API2-MALT1 possesses an antiapoptotic effect, in part, through its direct interaction with apoptotic regulators. These findings therefore led us to hypothesize that the antiapoptotic effect by API2-MALT1 may be mediated by its interaction with apoptotic regulators, on the one hand, and by NF-jB-mediated upregulation of apoptotic inhibitor genes on the other. We also found that BCL10 and MALT1 are shuttling between nucleus and cytoplasm, and that MALT1 can regulate the subcellular location of BCL10. Leukemia (2006) 20, 929-936.

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Section: Molecular Genetics Of Mucosa-associated Lymphoid Tissue Lympmentioning

confidence: 99%

Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

2006

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“…[40][41][42] However, recent studies have shown that methylation of these genes may be an early event in lymphomagenesis: DAPK and p16 gene methylation is frequently found in premalignant and low-grade lymphoid disorders, not associated with tumor progression, and their methylation status is maintained in higher-grade or advanced lymphoid neoplasms. [43][44][45][46][47][48] In line with these findings, methylation of DAPK and p16 is a common, early epigenetic phenomenon that allows tumor cells to promote cellcycle progression and escape the normal apoptosis of a non-antigen-stimulated expanded B-cell population. Unlike base substitutions or gene deletions, changes in DNA methylation are potentially reversible.…”

Section: Primary Cutaneous Marginal Zone B-cell Lymphoma H Takino Et Almentioning

confidence: 89%

Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathological study of cases from Asia, Germany, and the United States

Takino

et al. 2008

Modern Pathology

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Primary cutaneous marginal zone B-cell lymphoma is considered the cutaneous counterpart of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. Although its molecular pathogenesis is currently unknown, an etiological link with Borrelia burgdorferi infection has been identified in European, but not in American or Asian cases. To better understand the pathogenesis and the geographical differences of cutaneous marginal zone B-cell lymphoma, 60 cases from the East Asia, Germany, and the United States at their initial presentation were subjected to the following analyses; (1) clinicopathological comparison between the geographical regions, (2) detection of B. burgdorferi DNA, (3) detection of the API2-MALT1 fusion transcript, a gene alteration specific to mucosa-associated lymphoid tissue lymphoma, and (4) inactivation of tumor suppressor genes (death-associated protein kinase (DAPK), p16 INK4a , p14 ARF , MGMT, TIMP3, CDH1, and RARB) by hypermethylation of the CpG islands. Cases from the three geographical regions showed similar clinicopathological features. However, moderate/marked tissue eosinophilia was found in 9/25 Asian cases, but only 1/23 German cases (P ¼ 0.011) and 0/12 American cases (P ¼ 0.015). All 60 cases were negative for either Borrelia DNA or API2-MALT1 fusion. Tumors from the three regions were highly methylated for DAPK (38-50% of the cases, mean 43%) and p16 INK4a (42-70%, mean 49%), and the positivities were significantly higher than those of nonneoplastic skin (8%, P ¼ 0.0010 and 14%, P ¼ 0.0032, respectively). Methylation of these genes had no significant association with progressive features of the tumor. Primary cutaneous marginal zone B-cell lymphomas from the three geographical regions have common clinicopathological features, however, moderate/marked tissue eosinophilia is a feature found almost exclusively in Asian cases. Borrelia infection and API2-MALT1 fusion are not significant in this tumor. Methylation of DAPK and p16 INK4a genes is a frequent event in this lymphoma at its initial presentation, but may not be associated with tumor progression.

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“…Methylation of a large number of genes has been described in virtually all types of cancers. MALT lymphomas show a high grade of p16/INK4a methylation [29][30][31][32]40,41], suggesting that inactivation of p16/INK4a by methylation may play an important role in the development of MALT lymphomas. In particular, it has been suggested that methylation of this gene is one of the early events in the development of lymphoid malignancies [42][43][44].…”

Section: Discussionmentioning

confidence: 99%

Geographic variation and environmental conditions as cofactors in Chlamydia psittaci association with ocular adnexal lymphomas: a comparison between Italian and African samples

Carugi

Onnis

Antonicelli

et al. 2009

Hematological Oncology

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A particular extra-nodal lymphoma type arises from B cells of the marginal zone (MZ) of mucosa-associated lymphoid tissue (MALT). The aetiology of MZ lymphomas suggests that they are associated with chronic antigenic stimulation by microbial pathogens, among which Helicobacter pylori-associated gastric MALT lymphoma is the best studied. Recently, MALT lymphomas have been described in the context of chronic conjunctivitis, which can be associated with Chlamydia spp. infection. Studies from Italy showed the presence of Chlamydia psittaci in 87% of ocular adnexal lymphomas (OAL), and C. psittaci has been described in a large part of samples from Austria and Korea as well. However, this finding was not always confirmed by other studies, suggesting that the association with C. psittaci may depend on geographic heterogeneity. Interestingly, none of the studies up to now has been carried out in the African population, where a strong association between infectious agents and the occurrence of human neoplasms has been reported. This study was designed to investigate the possible association of Chlamydia psittaci in cases retrieved from Kenya, compared to cases from Italy. Our results showed that there was a marked variation between the two geographical areas in terms of association with C. psittaci, as 17% (5/30) of the samples from Italy were positive for C. psittaci, whereas no association with this pathogen was observed in any of the African samples (0/9), suggesting that other cofactors may determine the OAL occurrence in those areas. OAL cases are often characterized by down-regulation of p16/INK4a expression and promoter hypermethylation of the p16/INK4a gene. Our results showed a partial methylation of p16/INK4a promoter in C. psittaci-negative cases, whereas no hypermethylation of this gene was found in C. psittaci-positive cases, suggesting that mechanisms other than promoter hypermethylation lead to p16/INK4a silencing in C. psittaci-positive cases. We may conclude that the role of epidemiologic, environmental and genetic factors, must be considered in the aetiology of this disease.

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p16/INK4a gene methylation is a frequent finding in pulmonary MALT lymphomas at diagnosis

Cited by 15 publications

References 38 publications

Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathological study of cases from Asia, Germany, and the United States

Geographic variation and environmental conditions as cofactors in Chlamydia psittaci association with ocular adnexal lymphomas: a comparison between Italian and African samples

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