Original articles
hSNF5/INI1 gene mutations in lymphoid malignancy

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Abstract

hSNF5/INI1 is one of the components of the SWI/SNF multiprotein complex that is necessary for the transcriptional activation of several genes and functions by altering chromatin structure. This gene has been thought to be one of the tumor suppressor genes (TSGs) because deletions or mutations were reported in malignant rhabdoid tumors and atypical teratoid and rhabdoid tumors. To evaluate the hSNF5/INI1 gene as a TSG in lymphoid malignancies, we performed a mutational analysis in 23 patients with non-Hodgkin lymphoma (NHL), 24 with acute lymphoblastic leukemia (ALL), 24 with multiple myeloma (MM), 24 with adult T-cell lymphoma/leukemia (ATLL), and 19 with lymphoid cell lines, by polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis. Nonsense and missense mutations were found in 1 NHL case and 2 cell lines. Mutations from this NHL case proved to be somatic in origin. These data indicated that alterations in the hSNF5/INI1 gene might be involved in the pathogenesis of lymphoid malignancies.

Introduction

Many studies have demonstrated that genetic alterations are critical events in the development of lymphoid malignancies. Chromosomal translocations affecting the immunoglobulin heavy chain locus are often observed in B-cell lymphoid malignancies 1, 2, and the deregulation of various proto-oncogenes found at such chromosomal breakpoints is thought to play a critical role in the pathogenesis of these tumors 3, 4, 5. Inactivation of tumor suppressor genes (TSGs) is also proved to be important in the pathophysiology of malignancy. Mutations of the TP53 and p16 genes have been reported, suggesting the involvement of mutations of TSGs in the development and progression of lymphoid malignancies 6, 7, 8.

Recently, Versteege et al. reported deletions and somatic mutations in the hSNF5/INI1 gene, which might be a transcriptional modulator 9, 10, 11, 12, 13, in malignant rhabdoid tumors (MRTs) [14]. Malignant rhabdoid tumor is one of the aggressive cancers of early childhood, in which cytogenetic and molecular analyses have shown that the deletion of chromosome 22q11, on which the hSNF5/INI1 gene is located, is a recurrent genetic alteration 15, 16. Atypical teratoid and rhabdoid tumors (AT/RTs) were also reported as having homozygous deletions and mutations in the hSNF5/INI1 gene with considerable frequency [17]. Germline mutations of hSNF5/INI1 were also identified in some cases of AT/RTs. Grand et al. reported deletions of this gene in chronic phase and blast crisis of chronic myeloid leukemia (CML) by means of two-fusion fluorescence in situ hibridization analysis [18]. These observations suggested that loss-of-function mutations of the hSNF5/INI1 gene contributed to tumorigenesis.

Recurrent chromosomal deletions of 22q11 have been reported in non-Hodgkin lymphoma (NHL), multiple myeloma (MM), and other lymphoid malignancies by karyotyping 19, 20. To investigate the incidence of mutation of the hSNF5/INI1 gene in lymphoid malignancies, we examined this gene for mutation in various types of lymphoid neoplasms by polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) analysis.

Section snippets

Tissue samples and cell lines

Tumor DNA samples were obtained from 23 consenting patients with NHL (15 males and 8 females). The age range was from 18 to 87 years (median 56 years). Histological diagnoses were as follows: diffuse large B-cell lymphoma, 22 cases; mantle-cell lymphoma, 1 case (according to the WHO classification [21]). We also obtained tumor DNA samples from 24 ALL (11 males and 13 females), 24 MM (12 males and 12 females), and 24 ATLL (17 males and 7 females). Clinical samples were encoded as follows: B-NHL

Analysis of clinical cases

We examined 23 NHL, 24 ALL, 24 MM, and 24 ATL cases for mutation of the hSNF5/INI1 gene coding region (exons 1–9) by PCR-SSCP. Abnormal patterns were detected in one of the NHL cases (Fig. 1), 2 of ALL, 2 of MM, and 2 of ATL. DNA sequencing analysis of the PCR products from the exons involved confirmed point mutations in these cases Table 2, Table 3. They included 1 NHL case (BNHL21) that was diffuse large B-cell type, with a nonsense mutation which substituted 338Gln (CAG) in exon 8 to STOP

Discussion

hSNF5/INI1 is one of the components of the SWI/SNF complex 24, 25. This multiprotein complex, which consists of 13 proteins, is necessary for the transcriptional activation of several genes and functions by altering the chromatin structure, particularly promoter regions, in an ATP-dependent manner 9, 10, 11, 12, 13. The hSNF5/INI1 gene is also thought to be involved in the pathogenesis of cancers such as rhabdoid tumors and CML, which are associated with the deletion or mutation of this gene 14

Acknowledgements

We wish to thank Dr. Kunitada Shimotohno for providing ATLL samples, Dr. Isabella Versteege for the primer sequence to amplify the hSNF5/INI1 gene, and Ms. Kimie Kondo and Ms. Sonoko Hatano for their excellent technical assistance. Supported in part by a Grant-in-Aid for Cancer Research (9-10) from the Ministry of Health and Welfare of Japan.

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