Brain-derived neurotrophic factor Val/Met polymorphism and bipolar disorder. Association of the Met allele with suicidal behavior of bipolar patients.

BACKGROUND/AIMS: The substitution of valine by methionine in the brain-derived neurotrophic factor (BDNF Val/Met) gene alters the intracellular trafficking and regulated secretion of BDNF. This study tested whether the BDNF Val/Met polymorphism is associated with bipolar disorder in Korean subjects, and whether clinical features vary according to genotype. METHODS: The allelic and genotypic distributions of BDNF Val/Met were determined in a population of 169 bipolar patients and 251 normal controls. Between-genotype comparisons of clinical features were performed without a priori knowledge of the genotype of individual patients. RESULTS: Allelic distributions did not differ significantly between bipolar patients and controls (chi(2) = 0.400, p = 0.821). However, the rate of suicide attempts among the Val/Val (11.3%), Val/Met (28.8%) and Met/Met (38.9%) genotype groups were significantly different (chi(2) = 9.879, p = 0.007). Relative to patients with the Val/Val genotype, those with the Met/Met genotype had a 4.9-fold higher risk of suicide attempts (95% CI, 1.7-14.7). CONCLUSIONS: These findings suggest that BDNF Val/Met is related to the suicidal behavior of bipolar patients, and may have clinical relevance as a biological indicator of bipolar patients at risk of suicide.

Frequent mutations of Fas gene in nasal NK/T cell lymphoma.

Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling through binding of Fas ligand. Mutation of Fas gene in lymphoid cells results in accumulation of these cells, which might thus contribute to lymphomagenesis. We examined the open reading frame of Fas cDNA in 14 cases of nasal NK/T-cell lymphoma. Mutations of Fas gene were detected in seven (50%) of 14 cases which comprised four frameshift, two missense, and one silent mutations. Frameshift mutations were caused by insertion of 1 bp (A) at nucleotide 1095 in two cases and by deletion of 1 bp at nucleotide 597 and at 704, respectively, in one each. Mouse T-cell lymphoma cells transfected with two missense mutated genes and frameshift mutations caused by insertion of 1 bp (A) at nucleotide 1095 were resistant to apoptosis induced by the anti-Fas antibody. These findings suggested that accumulation of lymphoid cells with Fas mutations provides a basis for the development of nasal NK/T-cell lymphoma.

p53, K-ras, c-kit and beta-catenin gene mutations in sinonasal NK/T-cell lymphoma in Korea and Japan.

Mutations of p53, K-ras, c-kit, and beta-catenin gene were examined in 100 cases of sinonasal NK/T-cell lymphoma (NKTCL) from Korea and Japan. Age of patients ranged from 12 to 72 (median 41.0) in Korea and 27 to 82 (median 61.0) years in Japan. Gene mutations were analyzed on paraffin-embedded specimens by PCR-SSCP followed by direct sequencing. p53 is a well-known tumor suppressor gene. c-kit gene encodes a receptor tyrosine kinase, which plays a crucial role in proliferation and differentiation of hematopoietic stem cells. Mutations of K-ras and beta-catenin are frequently observed in cancers. Thirteen of 42 (31.0%) cases from Korea and 36 of 58 (62.1%) from Japan had p53 mutations, showing significant differences in the incidence of p53 mutation between two countries. Of the Japanese cases 18 (31.0%) had mutations in exon 4, while only 3 cases (7.1%) were found in Korea cases (p<0.01 by chi2 test). K-ras, c-kit and beta-catenin mutations were also found in higher incidence in Japanese cases. In conclusion, different frequency of p53 mutations with different pattern of exon involvement and difference in age of disease onset is evident between sinonasal NKTCL in Korea and Japan.

P53, N- and K-Ras, and beta-catenin gene mutations and prognostic factors in nasal NK/T-cell lymphoma from Hokkaido, Japan.

We have shown previously that nasal natural killer (NK)/T-cell lymphoma was associated with Epstein-Barr virus (EBV) and had peculiar clinical features. However, little is known about its biological and genetic changes. The aim of this study is to determine the p53, N- and K-ras, and beta-catenin status in this lymphoma in relation to EBV status and clinical features. The study group consisted of 32 Japanese patients with nasal NK/T-cell lymphoma. The p53 and beta-catenin expression, phenotype, and EBV-oncogenic protein latent membrane protein type 1 (LMP-1) were determined by immunoperoxidase staining. The presence of EBV-encoded small nuclear early region (EBER) RNA was determined by in situ hybridization. The p53 mutations (exons 5 to 9), N- and K-ras mutations (exons 1 and 2), and beta-catenin mutations (exon 3) were analyzed by direct sequencing of the PCR-amplified products that were obtained from laser-microdissected tissues. CD56, CD43, and CD3 were expressed in 32 (100%), in 31 (96%), and in 18 (56%) tumors, respectively. EBER RNA was detected in 31 (96%) tumors. LMP-1 was expressed in 15 (48%) tumors, and p53 and beta-catenin protein were overexpressed in 18 (56%) and 4 (13%) tumors, respectively. Six mutations of the p53 gene, 1 mutation of each N- and K-ras gene, and 8 mutations of beta-catenin gene were detected in 6 (19%), 1 (3%), and 5 (16%) tumors, respectively. The p53 missense mutation was associated with LMP-1 expression (P = 0.038), but not with p53 overexpression. Kaplan-Meier analysis as well as univariate analysis using Cox proportional hazards model showed that high lactate dehydrogenase (LDH) level (P = 0.009, P = 0.0100, respectively), large cell, immunoblastoid polymorphous histology (P = 0.005, P = 0.0162, respectively), and p53 missense mutations (P = 0.021, P = 0.0342, respectively) were significantly related to worse cause-specific survival. Multivariate analysis showed that p53 missense mutation was the most independent among these 3 factors. Although the incidence of thep53, N- and K-ras, and beta-catenin gene mutations is not high, p53 missense mutation has a prognostic value for aggressive course in nasal NK/T-cell lymphoma.

Origin of malignant centrofacial granulomas: surface markers and gene rearrangement of malignant cells.

Malignant centrofacial granuloma (MCFG) is a clinical entity characterized by a relentless ulceration of the upper airway involving the nose, palate, and face, without any demonstrable etiology. The origin of 11 cases were analyzed with the help of cell-surface immunostaining in all and with T-cell receptor gene (TCR) rearrangement in 3. The results show that most of the cases of MCFG are in fact T-cell lymphomas with cell-surface antigens (CD2, CD7, CD3) consistent with either early or mature T lymphocytes. However, some cases exhibit B-lymphoid (CD19, CD20) or histiomonocytic (CD13, CD14) lineage-specific markers. In conclusion, despite its remarkable clinical unity, MCFG is a heterogeneous group of neoplastic diseases, most but not all of which may be classified as T-cell lymphoma.

[Genotypic analysis of lethal midline granuloma].

So-called lethal midline granuloma is of great clinical and theoretical interest. The etiology of lethal midline granuloma is unknown and the pathogenesis is variable, with debate as to precise classification and natural history. In this study, we reported genotypic and immunopathological features in 3 cases of lethal midline granuloma. The histopathological diagnosis of their biopsy specimens was initially polymorphic reticulosis/midline malignant reticulosis. Immunohistologic study of the specimens revealed that immature or atypical cells had phenotypes of T-cells, CD2, CD3, CD4 (Case 1), CD4 (Case 2), and CD2, CD3 (Case 3). Those cells were also found to be positive for HLA-DR, which indicated that they were activated T-cells. Immunohistology in T-cells, however, was not able to give a similar clue to clonarity as it was possible within B-cell neoplasms by immunophenotyping the light chains. With the establishment of cDNA probes for the T-cell receptor genes it was possible to analyze neoplasms of lymphocyte origin for lineage and clonality. The Southern blot analysis of 3 cases showed rearrangement of TCR gene, TCR beta and TCR gamma chain (Cases 1 and 2) and TCR beta and TCR delta chain (Case 3), whereas none of them showed rearrangement of immunoglobulin heavy chain. These findings represented conclusive evidence for a monoclonal T-cell proliferation within lethal midline granuloma. On the ground of immunohistological and genotypic studies, lethal midline granuloma histologically diagnosed as polymorphic reticulosis/midline malignant reticulosis are proven to be a T-cell lymphoproliferative disorder.

Lymphomatoid granulomatosis--evidence of a clonal T-cell origin and an association with lethal midline granuloma.

Lymphomatoid granulomatosis and lethal midline granuloma are both characterized histologically by atypical pleomorphic angiocentric infiltrates. Whether these conditions are malignant lymphoproliferative disorders remains controversial. Here we report the results of studies carried out in a patient with coeliac disease, who developed recurrent self-healing subcutaneous nodules with the histological changes of lymphomatoid granulomatosis and an invasive nasal tumour with the histological features of lethal midline granuloma. The patient subsequently also developed an erythrophagocytic syndrome. Immunocytochemical labelling of both cutaneous and nasal lesions demonstrated a predominant population of T cells with a CD4-negative CD8-positive phenotype. Analysis of DNA from cutaneous tissue revealed a discrete rearrangement of the beta and gamma T-cell receptor genes. These findings suggest that lymphomatoid granulomatosis is a clonal T-cell lymphoproliferative disorder and its association with lethal midline granuloma indicates that both conditions may have a common histogenesis.

Characterization of novel natural killer (NK)-cell and gammadelta T-cell lines established from primary lesions of nasal T/NK-cell lymphomas associated with the Epstein-Barr virus.

Studies on nasal T/natural killer (NK)-cell lymphoma have been hampered by its tendency to cause necrosis. Thus, the establishment of cell lines of this neoplasm would seem to be valuable. This study attempted to establish cell lines from primary lesions of this tumor, and successfully obtained 2 novel Epstein-Barr virus (EBV)-positive cell lines, SNK-6 and SNT-8, by means of high-dose recombinant interleukin 2. Flow cytometry showed that SNK-6 had an NK-cell phenotype, CD3- CD4- CD8- CD19- CD56+ T-cell receptor (TCR) alpha/beta- TCR gamma/delta-, whereas SNT-8 was CD3+ CD4- CD8- CD19- CD56+ TCR alpha/beta- TCR gamma/delta+. These were consistent with immunophenotypes of their original tumors, and the cell lines had monoclonal EBV clones identical to ones in their original tumors. Thus, the cell lines developed from cells forming the primary lesions. Genotypic analysis showed that SNK-6 had unrearranged TCR and immunoglobulin heavy-chain genes, supporting the conclusion that SNK-6 was of NK-cell lineage. On the other hand, SNT-8 had rearranged TCR beta-, gamma-, and delta-chain genes, and together with its phenotype, SNT-8 proved to be a gammadelta T-cell line. This is the first report of the establishment of cell lines from primary lesions of nasal T/NK cell lymphomas, and the results demonstrated that there are at least 2 lineages, NK- and gammadelta T-cell, in this neoplasm. Moreover, it has been suggested that nasal T/NK cell lymphomas of these lineages may belong to the same clinicopathologic entity because both types of cases shared common clinical and histopathologic features.

Lethal midline granuloma (peripheral T-cell lymphoma) after lymphomatoid papulosis.

A Japanese woman with an 8-year history of lymphomatoid papulosis (LP) had lethal midline granuloma (LMG) develop at the age of 51 years. There were histologic similarities between LP and LMG seen in this patient. Surface phenotypic studies on nasal and cutaneous lesions demonstrated a population of T-cells expressing CD2, CD4, CD25, CD30, and histocompatibility antigen-DR (HLA-DR). Genotypic analyses of nasal and skin biopsy specimens disclosed a clonal rearrangement of the beta T-cell receptor gene with the same rearrangement pattern. These data indicate that this patient had LMG characterized by clonal peripheral T-cell lymphoma, which probably resulted from progression of the LP.

Frequent expression of P-glycoprotein/MDR1 by nasal T-cell lymphoma cells.

BACKGROUND: Lethal midline granuloma is now considered to be a malignant lymphoma derived from peripheral T cells or from natural killer cells. The therapeutic outcome of nasal T-cell lymphoma (NL) treated by conventional chemotherapy for non-Hodgkin's lymphoma is poor, although some patients have a good response to radiotherapy. To clarify the mechanisms of drug resistance, the expression of P-glycoprotein (P-gp)/MDR1, which is the product of the multidrug resistance (MDR) 1 gene, and MDR3 mRNA in NL cells, were examined. METHODS: Ten Japanese patients with NL were studied. Nine of these patients were examined before therapy. P-glycoprotein expression and phenotypes of lymphoma cells were examined by immunohistochemical staining using UIC2 as an anti-P-gp monoclonal antibody. In one case, the Rhodamine-123 efflux test was performed. MDR1 and MDR3 mRNA were detected by reverse transcription polymerase chain reaction. RESULTS: Nine of the 10 patients were P-gp positive. In one of nine, functional P-gp expression was observed. MDR1 mRNA was detected in all seven examined patients with P-gp positive NLs, whereas MDR3 mRNA was negative. Retrospectively, patients who received chemotherapy alone had poorer outcome than those treated by combination chemotherapy after irradiation. CONCLUSION: The poor prognosis for patients with NL treated with chemotherapy may be explained by P-gp expression of the NL cells.