Tetsuhiro Kasamatsu

Interleukin-10 gene polymorphism reflects the severity of chronic immune thrombocytopenia in Japanese patients

Introduction:  T‐helper cell type 1 (Th1) polarization of the immune response has been documented in patients with chronic immune thrombocytopenia (ITP). Interleukin (IL)‐10 is the most important factor regulating Th1 and T‐helper type 2 cytokine synthesis. This study evaluated the impact of IL‐10 polymorphisms on both susceptibility to, and severity of, chronic ITP.

Polymorphisms of IL‐10 affect the severity and prognosis of myelodysplastic syndrome

Polymorphisms of the interluekin‐10 (IL‐10) gene, which alter the production of IL‐10, have been implicated in many cancers. We investigated the association between gene polymorphisms of the promoter region of IL‐10 (‐1082 G/A, IL‐10‐819 C/T, and ‐592 C/A) and the risk to develop myelodysplastic syndrome (MDS) and clinical features of MDS. Genomic DNA was extracted from 119 patients with MDS or chronic myelomonocytic leukemia and 202 healthy controls. Genotypes were determined by PCR‐restriction fragment length polymorphism. There were no statistically significant differences in the genotype, allele, and haplotype frequencies of IL‐10 ‐1082 G/A, IL‐10‐819 C/T, and ‐592 C/A between the patients with MDS and the control group. However, the IL‐10 ‐592 CC genotype group (IL‐10 high producer type) was associated with lower hemoglobin level (7.85 ± 2.02 g/dL vs. 9.37 ± 2.25 g/dL, P = 0.027) and poorer prognosis as compared to the IL‐10 ‐592 non‐CC genotype group (median survival time 50.2 m vs. not reached, p = 0.026). In addition, the IL‐10 high producer haplotype group (GCC/ACC or ACC/ACC) was also associated with lower hemoglobin level and shorter survival time. Our findings indicate that IL‐10 gene polymorphisms may not contribute to susceptibility to MDS, but they may be associated with the severity and prognosis of MDS.

Polymorphism of IL-10 receptor β affects the prognosis of multiple myeloma patients treated with thalidomide and/or bortezomib.

Interleukin‐10 (IL‐10) and IL‐10 receptor (IL‐10R) single nucleotide polymorphisms have been implicated in the pathogenesis of many cancers. We investigated the influence of IL‐10 −592C/A, IL‐10RA I224V, and IL‐10RB K47E on the risk of developing multiple myeloma (MM) and the clinical features of MM. We extracted the genomic DNA from 128 MM patients and 202 healthy controls and used polymerase chain reaction–restriction fragment length polymorphism method to detect IL‐10 promoter −592C/A (rs1800872), IL‐10RA (rs2228055), and IL‐10RB K47E (rs2834167) genotypes. Overall survival (OS) was defined as the interval from the date of diagnosis to the date of death or last clinical appointment. No statistically significant difference was observed in the genotype and allele frequencies of IL‐10 −592C/A, IL‐10RA I224V, and IL‐10RB K47E between MM patients and healthy controls. IL‐10RA II genotype was significantly associated with a hemoglobin level lower than that of IV and VV genotypes (mean ± standard deviation, 9.21 ± 2.46 vs 10.3 ± 2.33 g/dL; P = .021). IL‐10 −592 AA genotype was significantly associated with OS better than that of CA and CC genotypes (median OS, 74.5 vs 46.3 months; P = .047). We observed significant differences in survival between patients treated with thalidomide and/or bortezomib and those treated with conventional treatments (median OS, 74.5 vs 38.2 months; P = .021). Therefore, we also examined the effect of IL‐10 and IL‐10R polymorphisms on the clinical variables and OS of patients treated with thalidomide and/or bortezomib. In addition, IL‐10RB EE genotype was significantly associated with poorer survival than KK and KE genotypes (median OS, 46.3 vs 78.8 months; P = .015). Our findings indicate that IL‐10 and IL‐10R gene polymorphisms may not contribute to the susceptibility to MM but may be associated with the severity and prognosis of MM. In particular, IL‐10RB K47E polymorphism may contribute to the poor prognosis of MM patients treated with thalidomide and/or bortezomib.

PDCD1 and CTLA4 polymorphisms affect the susceptibility to, and clinical features of, chronic immune thrombocytopenia

Programmed death‐1 (PD‐1, PDCD1) and cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4, CTLA4) play central roles in immune checkpoint pathways. Single nucleotide polymorphisms (SNPs) of PDCD1 and CTLA4 have been reported to be associated with susceptibility to some autoimmune diseases. However, the potential association between SNPs in these immune checkpoint genes and risk of chronic immune thrombocytopenia (cITP) remain controversial and obscure. The aims of this study were to clarify the influence of PDCD1 and CTLA4 SNPs on the risk of developing cITP and its clinical features. We obtained genomic DNA from 119 patients with cITP and 223 healthy controls; their genotypes were determined by the polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) method. Patients with cITP had a significantly higher frequency of the PDCD1 +7209 TT genotype compared with healthy controls. The CTLA4 −1577 GG genotype and CT60 GG genotype showed higher frequencies of platelet count <5 × 109/l at diagnosis, minimum platelet count <5 × 109/l, and bleeding symptoms. Moreover, the PDCD1 −606 AA genotype and +63379 TT genotype were significantly associated with a lower number of patients who achieved a complete response to prednisolone treatment. Our results suggest that the immune checkpoint polymorphisms may affect the susceptibility to the clinical features of cITP, and treatment response of the affected patients.

Short-term administration of recombinant human erythropoietin decreases B cell number in human peripheral blood

OBJECTIVES There are conflicting results on the influence of recombinant human erythropoietin (rHuEPO) administration to lymphocytes, especially to B cells. METHODS We analyzed peripheral white blood cell (WBC) subsets in patients who received one bolus administration of rHuEPO. 119 autologous blood donors were enrolled in this study. Fourty-nine out of them were treated with rHuEPO. Blood samples were obtained before the first phlebotomy and one week later before the second one. By flow cytometry, we measured the numbers of WBC, lymphocytes, dendritic cells, CD4+ T cells, CD8+ T cells, natural killer (NK) cells, B cells, monocytes, and neutrophils, further details of B cell subsets. RESULTS In the EPO-treatment group, absolute numbers of lymphocytes, especially CD8+ T cells, NK cells, and B cells, significantly decreased after rHuEPO administration. In B cell subsets, absolute numbers of naïve B cells and IgD-CD27- B cells significantly decreased. Other B cell subsets, such as transitional B cells, memory B cells, and marginal zone B cells, also showed a decreasing trend. CONCLUSION These findings suggest that a single administration of rHuEPO can influence human immune system via reduction of B cell number in peripheral blood.

Association between OGG1 S326C CC genotype and elevated relapse risk in acute myeloid leukemia

Recent studies have shown that tumors of relapsed acute myeloid leukemia (AML) present additional genetic mutations compared to the primary tumors. The base excision repair (BER) pathway corrects oxidatively damaged mutagenic bases and plays an important role in maintaining genetic stability. The purpose of the present study was to investigate the relationship between BER functional polymorphisms and AML relapse. We focused on five major polymorphisms: OGG1 S326C, MUTYH Q324H, APE1 D148E, XRCC1 R194W, and XRCC1 R399Q. Ninety-four adults with AML who achieved first complete remission were recruited. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The OGG1 S326C CC genotype (associated with lower OGG1 activity) was observed more frequently in patients with AML relapse [28.9 vs. 8.9%, odds ratio (OR) = 4.10, 95% confidence interval (CI) = 1.35–12.70, P = 0.01]. Patients with the CC genotype exhibited shorter relapse-free survival (RFS). Moreover, the TCGA database suggested that low OGG1 expression in AML cells is associated with a higher frequency of mutations. The present findings suggest that the OGG1 S326C polymorphism increased the probability of AML relapse and may be useful as a prognostic factor for AML relapse risk.

Unsuppressed serum albumin levels may jeopardize the clinical relevance of the international staging system to patients with light chain myeloma

The international staging system (ISS) is the most commonly used risk‐stratification system for patients with multiple myeloma (MM) and is determined by serum albumin and β2‐microglobulin levels. In the two determinants, β2‐microglobulin levels are frequently observed to be elevated in patients with myeloma, particularly in those with renal impairment. In comparison with patients with intact immunoglobulin myeloma, patients with LC myeloma do not necessarily show decreased levels of serum albumin. The clinical impact of ISS in patients with LCMM, in particular the distinction between ISS I and II, may be complicated due to non‐decreased levels of serum albumin in both stages. Accordingly, we have attempted to assess clinical relevance of the ISS in patients with LC myeloma. The clinical data of 1899 patients with MM diagnosed between January 2001 and December 2012 were collected from 38 affiliated hospitals of the Japanese Society of Myeloma. Significant difference was not found between stage I (n = 72) and stage II (n = 92) in LC myeloma patients (n = 307). The mean serum albumin concentration of patients with LC myeloma was within the reference range but higher than that of patients with IgG + IgA myeloma (n = 1501), which complicates the distinction between ISS stage I and II myeloma. Patients with LC myeloma had low frequencies of t(4; 14) and high frequency of elevated lactate dehydrogenase, and despite a relevant amount of missing data in our registry (R‐ISS stage I; n = 11, stage II; n = 32, and stage III: n = 18), the information included in the R‐ISS scoring system seems to be more accurate than ISS to obtain a reliable risk stratification approach in non‐ISS stage III LC myeloma patients.

IL17A and IL23R gene polymorphisms affect the clinical features and prognosis of patients with multiple myeloma

Single nucleotide polymorphisms (SNPs) in interleukin 17 (IL17A) and IL‐23 receptor (IL23R) are involved in the pathogenesis of many cancers and autoimmune diseases. We investigated the influence of IL17A and IL23R SNPs on the risk of developing multiple myeloma (MM) and its clinical features. We obtained genomic DNA from 120 patients with MM and 201 healthy controls and detected IL17A −197 G/A (rs2275913) and IL23R H3Q (rs1884444) genotypes using the polymerase chain reaction‐restriction fragment length polymorphism method. There were no significant differences in the genotype and allele frequencies of IL17A −197 G/A and IL23R H3Q between the controls and patients with MM. Compared with the GG and GA genotypes, the IL17A AA genotype was significantly associated with lower hemoglobin levels. The IL23R HH genotype was significantly associated with higher frequency of bone lesions and plasmacytoma than the HQ and QQ genotypes. We observed significant differences in overall survival (OS) between patients treated with thalidomide and/or bortezomib and those treated conventionally. Therefore, we also examined the effect of IL17A and IL23R polymorphisms on the clinical variables and OS in patients treated with thalidomide and/or bortezomib. We observed that the IL23R HH genotype was significantly associated with poor survival compared with the QH and HH genotypes in these patients. Our findings indicate that IL17A −197 G/A and IL23R H3Q are not associated with susceptibility to MM. However, IL‐17 and IL‐23R polymorphisms may affect severity, bone lesions, and extra‐medullary disease in patients with MM. Moreover, IL23R polymorphisms may contribute to poor prognosis in patients with MM treated with thalidomide and/or bortezomib.

Abstract 3857: The polymorphisms of XRCC1 Arg194Trp and the XRCC1Arg399Gln affect the clinical features and the prognosis of MDS

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: X-ray repair cross-complementing group 1 (XRCC1) is involved an important role in base excision repair (BER) system of DNA repair. Polymorphism in DNA repair genes may be modified of DNA repair capacity. However, it is unclear that the polymorphisms of XRCC1alter the clinical features of MDS patients. Our study was performed to evaluate the effect of the XRCC1Arg194Trp and the XRCC1Arg399Gln with the susceptibility and clinical features of MDS. Methods: We genotyped the polymorphisms by using polymerase chain reaction -restriction fragment-length polymorphism (PCR-RFLP) analysis in 119 patients with MDS [median 67.9 years, range 17.1-86.5 years; male/female 81/38; RCUD (n = 40), RARS (n = 6), RCMD (n = 21), MDS-U (n = 13), RAEB-1(n = 14), RAEB-2 (n = 12), others (n = 13)] and 202-health controls. Results: In the allele and genotype frequencies of the XRCC1Arg194Trp and the XRCC1Arg399Gln were not statistically significant difference in patients and the controls. However, Arg/Arg genotypes of XRCC1 194 and the XRCC1 399 were significantly associated with lower Hb. In addition, XRCC1 399 non Arg/Arg genotype was significantly associated with previous history of radiotherapy and multiple cancers. Furthermore, XRCC1Arg194Trp non Arg/Arg genotype and XRCC1Arg399Gln Arg/Arg genotype were significantly associated with poor prognosis of MDS patients. Conclusion: We found that the polymorphisms of XRCC1 may be affected the clinical features and the prognosis of MDS. Citation Format: Batchimeg Norjmaa, Takayuki Saitoh, Tetsuhiro Kasamatsu, Yusuke Minato, Noriaki Sunaga, Hirokazu Murakami. The polymorphisms of XRCC1 Arg194Trp and the XRCC1Arg399Gln affect the clinical features and the prognosis of MDS. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3857. doi:10.1158/1538-7445.AM2015-3857