Shuhua Yi

The Impact of Clone Size on the Prognostic Value of Chromosome Aberrations by Fluorescence In Situ Hybridization in Multiple Myeloma

Purpose: Accumulating evidence indicates that intratumor heterogeneity is prevalent in multiple myeloma and that a collection of multiple, genetically distinct subclones are present within the myeloma cell population. It is not clear whether the size of clonal myeloma populations harboring unique cytogenetic abnormalities carry any additional prognostic value. Experimental Design: We analyzed the prognostic impact of cytogenetic aberrations by fluorescence in situ hybridization at different cutoff values in a cohort of 333 patients with newly diagnosed myeloma and 92 patients with relapsed myeloma. Results: We found that nearly all IgH-related arrangements were observed in a large majority of the purified plasma cells; however, 13q deletion, 17p deletion, and 1q21 amplification appeared in different percentages within the malignant plasma cell population. Based on the size of subclones carrying these cytogenetic aberrations, the patients were divided into four groups: 0%–10%, 10.5%–20%, 20.5%–50%, and >50%. Receiver-operating characteristics analysis was applied to determine the optimal cutoff value with the greatest differential survival and showed that the most powerful clone sizes were 10% for 13q deletion, 50% for 17p deletion, and 20% for 1q21 gains, which provided the best possible cutoffs for predicting poor outcomes. Conclusions: Our study indicated that the impact of clone size on prognostic value varies between specific genetic abnormalities. Prognostic value was observed for even a subgroup of plasma cells harboring the cytogenetic aberration of 13q deletion and 1q21 gains; however, 17p deletion displayed the most powerful cutoff for predicting survival only if the predominant clones harbored the abnormality. Clin Cancer Res; 21(9); 2148–56. ©2015 AACR.

MicroRNA-223 expression is uniformly down-regulated in B cell lymphoproliferative disorders and is associated with poor survival in patients with chronic lymphocytic leukemia

Abstract MicroRNA-223 (miR-223) expression has been demonstrated to be stage-specific in B cell differentiation and associated with the outcome of chronic lymphocytic leukemia (CLL). However, the expression pattern of miR-223 in B cell lymphoproliferative disorders and its association with the outcome of Chinese patients with CLL have not been investigated. In this study, we demonstrated that miR-223 expression was significantly decreased in CLL, mantle cell lymphoma (MCL) and splenic marginal zone lymphoma (SMZL). In CLL, miR-223 expression decreased significantly with progression from early to advanced clinical stages and was significantly lower in patients with elevated β2-microglobulin, unmutated immunoglobulin variable heavy chain (IgVH) gene or with disease progression or death. Using a cut-off determined by receiver operating characteristic (ROC) analysis optimizing concordance with IgVH mutational status, miR-223-negative and -positive groups were defined for 22 and 31 patients, respectively. The median progression-free survival (PFS) and overall survival of the miR-223-negative group were 13 and 40 months, respectively, significantly shorter than for the miR-223-positive group (both not reached; p = 0.002 and p = 0.018, respectively). Multivariate analysis revealed that the absence of miR-223 was the only independent factor capable of predicting shorter PFS. In conclusion, miR-223 is uniformly down-regulated in B-LPDs and is a useful prognostic factor for patients with CLL.

Serum high expression of miR-214 and miR-135b as novel predictor for myeloma bone disease development and prognosis.

Multiple myeloma (MM) originates from malignant plasma cells, leading to multiple destructive lytic bone lesions that occur in more than 80% of MM patients. MicroRNAs have been reported to be involved in development of bone lesions in MM. However, the circulating microRNA as diagnostic and prognostic biomarkers for bone lesions has not been elucidated yet. In this study, we identified differentially expressed miRNAs that are potentially involved in myeloma-related bone disease in serum of MM patients. MiR-214 and miR-135b was shown to be increased in serum of MM patients with bone lesions. Serum level of miR-214 and miR-135b was highly correlated with the severity of lytic bone lesions and demonstrated as a diagnostic tool for identifying bone diseases based on results of a receiver operating characteristic analysis (ROC). In addition, patients with high levels of serum miR-214 had a dismal survival with significantly shortened progression free survival (PFS) and overall survival (OS). Interestingly, bisphosphonates treatment significantly extended PFS and OS in patients with higher level of miR-214 comparing to patients without bisphosphonates treatment. Taken together, our findings revealed the significance of circulating miR-214 and miR-135b levels in detection of bone disease and in prediction of prognosis of patients with multiple myeloma, suggesting its potential clinical applications. The result of this study also set the foundation for searching more circulating miRNA as biomarker for tumor bone lesions.

miR-29c down-regulation is associated with disease aggressiveness and poor survival in Chinese patients with chronic lymphocytic leukemia

Abstract Aberrant expression of microRNAs in chronic lymphocytic leukemia (CLL) has been reported to be associated with clinical outcome and improve prognostic stratification. The aim of this study was to explore the association of miR-29c expression with clinical parameters and survival in 53 Chinese patients with CLL. We showed that the miR-29c expression level decreased significantly from early to advanced clinical stages, and was significantly lower in patients with β2-microglobulin higher than 3.5 mg/L or with disease progression or death. With the cut-off determined by receiver operating characteristic (ROC) curve analysis, optimizing concordance with immunoglobulin heavy chain (IgVH) mutation status, miR-29c negative and positive groups were defined as including 17 and 36 patients, respectively. The miR-29c negative group had a higher percentage of patients with trisomy 12 or deletion of 11q or 17p (70.6% vs. 34.3%; p = 0.014) compared to the miR-29c positive group. The median progression-free survival and overall survival of the miR-29c negative group were 21 and 92 months, respectively, significantly shorter than in the miR-29c positive group (both not reached; p = 0.002 and p = 0.042, respectively), and miR-29c down-regulation was an independent prognostic factor for PFS. In conclusion, down-regulation of miR-29c is associated with higher tumor burden and significantly predicts short survival in Chinese patients with CLL.

MicroRNA-15a/16-1 cluster located at chromosome 13q14 is down-regulated but displays different expression pattern and prognostic significance in multiple myeloma

MiRNA-15a/16-1 cluster located at chromosome 13q14 has been confirmed to regulate critical genes associated with cell proliferation, apoptosis and drug resistance in multiple myeloma (MM). However, little is known about their expression pattern and prognostic value in MM patients. In this study, we have analyzed the expression levels of miR-15a/16-1 in 117 MM patients (90 newly diagnosed, 11 relapsed and 16 remission patients) and 19 health donors (HDs) by quantitative real-time PCR. Our results indicated that the expression levels of miR-15a and 16-1 were down-regulated in newly diagnosed MM patients as compared to HDs (P = 0.025; P < 0.001) and independent of del(13q14). Downregulation of miR-15a was significantly associated with disease progression and poor prognosis while miR-16-1 seemed to be a good diagnostic marker to distinguish MM from HDs with area under the curve (AUC) of 0.864, sensitivity of 100% and specificity of 73%. Furthermore, patients with miR-15a < 2.35 (low expression group) had significantly shorter PFS (P < 0.001) and OS (P < 0.001). After adjustment of the established prognostic variables including del(13q), del(17p), amp(1q21) and high risk genetic abnormality, low miR-15a expression (<2.35) was still a powerful independent predictor for PFS (P = 0.008) and OS (P = 0.038). In addition, miR-15a combined with high β2-MG and high risk genetic abnormality can further identify the high-risk subpopulations. Therefore, our data suggest that the expression patterns of miR-15a/16-1 are different in MM patients, and miR-15a seems to be linked with disease progression and prognosis while miR-16-1 acts as a valuable diagnostic marker.

Mutations or copy number losses of CD58 and TP53 genes in diffuse large B cell lymphoma are independent unfavorable prognostic factors

The advent of next generation sequencing (NGS) technologies has expedited the discovery of novel genetic lesions in DLBCL. The prognostic significance of these identified gene mutations is largely unknown. In this study, we performed NGS for the 27 genes most frequently implicated in 196 patients. Interestingly, TP53 mutations were found to be significantly more common in DLBCL with MYC translocations (r = 0.446, P = 0.034). While no gene mutation was found to be more prevalent in patients with DLBCL with bone marrow involvement, MYD88 mutations were more common in primary DLBCL of the CNS or testis. To evaluate the prognostic significance of the abnormalities of these 27 genes, a total of 165 patients with newly diagnosed DLBCL, NOS were included in a multivariate survival analysis. Surprisingly, in addition to the TP53 mutation, CD58 mutation was found to predict poor clinical outcome. Furthermore, copy number loss of CD58 or TP53 was also identified to be an independent negative prognostic factor. Our results have uncovered the previously unknown critical impact of gene mutations on the prognosis of DLBCL and are fundamentally important for the future design of tailored therapy for improved clinical outcomes.

High incidence of MYC and BCL2 abnormalities in mantle cell lymphoma, although only MYC abnormality predicts poor survival

The incidence and prognostic role of MYC and BCL2 rearrangements in mature B-cell lymphomas have been extensively studied, except the infrequent mantle cell lymphoma (MCL). Here, we analyzed the MYC and BCL2 abnormalities and other cytogenetic aberrations by fluorescence in situ hybridization (FISH) in 50 MCL patients with bone marrow involvement. Eighteen patients (36.0%) had MYC gains and/or amplifications, and twelve patients (24.0%) had BCL2 gains and/or amplifications. Among the 18 patients with MYC abnormality, four had simultaneous MYC translocations, but no BCL2 translocation was detected among patients with BCL2 abnormality. Only two patients (4.0%) had both MYC and BCL2 abnormalities. The patients with a MYC abnormality had a significantly higher tumor burden, a higher percentage of medium/high risk MIPI group and genomic instability compared to those without this abnormality. However, no significant difference was observed between patients with or without a BCL2 abnormality in terms of clinical and cytogenetic factors. Patients with a MYC abnormality had poorer progress-free survival (PFS) (9.0 vs. 48.0 months, p = .000) and overall survival (OS) (12.0 vs. 94.5 months, p = .000), but the presence of a BCL2 abnormality did not significantly influence either PFS or OS. In multivariate analysis, the MYC abnormality was the independent adverse factor for both PFS and OS, and intensive chemotherapy did not improve the outcome of these patients. Thus, the presence of a MYC but not BCL2 abnormality predicted the poor survival of MCL patients, and a new treatment strategy should be developed for these patients.

Comparison Among Immunologically Different Subtypes of 595 Untreated Multiple Myeloma Patients in Northern China

BACKGROUND Generally, characteristics of heterogeneous multiple myeloma (MM) have been described as a whole. Actually, isolated immunologic subtypes of MM may be associated with prognostic significance. PATIENTS AND METHODS The aim of this retrospective single-center study was to determine the characteristics of immunologically different subtypes among 595 evaluable cases with previously untreated MM in northern China. RESULTS The major distribution of MM subtypes were immunoglobulin (Ig)G, 47.9%; IgA, 23.3%; and light-chain, 21.0%. Nonsecretory, IgD, and biclonal subtypes were rarely seen, comprising only 7.7%. The male-to-female ratio was 1:7, and the median age was 59 years. In the IgG subtype, more patients presented with elevated M protein, fulfilling the major diagnostic criteria determined by Durie, and infection occurred more frequently; however, the prognosis was favorable. In the IgA subtype, in which survival was significantly poorer, the extent of anemia was more severe, and nonhyperdiploid abnormality may be its adverse indicator. In the light-chain subtype, the mean level of serum IL-6 was the highest, and more patients presented with advanced renal dysfunction, bone destruction, and thrombocytopenia. However, more light-chain patients were staged at International Staging System I, partially resulting in the favorable median survival of 51 months (almost equivalent to 50 months with the IgG subtype). Another rare subtype with unfavorable outcome was IgD myeloma, in which the median age was 50 years, and the serum calcium level was significantly decreased. Intriguingly, we also noted that more patients presented hypocalcemia than hypercalcemia (37.7% vs. 15.7%) in the current series. Multivariate analysis revealed that independent adverse indicators included age > 50 years, Durie-Salmon stage III, and increased values of C-reactive protein and beta2-microglobulin. CONCLUSION The median duration of survival in MM reached 36.0 months. Distinctions among immunologically different subtypes can predict prognostic significance, namely, favorable in IgG and light-chain subtypes but significantly poorer in IgA and IgD subtypes.

The Significance of Bone Marrow Involvement in Aggressive Lymphomas: A Retrospective Comparison of Clinical Outcomes between Peripheral T Cell Lymphoma and Diffuse Large B Cell Lymphoma in China

Background: Peripheral T cell lymphomas (PTCL) have been demonstrated to have a poorer prognosis than diffuse large B cell lymphoma (DLBCL) due to a high frequency of bone marrow involvement (BMI). However, the clinical characteristics of PTCL with BMI have not been fully described, and the clinical outcomes of PTCL with BMI and DLBCL with BMI have not been well compared. Methods: The clinical characteristics and survival of 25 nodal PTCL cases with BMI and 42 DLBCL cases with BMI were compared. Results: Most of the PTCL patients with BMI had lymphadenopathy (88%), B symptoms (76%), an elevated LDH level (68%), anemia (64%), splenomegaly (60%), and a poor performance status (52%). Except for the differences of lymphadenopathy and thrombocytopenia between PTCL with BMI and DLBCL with BMI, similarities in gender, age, hepatomegaly, splenomegaly, a bulky mass, B symptoms, elevated LDH, ≧2 extranodal sites, ECOG scores ≧2, anemia, and international prognostic index (IPI) and age-adjusted IPI scores were observed between the 2 groups. The 2 groups also had similar 3-year overall survival (25.8 vs. 30.0%, p = 0.846) and progressive-free survival (21.3 vs. 25.2%, p = 0.815) rates. Conclusions: PTCL with BMI have a similar aggressive course and poor survival compared to DLBCL with BMI. Thus, the immunophenotype of either T or B lineage may not be a crucial prognostic indicator of survival for these 2 aggressive lymphomas.

Downregulated miR-33b is a novel predictor associated with disease progression and poor prognosis in multiple myeloma

MiRNAs located at chromosome fragile sites play important roles in regulating critical genes associated with myeloma pathogenesis, disease progression and drug resistance. Our previous results have identified miR-33b (located in chromosome 17p) was one of the dysregulated miRNAs in the sera of newly diagnosed MM patients. However, little is known about its expression pattern in myeloma tumor cells and its prognostic value in MM patients. In the present study, we investigated the expression pattern of miR-33b in 58 newly diagnosed, 11 relapsed, 12 remission MM patients and 18 health donors by quantitative real-time PCR. Our results showed the expression of miR-33b was obviously down-regulated in newly diagnosed and relapsed MM patients compared to remission patients and health donors (p<0.001). Moreover, patients with del(13q), del(17p), t(4;14) and high-risk genetic abnormalities have lower expression levels of miR-33b compared to patients without those of abnormalities (p=0.032, 0.018, 0.034, 0.005). Survival analysis showed patients with miR-33b low expression had significantly shortened PFS (p=0.016) and OS (p=0.033) and might be associated with drug resistance to bortezomib-based treatment. Our data suggest that down-regulated miR-33b might be a novel predictor associated with disease progression and poor prognosis in MM.