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Identification and validation of a two-gene expression index for subtype classification and prognosis in Diffuse Large B-Cell Lymphoma.

Xu Q, Tan C, Ni S, Wang Q, Wu F, Liu F, Ye X, Meng X, Sheng W, Du X - Sci Rep (2015)

Bottom Line: Using a training set of 350 patients, we identified a two-gene expression signature, "LIMD1-MYBL1 Index", which is significantly associated with cell-of-origin subtypes and clinical outcome.Furthermore, the performance of LIMD1-MYBL1 Index was satisfactory compared with common immunohistochemical algorithms.Our results might prompt the further development of this two-gene index to a simple assay amenable to routine clinical practice.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [2] Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China [3] Institute of Pathology, Fudan University, Shanghai, China [4] Fudan University Shanghai Cancer Center - Institut Mérieux Laboratory, Shanghai, China [5] bioMérieux (Shanghai) Company Limited, Shanghai, China.

ABSTRACT
The division of diffuse large B-cell lymphoma (DLBCL) into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes based on gene expression profiling has proved to be a landmark in understanding the pathogenesis of the disease. This study aims to identify a novel biomarker to facilitate the translation of research into clinical practice. Using a training set of 350 patients, we identified a two-gene expression signature, "LIMD1-MYBL1 Index", which is significantly associated with cell-of-origin subtypes and clinical outcome. This two-gene index was further validated in two additional dataset. Tested against the gold standard method, the LIMD1-MYBL1 Index achieved 81% sensitivity, 89% specificity for ABC group and 81% sensitivity, 87% specificity for GCB group. The ABC group had significantly worse overall survival than the GCB group (hazard ratio = 3.5, P = 0.01). Furthermore, the performance of LIMD1-MYBL1 Index was satisfactory compared with common immunohistochemical algorithms. Thus, the LIMD1-MYBL1 Index had considerable clinical value for DLBCL subtype classification and prognosis. Our results might prompt the further development of this two-gene index to a simple assay amenable to routine clinical practice.

No MeSH data available.


Related in: MedlinePlus

The LIMD1-MYBL1 Index was significantly associated with COO subtypes and clinical outcomes in DLBCL-1(a) The gene MYBL1 (v-myb myeloblastosis viral oncogene homolog (avian)-like 1) was highly expressed in GCB subtype compared with ABC subtype (P = 1.5E-64). (b) The gene LIMD1 (LIM domains containing 1) was significantly over-expressed in ABC subtype compared with GCB subtype (P = 5.7E-58). (c) For each patient, a Bayesian probability score was estimated. A sample is classified as ABC or GCB subtype if the probability that it belongs to the ABC or GCB subgroup is greater than 80%; otherwise it is considered as unclassified subtype. (d) The Kaplan-Meier estimates of overall survival for 350 patients classified by the LIMD1-MYBL1 Index. GCB group had significantly higher overall survival rates compared with ABC group (P < 0.001).
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f1: The LIMD1-MYBL1 Index was significantly associated with COO subtypes and clinical outcomes in DLBCL-1(a) The gene MYBL1 (v-myb myeloblastosis viral oncogene homolog (avian)-like 1) was highly expressed in GCB subtype compared with ABC subtype (P = 1.5E-64). (b) The gene LIMD1 (LIM domains containing 1) was significantly over-expressed in ABC subtype compared with GCB subtype (P = 5.7E-58). (c) For each patient, a Bayesian probability score was estimated. A sample is classified as ABC or GCB subtype if the probability that it belongs to the ABC or GCB subgroup is greater than 80%; otherwise it is considered as unclassified subtype. (d) The Kaplan-Meier estimates of overall survival for 350 patients classified by the LIMD1-MYBL1 Index. GCB group had significantly higher overall survival rates compared with ABC group (P < 0.001).

Mentions: The DLBCL-1 cohort included 167 ABC and 183 GCB DLBCL patients according to the gold standard method described by Wright et al.5. We performed a two-class unpaired t-test to select genes that were differentially expressed between ABC and GCB subgroups, and then ranked the genes in descending order according to their statistical significance. The top two probesets were particularly interesting. One probeset, “213906_at”, which targets the gene MYBL1 (v-myb myeloblastosis viral oncogene homolog (avian)-like 1), exhibited a 10-fold higher expression level in the GCB group compared with the ABC group (P = 1.5E-64; Fig. 1a). Sensitivity versus 1-specificity was plotted to construct a Receiver Operating Characteristic (ROC) curve, and a good discrimination between the two groups was observed, with an Area Under Curve (AUC) of 0.93. In sharp contrast, the probeset “222762_x_at”, targeting the gene LIMD1 (LIM domains containing 1), was significantly over-expressed in the ABC group compared with the GCB group (P = 5.7E-58; Fig. 1b). The discriminatory power measured by the AUC was 0.94.


Identification and validation of a two-gene expression index for subtype classification and prognosis in Diffuse Large B-Cell Lymphoma.

Xu Q, Tan C, Ni S, Wang Q, Wu F, Liu F, Ye X, Meng X, Sheng W, Du X - Sci Rep (2015)

The LIMD1-MYBL1 Index was significantly associated with COO subtypes and clinical outcomes in DLBCL-1(a) The gene MYBL1 (v-myb myeloblastosis viral oncogene homolog (avian)-like 1) was highly expressed in GCB subtype compared with ABC subtype (P = 1.5E-64). (b) The gene LIMD1 (LIM domains containing 1) was significantly over-expressed in ABC subtype compared with GCB subtype (P = 5.7E-58). (c) For each patient, a Bayesian probability score was estimated. A sample is classified as ABC or GCB subtype if the probability that it belongs to the ABC or GCB subgroup is greater than 80%; otherwise it is considered as unclassified subtype. (d) The Kaplan-Meier estimates of overall survival for 350 patients classified by the LIMD1-MYBL1 Index. GCB group had significantly higher overall survival rates compared with ABC group (P < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4419520&req=5

f1: The LIMD1-MYBL1 Index was significantly associated with COO subtypes and clinical outcomes in DLBCL-1(a) The gene MYBL1 (v-myb myeloblastosis viral oncogene homolog (avian)-like 1) was highly expressed in GCB subtype compared with ABC subtype (P = 1.5E-64). (b) The gene LIMD1 (LIM domains containing 1) was significantly over-expressed in ABC subtype compared with GCB subtype (P = 5.7E-58). (c) For each patient, a Bayesian probability score was estimated. A sample is classified as ABC or GCB subtype if the probability that it belongs to the ABC or GCB subgroup is greater than 80%; otherwise it is considered as unclassified subtype. (d) The Kaplan-Meier estimates of overall survival for 350 patients classified by the LIMD1-MYBL1 Index. GCB group had significantly higher overall survival rates compared with ABC group (P < 0.001).
Mentions: The DLBCL-1 cohort included 167 ABC and 183 GCB DLBCL patients according to the gold standard method described by Wright et al.5. We performed a two-class unpaired t-test to select genes that were differentially expressed between ABC and GCB subgroups, and then ranked the genes in descending order according to their statistical significance. The top two probesets were particularly interesting. One probeset, “213906_at”, which targets the gene MYBL1 (v-myb myeloblastosis viral oncogene homolog (avian)-like 1), exhibited a 10-fold higher expression level in the GCB group compared with the ABC group (P = 1.5E-64; Fig. 1a). Sensitivity versus 1-specificity was plotted to construct a Receiver Operating Characteristic (ROC) curve, and a good discrimination between the two groups was observed, with an Area Under Curve (AUC) of 0.93. In sharp contrast, the probeset “222762_x_at”, targeting the gene LIMD1 (LIM domains containing 1), was significantly over-expressed in the ABC group compared with the GCB group (P = 5.7E-58; Fig. 1b). The discriminatory power measured by the AUC was 0.94.

Bottom Line: Using a training set of 350 patients, we identified a two-gene expression signature, "LIMD1-MYBL1 Index", which is significantly associated with cell-of-origin subtypes and clinical outcome.Furthermore, the performance of LIMD1-MYBL1 Index was satisfactory compared with common immunohistochemical algorithms.Our results might prompt the further development of this two-gene index to a simple assay amenable to routine clinical practice.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China [2] Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China [3] Institute of Pathology, Fudan University, Shanghai, China [4] Fudan University Shanghai Cancer Center - Institut Mérieux Laboratory, Shanghai, China [5] bioMérieux (Shanghai) Company Limited, Shanghai, China.

ABSTRACT
The division of diffuse large B-cell lymphoma (DLBCL) into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes based on gene expression profiling has proved to be a landmark in understanding the pathogenesis of the disease. This study aims to identify a novel biomarker to facilitate the translation of research into clinical practice. Using a training set of 350 patients, we identified a two-gene expression signature, "LIMD1-MYBL1 Index", which is significantly associated with cell-of-origin subtypes and clinical outcome. This two-gene index was further validated in two additional dataset. Tested against the gold standard method, the LIMD1-MYBL1 Index achieved 81% sensitivity, 89% specificity for ABC group and 81% sensitivity, 87% specificity for GCB group. The ABC group had significantly worse overall survival than the GCB group (hazard ratio = 3.5, P = 0.01). Furthermore, the performance of LIMD1-MYBL1 Index was satisfactory compared with common immunohistochemical algorithms. Thus, the LIMD1-MYBL1 Index had considerable clinical value for DLBCL subtype classification and prognosis. Our results might prompt the further development of this two-gene index to a simple assay amenable to routine clinical practice.

No MeSH data available.


Related in: MedlinePlus