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Prediction and characterization of dlbcl cell of origin subtypes

A technology of B cells and cells, applied in the field of prediction and characterization of cell subtypes of DLBCL origin, which can solve problems such as different histories of precursor cells

Pending Publication Date: 2021-05-07
GENENTECH INC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although previous reports did not identify differences in mutational signatures between subtypes, it is hypothesized that there are differences in mutational signatures between GCB and ABC tumors and that these differences are likely the result of different precursor cell histories

Method used

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  • Prediction and characterization of dlbcl cell of origin subtypes
  • Prediction and characterization of dlbcl cell of origin subtypes
  • Prediction and characterization of dlbcl cell of origin subtypes

Examples

Experimental program
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Effect test

example 1

[0047] Example 1: Sample

[0048] Clinical and genomic data are available from patients treated in the following trials: GOYA clinical trial (NCT01287741; R-CHOP and G-CHOP) (Vitolo, U. et al., Obinutuzumab or Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in PreviouslyUntreated Diffuse Large B Cell Lymphoma. Journal of Clinical Oncology 35, 3529-3537 (2017)), and the MAIN clinical trial (NCT00486759; R-CHOP+ / -Bevacizumab) (Seymour, J.F. et al., R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B Cell lymphoma: final MAIN study outcomes. Haematologica 99, 1343-1349 (2014)). The protocols of the original trials were approved by local or national ethics committees according to the laws of the respective countries, and the studies were performed in accordance with the Declaration of Helsinki. Activated B-cell (ABC) / germinal center B-cell (GCB) / unclassified DLBCL prognostic subtypes were determined by Nanostring as...

example 2

[0049] Example 2: DNA Sequencing

[0050] use The DNA component of the platform sequenced all samples and included targeted DNA sequencing of approximately 465 genes as described in: He, J. et al., Integrated genomicDNA / RNA profiling of hematologic malignancies in the clinical setting . Blood 127, 3004-3014 (2016). In addition to validated short variants, copy number alterations (advanced amplifications and deep deletions), rearrangements, tumor mutational burden (TMB), and microsatellite instability (MSI) status, studies using only platform signatures were utilized , including chromosome arm-level copy number and loss of heterozygosity (LOH) metrics.

example 3

[0051] Example 3: Machine Learning

[0052]The COODC model was developed using penalized Lasso regression using 25-fold internal cross-validation implemented from the glmnet package (version 2.0-10) in R version 3.3.2 and using RStudio version 1.0.136. The 482 GOYA samples with Nanostring data were divided into training set (70% of samples) and validation set (30% of samples). The initial training set is further refined by removing Nanostring unclassified samples so that the training focuses on ABC or GCB detection. 296 samples are used for the final training set, while 139 samples are used for the validation set. 592 features are used in the model. z-scores continuous features to maintain a consistent scale between continuous and binary features. The final COODC model includes 74 non-zero features (Table 1). The per-sample probabilities extracted from the model are used to determine ideal cutoffs. Generate ROC curve ( Figure 1A and 1B ), and choose the "best" cutoff ...

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Abstract

Provided are methods of determining cell of origin (COO) for diffuse large B Cell lymphoma (DLBCL) using DNA for the analysis. The methods include identification of DLBCL COO as activated B Cell (ABC) and germinal center B Cell (GCB).

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 713,434, filed August 1, 2018, the contents of which are incorporated herein by reference in their entirety. Background technique [0003] Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, with more than 25,000 new cases reported each year in the United States (R., T.L. et al., 2016 US lymphoid malignancy statistics by WorldHealth Organization subtypes. CA: A Cancer Journal for Clinicians 66, 443-459 (2016)). The prognosis of DLBCL patients is quite good, with a five-year survival rate between 55% and 62% (R., T.L. et al., 2016 US lymphoid malignancy statistics by World Health Organization subtypes. CA: ACancer Journal for Clinicians 66, 443-459 (2016)). However, relapsed patients and those who initially do not respond to standard of care remain limited options, mainly consisting of autologo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886
CPCC12Q2600/118C12Q2600/112C12Q2600/158C12Q1/6886G16H50/30G16H50/20C12Q1/6806
Inventor S·E·特拉布科C·R·伯伦M·Z·奥斯特加德E·S·索科尔L·A·奥尔巴克
Owner GENENTECH INC
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