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| Status |
Public on Nov 15, 2019 |
| Title |
Prognostic implications of 5-hydroxymethylcytosines from circulating cell-free DNA in diffuse large B-cell lymphoma |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by high throughput sequencing
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| Summary |
Elevated level of circulating cell-free DNA (cfDNA) has been associated with poor prognosis and relapse in patients with diffuse large B-cell lymphoma (DLBCL), but the tumor-specific molecular alterations in cfDNA with prognostic significance remain unclear. We investigated the association between 5-hydroxymethylcytosines (5hmC), a mark of active demethylation and gene activation, in cfDNA from blood plasma and prognosis in DLBCL. We used the 5hmC-Seal, a highly sensitive chemical labeling technique, to profile genome-wide 5hmC in plasma cfDNA samples from 48 newly diagnosed patients with DLBCL at the University of Chicago between 2010 and 2012. Patients were followed through December 31, 2017. We found a distinct genomic distribution of 5hmC in cfDNA marking tissue-specific enhancers, consistent with their potential roles in gene regulation. The 5hmC profiles in cfDNA differed by cell-of-origin, and were associated with clinical prognostic features including Ann Arbor stage, serum lactate dehydrogenase (LDH) level, and the International Prognostic Index (IPI). We developed a 29 gene-based weighted prognostic score (wp-score) for predicting event-free survival (EFS) and overall survival (OS), by applying the elastic net regularization on the Cox proportional hazard model. The wp-scores showed significantly improved prognostic accuracy and/or sensitivity/specificity than the established prognostic factors. In multivariate Cox models, patients with high wp-scores were associated with worse event-free survival (Hazard Ratio [HR] = 9.17, 95% confidence interval [CI] = 2.01- 41.89, p = 0.004), compared with those in the low risk group. Our findings suggest that the 5hmC signatures in cfDNA at the time of diagnosis are associated with clinical outcomes in DLBCL and may provide a novel non-invasive prognostic approach for DLBCL.
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| Overall design |
We used the 5hmC-Seal, a highly sensitive chemical labeling technique, to profile genome-wide 5hmC in plasma cfDNA samples from 48 newly diagnosed patients with DLBCL at the University of Chicago between 2010 and 2012. Patients were followed through December 31, 2017. We found a distinct genomic distribution of 5hmC in cfDNA marking tissue-specific enhancers, consistent with their potential roles in gene regulation. The 5hmC profiles in cfDNA differed by cell-of-origin, and were associated with clinical prognostic features including Ann Arbor stage, serum lactate dehydrogenase (LDH) level, and the International Prognostic Index (IPI). We developed a 29 gene-based weighted prognostic score (wp-score) for predicting event-free survival (EFS) and overall survival (OS), by applying the elastic net regularization on the Cox proportional hazard model. The wp-scores showed significantly improved prognostic accuracy and/or sensitivity/specificity than the established prognostic factors. In multivariate Cox models, patients with high wp-scores were associated with worse event-free survival (Hazard Ratio [HR] = 9.17, 95% confidence interval [CI] = 2.01- 41.89, p = 0.004), compared with those in the low risk group. Our findings suggest that the 5hmC signatures in cfDNA at the time of diagnosis are associated with clinical outcomes in DLBCL and may provide a novel non-invasive prognostic approach for DLBCL.
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| Contributor(s) |
Zhang W, Chiu BC, Zhang Z, You Q, Zeng C, Stepniak E, Bracci PM, Venkataraman G, He C, Smith SM |
| Citation(s) |
31570490 |
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| Submission date |
Feb 17, 2019 |
| Last update date |
Nov 17, 2019 |
| Contact name |
Wei Zhang |
| E-mail(s) |
wei.zhang1@northwestern.edu
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| Organization name |
Northwestern University
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| Department |
Preventive Medicine
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| Street address |
680 N Lake Shore Drive, Suite 1400
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| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60611 |
| Country |
USA |
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| Platforms (1) |
| GPL18573 |
Illumina NextSeq 500 (Homo sapiens) |
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| Samples (46)
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| Relations |
| BioProject |
PRJNA522918 |
| SRA |
SRP186129 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE126676_DLBCL_Count_Matrix.csv.gz |
1.2 Mb |
(ftp)(http) |
CSV |
| GSE126676_Sample.Info.xlsx |
13.5 Kb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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