Major Histocompatibility Class II (MHCII) and Germinal Center Associated Gene Expression Correlate with Overall Survival in Ritiximab and CHOP-Like Treated Diffuse Large B Cell Lymphoma (DLBCL) Patients Using Formalin Fixed Paraffin Embedded (FFPE) Tissues.
Bibliographic record
Abstract
Abstract Large studies using snap frozen tissue for gene expression profiling (GEP) have identified a limited number of genes predicting outcome in DLBCL treated with CHOP alone (17 genes from Rosenwald et al NEJM 2002, 13 from Shipp et al, Nat Med 2002, 6 from Lossos et al, NEJM 2004, 2 from Tome et al, Blood 2005). Our objective was to test the prognostic value of these genes (38 total, 36 different genes) using FFPE tissues and compare results from patients treated with CHOP or CHOP-like regimen alone (C) (N=93) to those treated with CHOP + rituximab (R) (N=101). We used a multiplexed quantitative nuclease protection assay, the ArrayPlate (High Throughput Genomics), to measure mRNA levels reliably in FFPE samples as recently described. (Roberts et al, Lab Invest, ePub, 13 Aug 2007). Of 194 cases attempted, there was only 1 that did not result in adequately detectable signal. Univariate associations between gene levels and patient OS were performed using Cox proportional hazard regression models. For C alone cases, gene expression levels were significantly correlated with overall survival (OS) at p < 0.05 for 15/36 prognostic genes including the MHCII genes HLA-DR and HLA-DP, as well as C-MYC, BCL-6, BCL-2 and ten other genes. These genes represented all 4 Rosenwald prognostic signatures, 3/6 of Lossos genes, and 4/13 Shipp genes. In the R-treated cases, 8/36 genes correlated with OS including HLA-DR and HLA-DQ, the germinal center B-cell (GCB) genes BCL-6, and SERPINA9 as well as C-MYC, PLAU, PDCD4, and MnSOD. Again, all 4 Rosenwald signatures were represented. In our assay, genes that represent key gene expression signatures previously identified as the most prognostically important in large discovery-oriented GEP experiments were significantly associated with patient OS using FFPE tissues and retained significance in the R-treated patients, suggesting that previous findings remain relevant in the R-CHOP era. For most genes in both treatment groups, the estimated hazard ratios tended in the direction originally predicted, suggesting these genes would be significantly related to survival in a larger, more powered study. Previous studies have relied on unfixed, snap-frozen tissues which are available only in a minority of patients for GEP or quantitative RT-PCR measurements of mRNA expression. The ArrayPlate assay can assess prognostic genes in patients for which only FFPE material is available, is highly correlated with discovery microarray results, and should be easily adaptable as more prognostic genes are identified. Importantly, previously identified prognostically important genes such as MHCII and GCB genes remain correlated with survival in the R-CHOP treatment era.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".