Association of <i>isocitrate dehydorgenase-1</i> (<i>IDH-1</i>) mutations with elevated oncometabolite 2-hydroxyglutarate (2HG) in advanced colorectal cancer.
Bibliographic record
Abstract
627 Background: IDH-1 mutations are common in AML, gliomas, and intrahepatic cholangiocarcinoma. The enzyme product of the IDH-1 R132 variant preferentially catalyzes the NADPH-dependent reduction of alpha-ketoglutarate to the oncometabolite R-2-Hydroxyglutarate (R-2HG), resulting in accumulation of R-2HG, relative to its enantiomer, S-2HG. Elevated plasma levels of 2HG and/or higher ratios of R/S have been observed in AML and intrahepatic cholangiocarinoma, but not in gliomas. Only a few cases of IDH-1/2 mutations have been reported in advanced colorectal cancers (CRC). We investigated plasma levels of 2HG and relative ratios of R/S in CRC patients harboring IDH-1/2mutations. Methods: Between 2012 and 2015, 428 patients with advanced CRC were molecularly profiled through the COMPACT and IMPACT programs at the Princess Margaret Cancer Centre. Tumor DNAs were isolated from FFPE archived samples and genotyped using a customized Sequenom panel or Illumina MiSeq TruSeq Amplicon Cancer Panel in a CLIA-certified laboratory. Plasma samples from patients harboring IDH-1/2mutations and 4 gender/age matched control patients were analyzed for 2HG, R-2HG and S-2HG using HPLC tandem mass spectrometry coupled with a CHIROBIOTIC R column. Results: Of 428 patients with advanced CRC, 4 (0.9%) patients were identified to harbor IDH-1 mutation. No IDH-2 mutations were detected. The variants identified were R132C (2 patients), R132S, and R132H. 3 of 4 patients also harbored KRAS mutations. Patients with IDH-1 mutations had higher levels of 2HG (319 ± 102 ng/ml vs 195 ± 43 ng/ml, p = 0.043). The ratio of R/S were 0.44, 0.75, 1.59, and 2.60 in 4 patients with IDH-1 mutations and 1.3, 0.90, 0.41 and 0.67 in 3 patients without IDH-1mutations. Conclusions: IDH-1 mutations are rare in advanced CRC. 3 of 4 patients in our study had concurrent KRAS mutations. Patients with IDH-1 mutations had higher levels of oncometabolite 2HG compared with controls with no difference in R/S ratio.
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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 | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".