LINE‐1 hypomethylation is inversely associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer
Bibliographic record
Abstract
The CpG island methylator phenotype (CIMP) with widespread promoter CpG island methylation is a phenotype in colorectal cancer, associated with microsatellite instability (MSI) and BRAF mutation. Genome-wide hypomethylation may also play an important role in genomic instability. However, the relation between global DNA methylation level and methylation in individual CpG islands remains uncertain. Utilizing 869 population-based colorectal cancers, we measured long interspersed nucleotide element-1 (LINE-1) methylation level by Pyrosequencing, which correlates with global DNA methylation level. We quantified DNA methylation in 8 CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) by real-time PCR (MethyLight technology). LINE-1 methylation levels in tumors were approximately normally distributed (mean, 61.4%; median, 62.3%; standard deviation, 9.6%). Among the 869 tumors, 128 (15%) were classified as CIMP-high (>or=6/8 methylated promoters). The mean LINE-1 methylation level was higher in CIMP-high tumors (65.1%, p < 0.0001) than non-CIMP-high tumors (60.7%), and higher in MSI-high tumors (64.7%, p < 0.0001) than non-MSI-high tumors (60.7%). When tumors were stratified by MSI/CIMP status, compared to non-MSI-high non-CIMP-high tumors (mean LINE-1 methylation level, 60.4%), the mean LINE-1 methylation level was higher in MSI-high CIMP-high (64.8%, p < 0.0001), MSI-high non-CIMP-high (64.6%, p = 0.03) and non-MSI-high CIMP-high tumors (66.1%, p = 0.0003). In addition, 18q loss of heterozygosity in non-MSI-high tumors was correlated with LINE-1 hypomethylation (p = 0.004). In conclusion, both CIMP-high and MSI-high are inversely associated with LINE-1 hypomethylation, suggesting that CIMP/MSI and genomic hypomethylation may represent different pathways to colorectal cancer. Our data also support a possible link between global hypomethylation and chromosomal instability.
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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 | 0.000 |
| 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".