GPNMB methylation: a new marker of potentially carcinogenic colon lesions
Bibliographic record
Abstract
BACKGROUND: Epigenetic plays an important role in colorectal neoplasia process. There is a need to determine sound biomarkers of colorectal cancer (CRC) progression with clinical and therapeutic implications. Therefore, we aimed to examine the role and methylation status of Glyco Protein Non-Metastatic GPNM B (GPNMB) gene in normal, adenoma and CRC in African American (AA) patients. METHODS: The methylation status of 13 CpG sites (chr7: 23287345-23,287,426) in GPNMB gene's promoter, was analyzed by pyrosequencing in human CRC cell lines (HCT116, SW480, and HT29) and microdissected African American paraffin embedded samples (20 normal, 21 non-advanced adenoma (NA), 48 advanced adenoma (AD), and 20 cancer tissues. GPNMB expression was analyzed by immunohistochemistry (IHC) on tissue microarrays (TMA). Correlations between GPNMB methylation and expression with clinicopathological features were analyzed. GPNMB functional analysis was performed in triplicates using cell proliferation, migration and invasion assays in HCT116 colon cell line after stable transfection with a GPNMB-cDNA expression vector. RESULTS: GPNMB methylation was lower in normal mucosa compared to CRC samples (1/20 [5%] vs. 18/20 [90%]; P < 0.001). AD also had a significantly higher GPNMB methylation frequency than normal colon samples (42/48 [88%] vs 1/20 [5%]; P < 0.001). GPNMB was more frequently methylated in AD than in matched normal mucosa from three patients (3/3 [100%] vs 1/3 [33.3%]; P < 0.001). The frequency of GPNMB methylation in NA differed significantly from that in the normal mucosa (16/21 [76%] vs 1/20 [5%]; P = 0.008). There was statistically significant correlation of higher methylation at advanced stages and lower methylation at stage 1 CRCs (P < 0.05). In agreement with these findings, GPNMB protein expression decreased in CRC tissues compared with AD and NA colon mucosa (p < 0.05). GPNMB overexpression in HCT116 colon cancer cell line decreased cell proliferation [(24 h, P = 0.02), (48 h, P < 0.001, 72 h, P = 0.007)], invasion (p < 0.05) and migration (p > 0.05) compared to the mock-transfected cells. CONCLUSION: Our data indicate a high methylation profile leading to a lower GPNMB expression in adenoma and CRC samples. The functional analysis established GPNMB as a potential tumor suppressor gene. As such, GPNMB might be useful as a biomarker of adenomas with high carcinogenic potential.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| 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) | 0.000 | 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 teacher head, 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".