Elucidating genetic events in human hepatocellular carcinoma
Bibliographic record
Abstract
e15590 Background: Hepatocellular carcinoma (HCC) is prevalent world wide with increasing incidence in North America. 4q is a commonly deleted region in HCC and is lost in 32% of premalignant cirrhotic nodules but the precise molecular lesion involved in tumor initiation remains unknown. Human Plk4, a member of the polo family of cell cycle regulating serine /threonine kinases is located on 4q28. Plk4 is a haploinsufficient tumor suppressor in mice, with 50% of animals developing spontaneous tumors, most commonly multifocal primary HCC. We hypothesize that Plk4 plays a role in the initiation of human HCC. Our purpose was to determine the levels of Plk4 in human HCC and investigate possible genetic interactions with the tumor suppressor p53. Methods: Formalin-fixed paraffin-embedded sections of human HCCs, adjacent non-neoplastic liver tissue and gallbladder tissue were microdissected. DNA was extracted and manual LOH analysis was performed. To asses Plk4 expression, RNA from the hepatoma cases was used for real time RT-PCR. To elucidate a genetic interaction, Plk4 p53 compound mutant mice were generated and murine embryonic fibroblasts (MEFs) were derived and cultured. Results: In HCC Plk4 LOH rates varied from 57% for the marker closest to Plk4 to 8% for the marker furthest away (n=32). Using an intragenic marker the rate of LOH was 45% (n=24). Studies in CRC (n=46) and pancreas cancer specimens (n=40) showed only background levels of LOH. Expression of Plk4 in HCC tumor samples that displayed LOH at the Plk4 locus was reduced compared to non-neoplastic liver. Plk4±p53−/− mice showed acceleration of tumor formation compared to Plk4+/+p53−/− mice. Plk4±p53−/− MEFs had increased levels multinucleation, centrosome amplification and aneuploidy compared to Plk4+/+p53−/− cells. In addition these cells were tumorigenic in vivo whereas Plk4+/+p53−/− cells were not. Conclusions: Our results demonstrate significant rates of LOH at the Plk4 locus specifically in human HCC and indicate that this is associated with decreased Plk4 expression. In addition, our studies of compound mutant mice suggest a possible genetic interaction of Plk4 and p53 in tumor development. No significant financial relationships to disclose.
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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 | 0.000 |
| 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) | 0.002 | 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".