Functional promoter SNPs in TGFβ1 and the susceptibility to childhood leukemia
Bibliographic record
Abstract
AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 390 Transforming growth factor β1 (TGFβ1) controls proliferation, differentiation, and other cellular processes in a number of cell types. Not surprisingly, pathological deregulation of the TGFβ pathway has been implicated in the development of several major disease groups, including cancers. In keeping with this paradigm, we proposed that sequence variation in the promoter region of TGFβ1 could potentially lead to abnormal expression and variation in gene dosage, thereby predisposing carriers of such susceptibility variants to disease. Here we screened the proximal promoter region of TGFβ1 for single nucleotide polymorphisms (pSNPs) and performed in silico analysis and in vitro functional assays in conjunction with genetic association studies, in order to assess the functional impact of regulatory polymorphisms in TGFβ1 on the development of leukemia in children. Using denaturing high performance liquid chromatography we identified 4 pSNPs that were common in Europeans and that all lead to either a predicted gain and/or loss of putative transcription factor binding sites. When tested for differential binding by electrophoretic mobility shift assays, two of these pSNPs, -1886A>G and -1550DelAGG, showed differential allelic DNA-protein binding in at least one of the cell lines tested. From these common pSNPs we were able to construct 8 promoter haplotypes and following subcloning into a gene reporter system, we demonstrated that the two major promoter haplotypes significantly influenced transcriptional activity in an allele-specific manner. Moreover, a case-control study conducted in 258 acute lymphoblastic leukemia (ALL) patients and 277 healthy controls combined with a family-based analysis using 147 parental trios, all of European descent, was used to evaluate single site genotypic as well as multilocus haplotypic associations. Interestingly, the family-based association test revealed that the TGFβ1 low-expressing promoter haplotype was associated with an increased risk of ALL and was shown to be significantly over-transmitted to affected offspring ( P = 0.032). Although the biological significance of these observations remains to be elucidated, these findings suggest that the expected variability of TGFβ1 expression levels due to regulatory polymorphisms could indeed influence the risk of childhood leukemia and contribute to carcinogenesis.
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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) | 0.007 | 0.001 |
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".