Polymorphisms in the Hyaluronan Synthase 1 Gene May Be Predisposing Factors for Waldenstrom’s Macroglobulinemia.
Bibliographic record
Abstract
Abstract The hyaluronan synthase 1 gene (HAS1), which maps to chromosome location 19q13.4 encodes a plasma membrane protein, which synthesizes hyaluronan (HA), an extracellular matrix molecule. Previously, in WM patients we detected up-regulation of HAS1 transcripts and identified aberrant splice variants of this gene, termed HAS1Va, Vb, and Vc. In patients with multiple myeloma, expression of HAS1Vb either alone or in combination with HAS1 and other variants strongly correlates with poor survival (P=0.001). Our gene expression analysis of the HAS1 family members demonstrated that 76–97% of individual CD20+ IgM+ WM cells obtained from BM aspirates and from blood (PBMC) express HAS1Va or HAS1Vb aberrant splice variants, often in the absence of full length HAS1 transcripts. Aberrant splicing of HAS1 is the result of activation of cryptic splice sites, which lead to exon skipping and/or intron retention. In turn, activation of cryptic donor and acceptor splice sites of the gene can be promoted by the mutations occurring upstream of these sites and/or at the branch point of slicing. We measured the frequency of a known polymorphism in the HAS1 gene of 16 BM and 30 PB samples obtained from WM patients, in comparison with PBMC samples from 33 healthy donors. Our results indicate that in healthy individuals, the frequency of the two alleles each reached 50% perhaps reflecting stabilizing selection. The majority of healthy donors (61%) are heterozygous for the HAS1 gene polymorphism. In contrast, 92% of analyzed WM patients are homozygous for this same polymorphism. An expression analysis of HAS1 and variants in BM cells and PBMC obtained from the same group of WM patients demonstrated that only those patients who were homozygous for the HAS1 polymorphism express HAS1 and/or its variants. The few WM patients who are heterozygous for this polymorphism have no detectable expression of aberrantly spliced HAS1 variants or full length of HAS1, a phenotype identical to that of healthy donors. Thus, our observations so far suggest that polymorphisms in HAS1 may contribute to aberrations such as exon skipping and/or activation of a new cryptic splice site leading to aberrant splicing of HAS. Based on the results obtained thus far, we speculate that individuals who are homozygous for HAS1 polymorphism(s) are at enhanced risk of developing WM due to a predisposition towards aberrant HAS1 splicing and expression of HAS1 variants, with predicted oncogenic consequences. However, the study of a much larger number of patients and healthy donors is needed to confirm these speculations and to evaluate the prognostic significance of these findings.
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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) | 0.001 | 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 | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 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".