Common Variant in ALDH2 Modifies the Risk of Breast Cancer Among Carriers of the p.K3326* Variant in BRCA2
Bibliographic record
Abstract
PURPOSE The BRCA2 p.K3326* variant is considered a low-penetrance variant for breast cancer. Aldehydes that accumulate in cells under insufficient aldehyde oxidation were most recently shown to trigger carcinogenesis by promoting depletion of BRCA2 protein. Allele T of the common variant rs10744777 in the ALDH2 gene was associated with reduced expression of aldehyde dehydrogenase, the main enzyme in aldehyde oxidation. We hypothesized that this allele could modify breast cancer risk in women with the BRCA2 p.K3326* low-penetrance variant through reduced function of ALDH2, increased accumulation of cellular aldehydes, and depletion of BRCA2 protein. MATERIALS AND METHODS We genotyped 11,873 Polish women diagnosed with breast cancer and 7,615 ethnically matched controls for these two variants. Next, we extended our analysis of rs10744777 to 231 carriers of pathogenic BRCA2 mutations. RESULTS BRCA2 p.K3326* variant was associated with significant increase in breast cancer risk only in those who were homozygous for the T allele of the ALDH2 rs10744777 variant (odds ratio = 1.72; 95% CI, 1.19 to 2.48; P = .003). The BRCA2 p.K3326* variant did not increase the risk of breast cancer among those who were heterozygous or homozygous for the C allele of the ALDH2 rs10744777 variant (odds ratio = 1.05; 95% CI, 0.73 to 1.51; P = .81). In the carriers of high-risk BRCA2 mutations, the TT genotype of rs10744777 conferred a modest (18%) and not significant increase in breast cancer risk. CONCLUSION Our results suggest that BRCA2 p.K3326* variant, which is low-penetrance by itself, confers increased breast cancer risk on the background of the TT genotype of the ALDH2 rs10744777 variant in the Polish population.
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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 | 0.001 |
| 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) | 0.002 | 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".