Association of HOXB13 G84E With Prostate Cancer Among 592,158 Men
Bibliographic record
Abstract
BACKGROUND: The HOXB13 c.G251G>A:p.G84E (rs138213197) variant is associated with an increased risk of prostate cancer (PrCa); however, its link to aggressive PrCa remains controversial. Limited data from large, population-based cohorts are available to inform genetic counseling and clarify the PrCa risk associated with this variant. PATIENTS AND METHODS: We identified individuals heterozygous for HOXB13 p.G84E or homozygous wild-type among 592,158 male participants in single nucleotide polymorphism genotyping data from the Veterans Health Administration (VA) Million Veteran Program (MVP). Individuals with PrCa were identified, and Cox proportional hazards models were used to estimate age-specific risk of developing PrCa. In a subset of patients who underwent their first prostate biopsy within the VA health system, a multivariable logistic regression model-adjusting for known PrCa risk factors-was used to assess PrCa risk. RESULTS: Of the MVP participants, 1,660 (0.3%) were heterozygous for HOXB13 p.G84E. Heterozygosity was significantly associated with risk of any PrCa (hazard ratio [HR], 3.17 [95% CI, 2.90-3.46]; P<2.0E-16), metastatic PrCa (HR, 2.99 [95% CI, 2.32-3.84]; P<2.0E-16), and PrCa-specific mortality (HR, 2.63 [95% CI, 1.66-4.19]; P=4.4E-05). In the subset of MVP participants who underwent prostate biopsy within the VA health system (n=36,321), a multivariable logistic regression model controlling for known PrCa risk factors showed that HOXB13 p.G84E heterozygotes had a higher risk of PrCa diagnosis (odds ratio, 2.60 [95% CI, 1.94-3.52]; P<.001). HOXB13 p.G84E heterozygotes were diagnosed with PrCa at a slightly younger age but had similar Gleason score distributions and comparable rates of de novo, any, and castration-resistant metastatic disease. CONCLUSIONS: In the largest cohort of men with the HOXB13 p.G84E variant studied to date, we demonstrate a moderately increased lifetime risk of PrCa. However, the PrCa that develops is not more aggressive, although it may occur at younger ages. Further research is warranted to determine whether early PrCa screening in HOXB13 p.G84E heterozygotes improves outcomes.
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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 | 0.001 |
| 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) | 0.000 | 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".