WBP2NL – Breast Cancer

WBP2NL (HGNC:28389) has been implicated in modulating tamoxifen metabolism in breast cancer (MONDO_0007254) through several genome‑wide association studies. Two independent studies, one with 287 breast cancer patients (PMID:31344832) and another with 608 patients (PMID:38501904), have identified significant associations between variants in WBP2NL and sub‑threshold (Z)-endoxifen plasma levels, a key surrogate marker for tamoxifen efficacy.

In the first study, the most robust association was observed with SNP rs8138080 in WBP2NL, which emerged as the strongest predictor in a model that also considered other non‑CYP2D6 components. This finding was supported by multivariate regression that demonstrated an improved predictive accuracy for impaired tamoxifen metabolism when combining this SNP with CYP2D6 genotype information (PMID:31344832).

The second study further corroborated these observations by identifying a cluster of 430 variants within the WBP2NL region that were significantly associated with endoxifen serum concentrations. The study also highlighted that these variants were in strong linkage disequilibrium with CYP2D6, underscoring the complexity of the genetic architecture influencing tamoxifen metabolism (PMID:38501904).

Although no specific HGVS‑formatted coding variant was reported in these studies, the aggregate GWAS signals provide compelling genetic evidence that WBP2NL contributes to the variability in tamoxifen metabolism, thereby indirectly impacting breast cancer treatment responses.

Functional evidence remains limited as direct experimental assays, such as in vitro or in vivo functional studies on WBP2NL, have not been provided. Current data rely predominantly on statistical associations, and while these findings are robust across independent cohorts, the mechanistic underpinnings of how WBP2NL variations affect tamoxifen metabolism have not been fully established.

In conclusion, the integration of genetic evidence from two independent cohorts supports a moderate association between WBP2NL and breast cancer, particularly through its influence on tamoxifen metabolism. This association, while not yet bolstered by direct functional studies, holds promise for enhancing risk prediction models and therapeutic strategies in breast cancer management.

References

• Journal of clinical medicine • 2019 • Non‑CYP2D6 Variants Selected by a GWAS Improve the Prediction of Impaired Tamoxifen Metabolism in Patients with Breast Cancer PMID:31344832
• Clinical pharmacology and therapeutics • 2024 • A Genome‑Wide Association Study of Endoxifen Serum Concentrations and Adjuvant Tamoxifen Efficacy in Early‑Stage Breast Cancer Patients. PMID:38501904

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