HOXB13, a high-risk prostate cancer gene, also confers risk for breast cancer: novel variants of clinical significance, especially in hormone-positive patients

Germline mutations in high-risk genes, such as BRCA1 and BRCA2, are primarily responsible for inherited breast cancers, while mutations in moderate-risk genes also increase susceptibility. HOXB13 is established as a high-risk gene for prostate cancer (PCa), but few studies have explored its role in breast cancer. Here, we report, for the first time, novel HOXB13 variants identified in breast cancer patients, suggesting a potential association that warrants further investigation. This retrospective cohort study was conducted at the Medical Genetics Laboratory of Göztepe Prof. Dr. Süleyman Yalçın City Hospital, Turkey, between 2022 and 2025. A total of 4198 individuals who underwent hereditary cancer panel testing were screened. Targeted next-generation sequencing was performed using a Custom Hereditary Cancer (cHCS) panel on the Illumina NextSeq® platform. Raw sequencing data were analyzed using Dragen v3.6 and Sophia DDM pipelines. Among 4198 individuals, 1527 had a confirmed breast cancer diagnosis. Eleven patients harbored variants of uncertain significance (VUS) in HOXB13. Hormone-negative patients (n = 3) carried c.269del, c.766 T > C, and c.309_311del variants. Among hormone-positive patients (n = 8), two carried c.309_311del, one had c.404 G > A, and five carried c.728 A > G (p.K243R), the most frequent variant in this subgroup. The HOXB13 variant spectrum in the Turkish population differed from previously reported data. Novel HOXB13 variants, particularly c.728 A > G (p.K243R), may represent candidate variants of interest that require further validation before any clinical application. These findings highlight a potential association between HOXB13 variants and breast cancer, particularly in hormone receptor-positive patients, and emphasize the need for larger and functionally validated studies.