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

Sep 22, 2026

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Germline mutations in high-risk genes such as BRCA1 and BRCA2 drive inherited breast cancer, while moderate-risk gene variants further increase susceptibility. HOXB13 is established for prostate cancer risk, but breast cancer evidence is limited. This retrospective cohort study screened 4198 individuals undergoing hereditary cancer panel testing (2022–2025) and identified novel HOXB13 variants in breast cancer patients, including a recurrent c.728A>G (p.K243R) in hormone-positive cases. Findings suggest an association requiring further validation.

LanguageEnglish

CategoryResearch & Report

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Pages6

Reading Time15 min

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Introduction

Genetic risk factors in breast cancer

HOX gene family and HOXB13 background

Rationale for investigating HOXB13 in breast cancer

[www.nature.com/jhg](www.nature.com/jhg) ARTICLE OPEN HOXB13, a high-risk prostate cancer gene, also confers risk for breast cancer: novel variants of clinical signiﬁcance, especially in hormone-positive patients Filiz Ozen 1, Zeynep Yegin 2 ✉ and Diyar Sayit 1 © The Author(s) 2026 | | | | | --- | --- | --- | | | 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. | | | | | Journal of Human Genetics (2026) 71:565–570; [https://doi.org/10.1038/s10038-026-01481-y](https://doi.org/10.1038/s10038-026-01481-y) | | | | | | INTRODUCTION Breast cancer is a complex disease with varying degrees of risk among women and genetic liability plays a signiﬁcant role in the etiology of the disease [1] . It is both the most commonly diagnosed and the second leading cause of cancer death among Western women. Risk ratios for breast cancer varies from 1 .80 for one affected relative to 3.90 for three or more affected relatives underpinning the potential effect of family history [2] . Several germline variants which explain approximately half of the total genetic heritability have been reported [3] . BRCA1 and BRCA2 which are the major breast cancer susceptibility genes were identiﬁed in the 1990s and they are responsible for 15–20% of the inherited breast cancers. Germline mutations in these two highrisk genes constitute cumulative lifetime breast cancer risks by age 70 of 65 and 45%, respectively [1, 2] . Besides, some other mutations in moderate-risk genes such as ATM, CHEK2, PALB2, and RAD50 constitute 2-to 4-fold increased breast cancer risks. Many common low-risk alleles may also display small but additive effects which exhibit important effects in terms of individualized treatment regimens [2] . The homeobox transcription factor (HOX) gene family belongs to a larger homeobox superfamily of transcription factors characterized by a highly-conserved DNA-binding domain. HOX genes which are 39 in total are subdivided into four clusters (A, B, C, D) on chromosomal locations 7p15, 17q21, 12q13, and 2q31, respectively

FAQs

What was the study’s main objective regarding HOXB13 and breast cancer?

To identify novel HOXB13 variants in breast cancer patients and evaluate their potential clinical significance, especially in hormone-positive cases.

How were participants and genetic variants assessed in this study?

A retrospective cohort screened 4198 individuals using hereditary cancer panel testing, followed by targeted next-generation sequencing with bioinformatic analysis using DRAGEN v3.6 and Sophia DDM pipelines.

Which HOXB13 variant was most frequent among hormone-positive patients?

The c.728A>G variant (p.K243R) was the most frequent HOXB13 variant in the hormone-positive subgroup.

Sep 22, 2026

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