Association of DNA methyltransferase polymorphisms with breast cancer: a nested case‒control study of the Arkansas Rural Community Health study

Authors

• Sarah A. Mayberry, UT Southwestern Medical Center, Dallas, TX
• Ping-Ching Hsu, University of Arkansas for Medical Sciences, Little Rock, AR
• Hui-Yi Lin, LSU Health Sciences Center - New OrleansFollow
• Lora J. Rogers, University of Arkansas for Medical Sciences, Little Rock, AR
• Shelbie D. Stahr, University of Arkansas for Medical Sciences, Little Rock, AR
• L Joseph Su, UT Southwestern Medical Center, Dallas, TX

Document Type

Article

Publication Date

2-10-2026

Publication Title

BMC Cancer

Abstract

BACKGROUND: Breast cancer remains the most commonly diagnosed cancer and a leading cause of cancer-related mortality among women in the United States. While many risk factors have been identified, a substantial proportion of breast cancer cases occur in individuals without known risk profiles, underscoring the need to investigate novel genetic and epigenetic contributors. DNA methylation, an epigenetic modification regulated by DNA methyltransferase (DNMT) enzymes, plays a critical role in gene expression and genomic stability. METHODS: This nested case‒control study, conducted within the Arkansas Rural Community Health study (ARCH) cohort, examined the associations between polymorphisms in DNMT1, DNMT3A, and DNMT3B and breast cancer risk. Using TaqMan genotyping and genome-wide association analysis in a sample of 2407 participants (967 cases and 1440 controls), we assessed both individual single-nucleotide polymorphisms (SNPs) and haplotypes. RESULTS: DNMT3A SNP rs7605753 was significantly associated with increased breast cancer risk according to a recessive model (adjusted odds ratio [aOR]: 1.30; 95% confidence interval [CI]: 1.06, 1.59). Haplotype analysis revealed that DNMT3A haplotype TACGA was associated with increased breast cancer odds compared to the referent haplotype CGCGA (aOR: 1.42; 95% CI: 1.13, 1.79). Stratified analyses indicated that haplotypes CTACGA and CTGCAA were significantly associated with increased breast cancer risk among Black participants, with larger effect estimates than in White participants. No significant associations were observed for DNMT1 or DNMT3B variants. CONCLUSIONS: These findings suggest that genetic polymorphisms in DNMT3A may contribute to breast cancer susceptibility and that racial differences in haplotype distribution and associated risk merit further investigation. Understanding these genetic associations could enhance personalized risk profiling and inform future breast cancer prevention strategies, particularly in understudied and diverse populations. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12885-026-15695-y.

PubMed ID

41663987

Volume

26

Issue

357

Recommended Citation

Mayberry, Sarah A.; Hsu, Ping-Ching; Lin, Hui-Yi; Rogers, Lora J.; Stahr, Shelbie D.; and Su, L Joseph, "Association of DNA methyltransferase polymorphisms with breast cancer: a nested case‒control study of the Arkansas Rural Community Health study" (2026). School of Public Health Faculty Publications. 561.
https://digitalscholar.lsuhsc.edu/soph_facpubs/561
10.1186/s12885-026-15695-y