Abstract 4180: Association between genetic polymorphisms of DNMT genes and breast cancer in a nested case-control study of African Americans
Authors: Su L Joseph , Lin Hui-Yi , Chiang Tung-Chin , Runnells Gail , Rogers Lora , Hsu Ping-Ching , Henry-Tillman Ronda , Kadlubar Susan 
Published: August 2019

Abstract
Introduction/Purpose. DNA methylation plays a significant role in both the development and progression of various cancers. Although aberrant DNA methylation of CpG islands is a common epigenetic alternation found in cancers, the interpretation of observed DNA methylation and cancer risk remains a challenge. DNA methylation is typically mediated by DNA Methyltransferases (DNMTs). This study took advantage of the infrastructure and existing data and samples of Arkansas Rural Community Health (ARCH) Study cohort to conduct a pilot nested case-control study of breast cancer among African Americans examining the relationship between breast cancer and DNMT single nucleotide polymorphisms (SNPs).
Methods: ARCH Study cohort consists of 26,387 women aged 18 to 85 recruited from all 75 counties in Arkansas between 2007 and 2014. All cohort participants donated a saliva sample for DNA and completed a short questionnaire at baseline. 309 African American breast cancer cases and 530 age-group, race, and recruitment year frequency-matched controls were selected for this analysis. Genotyping of DNMT1, DNMT3A, and DNMT3B were conducted using Tagman method. Multivariable logistic regression (odds ratio (OR), 95% confidence interval (CI) was used to examine the association between breast cancer and each SNP while considering the factors of age, education, and status of obesity, child birth, breast feeding, and menstrual-stop as potential confounding variables. Hardy-Weinberg equilibrium for the loci examined were evaluated. Haplotype analyses were conducted.
Results: Among 16 SNPs evaluated, heterozygous genotypes rs7575625 in DNMT1 and rs7605753 in DNMT3A were positively associated with breast cancer risk; rs12991495 in DNMT3A and rs17123590 and rs2424910 in DNMT3B were inversely associated with breast cancer. Haplotype AGA of rs8101626, rs2290684, and rs11880388 in DNMT1, which accounts for 43.9% population, differed significantly as a risk factor between cases and controls after adjusting for confounders (OR = 2.05; 95%CI=1.34, 3.12). Haplotype AGGGGT of rs2304429, rs12991495, rs7605753, rs11892646, rs7575625, and rs10196635 in DNMT3A differed significantly as a risk factor between cases and controls (OR = 4.06; 95%CI=1.93, 8.52); while haplotype rs2424905, rs2424910, rs17123590, rs6088008, and rs6058896 in DNMT3B was inversely associated with breast cancer (OR = 0.02; 95%CI=0.001, 0.29).
Conclusions: Despite the knowledge of DNMTs on DNA methylation, very few studies examined its role in breast cancer, in particular among underserved and minority population. This study took advantage of the existing sample and data of African Americans in a cohort population and demonstrated DNMT genetic polymorphisms are associated with breast cancer. Further evaluation of methylation patterns could provide knowledge on the mechanistic pathways for the association observed.
Citation Format: L Joseph Su, Hui-Yi Lin, Tung-Chin Chiang, Gail Runnells, Lora Rogers, Ping-Ching Hsu, Ronda Henry-Tillman, Susan Kadlubar. Association between genetic polymorphisms of DNMT genes and breast cancer in a nested case-control study of African Americans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4180.