The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access)
SOCIAL-DEMOGRAPHICS, HEALTH BEHAVIORS, TELOMERE LENGTH IN MEXICAN-AMERICAN COHORT AND CIRCULATING DNA METHYLATION IN BLADDER CANCER
Date of Graduation
Masters of Science (MS)
Xifeng Wu, M.D., Ph.D.
Oliver Bogler, Ph.D.
Colin Dinney, M.D.
Jian Gu, Ph.D.
Alan Wang, Ph.D.
I. SOCIAL-DEMOGRAPHICS, HEALTH BEHAVIORS, AND TELOMERE LENGTH IN MEXICAN AMERICANS: A COHORT STUDY
Recent studies using a prospective cohort design have suggested that telomere length in peripheral blood leukocytes is not only a potential indicator of cellular aging that has been linked to stressful life experience and health behaviors, but also a prognostic marker for major chronic diseases; however, such study has never been done among adult Mexican Americans. In this current study, we examined cross-sectional associations among social-demographics, lifestyle behaviors, and relative telomere length (RTL) in peripheral blood leukocytes, as well as longitudinal relationships among major chronic diseases, weight gain, and RTL, among 12,792 Mexican Americans aged 20 to 85 years in the Mano-A-Mano, a Mexican American Cohort. As expected, RTL was inversely correlated with age (r=-0.15, p
II. METHYLATION IN SERUM CELL-FREE DNA AND CPG-SNP WITH BLADDER CANCER RISK
Epigenetic alterations are early events of cancers, including bladder cancer. In the present study, we aimed to examine methylation profiles of circulating DNA in serum of bladder cancer patients, in an effort to develop reliable DNA methylation signatures to diagnose the disease. Firstly, we performed whole genome DNA methylation profiling with Illumina Infinium HumanMethylation450 beadchip in 23 participants in a bladder cancer case control study. 396 target cytosine-phosphate- guanine (CpG) sites were identified as hypermethylated in cases compared with the controls. The top 5 candidate CpG sites hypermethylated in cases during the screening phase were further validated by pyrosequencing, in 100 bladder cancer patients (including 50 non-muscle invasive and 50 muscle invasive bladder cancers) and 50 healthy controls. Successful methylation data were obtained for 4 of the selected CpG sites, located in genes of TTC23, WWOX, ZNF624 and LOC2211122, respectively. Unfortunately, none of these 4 sites exhibited differential methylation between cases and controls in this validation. Interestingly, there was a SNP rs8038732 (G>A) in the methylation site of gene TTC23. The GG genotype showed near complete methylation, G/A heterozygotes half methylation, and AA complete loss of methylation. This SNP is clearly a functional SNP because the G>A transition almost completely knocks out methylation at this site. It would be interesting to see whether this SNP affect bladder cancer risk. However, this SNP was not genotyped in our previously published genome-wide association study (GWAS). But, we found that another SNP, rs1377267 (A>C), on the GWAS chip is in strong linkage disequilibrium (r2=0.85) with rs8038732. Moreover, the SNP rs1377267 significantly associated with the risk of bladder cancer in our GWAS study. Specifically, the heterozygous alleles (AC) was associated with higher bladder cancer risk (OR=1.34, 95% CI=1.09-1.65), whereas the homozygous alleles (CC) were marginally associated with lower risk of bladder cancer (OR=0.78, 95% CI= 0.59-1.03). From this result, we could infer that rs8038732 has similar association with the risk of bladder cancer. Our study suggests that rs8038732 affects the risk of bladder cancer by removing a cytosine-phosphate-guanine (CpG) dinucleotide and knocking out DNA methylation at this site. Loss of methylation may increase the expression of TTC23, which is a potential oncogene.