Chao A Hsiung | PubMed Health

PubMed2026

Elevated phthalate exposure and metabolic susceptibility increased breast cancer risk: A 20-y follow-up study in Taiwan.

Widely used phthalates, especially di-(2-ethylhexyl) phthalate (DEHP), increase breast cancer risk in experimental animals and humans, but long-term follow-up evidence of its human breast carcinogenicity remains inconclusive. This nested case-control study included 119 invasive breast cancer cases and 245 matched controls from a longitudinal cohort of 11,923 women recruited in 1991-1992 and followed to 2010 in Taiwan. Urine samples at baseline and follow-up visit were tested for 11 metabolites of seven phthalates using LC-ESI-MS/MS. DEHP metabolism susceptibility was evaluated by the percentage of mono-2-ethylhexyl phthalate (MEHP%) in the sum of five DEHP metabolites (∑DEHP). Odds ratios (ORs) with 95% CI from conditional logistic regression were used to examine risk predictors. DEHP was the only phthalate significantly associated with breast cancer risk. Risk increased significantly with elevated urinary levels of ∑DEHP (> 0.381 μmol/g creatinine, OR = 1.71, 95% CI = 1.02 to 2.43), MEHP (> 0.022 μmol/g creatinine, OR = 1.87, 95% CI = 1.07 to 3.25), and MEHP% (> 6.7%, OR = 1.65, 95% CI = 0.96 to 2.82). Elevated ∑DEHP and MEHP% combined with early menarche (≤ 14 years) was associated with further increased risk (OR = 7.52, 95% CI = 2.68 to 21.05). The intraclass correlation coefficient between paired baseline and follow-up samples of 152 women was 0.06 for ∑DEHP and 0.31 for MEHP%. High DEHP exposure, high MEHP%, and early menarche were associated with increased breast cancer risk. MEHP% was a better biomarker for DEHP metabolism.

Humans↗

PubMed2024

The Genetic Determinants and Genomic Consequences of Non-Leukemogenic Somatic Point Mutations.

Clonal hematopoiesis (CH) is defined by the expansion of a lineage of genetically identical cells in blood. Genetic lesions that confer a fitness advantage, such as point mutations or mosaic chromosomal alterations (mCAs) in genes associated with hematologic malignancy, are frequent mediators of CH. However, recent analyses of both single cell-derived colonies of hematopoietic cells and population sequencing cohorts have revealed CH frequently occurs in the absence of known driver genetic lesions. To characterize CH without known driver genetic lesions, we used 51,399 deeply sequenced whole genomes from the NHLBI TOPMed sequencing initiative to perform simultaneous germline and somatic mutation analyses among individuals without leukemogenic point mutations (LPM), which we term CH-LPMneg. We quantified CH by estimating the total mutation burden. Because estimating somatic mutation burden without a paired-tissue sample is challenging, we developed a novel statistical method, the Genomic and Epigenomic informed Mutation (GEM) rate, that uses external genomic and epigenomic data sources to distinguish artifactual signals from true somatic mutations. We performed a genome-wide association study of GEM to discover the germline determinants of CH-LPMneg. After fine-mapping and variant-to-gene analyses, we identified seven genes associated with CH-LPMneg (TCL1A, TERT, SMC4, NRIP1, PRDM16, MSRA, SCARB1), and one locus associated with a sex-associated mutation pathway (SRGAP2C). We performed a secondary analysis excluding individuals with mCAs, finding that the genetic architecture was largely unaffected by their inclusion. Functional analyses of SMC4 and NRIP1 implicated altered HSC self-renewal and proliferation as the primary mediator of mutation burden in blood. We then performed comprehensive multi-tissue transcriptomic analyses, finding that the expression levels of 404 genes are associated with GEM. Finally, we performed phenotypic association meta-analyses across four cohorts, finding that GEM is associated with increased white blood cell count and increased risk for incident peripheral artery disease, but is not significantly associated with incident stroke or coronary disease events. Overall, we develop GEM for quantifying mutation burden from WGS without a paired-tissue sample and use GEM to discover the genetic, genomic, and phenotypic correlates of CH-LPMneg.

Journal Article↗