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Marginalized populations experience disproportionate rates of preterm birth and early term birth. Exposure to per- and polyfluoroalkyl substances (PFAS) has been reported to reduce length of gestation, but the underlying mechanisms are unknown. In the present study, we characterized the molecular signatures of prenatal PFAS exposure and gestational age at birth outcomes in the newborn dried blood spot metabolome among 267 African American dyads in Atlanta, Georgia between 2016 and 2020. Pregnant people with higher serum perfluorooctanoic acid and perfluorohexane sulfonic acid concentrations had increased odds of an early birth. After false discovery rate correction, the effect of prenatal PFAS exposure on reduced length of gestation was associated with 8 metabolomic pathways and 52 metabolites in newborn dried blood spots, which suggested perturbed tissue neogenesis, neuroendocrine function, and redox homeostasis. These mechanisms explain how prenatal PFAS exposure gives rise to the leading cause of infant death in the United States.

Our earlier work has shown that genomic risk for schizophrenia converges with early life complications in affecting risk for the disorder and sex-biased neurodevelopmental trajectories. Here, we identify specific genes and potential mechanisms that, in placenta, may mediate such outcomes. We performed TWAS in healthy term placentae (N = 147) to derive candidate placental causal genes that we confirmed with SMR; to search for placenta and schizophrenia-specific associations, we performed an analogous analysis in fetal brain (N = 166) and additional placenta TWAS for other disorders/traits. The analyses in the whole sample and stratifying by sex ultimately highlight 139 placenta and schizophrenia-specific risk genes, many being sex-biased; the candidate molecular mechanisms converge on the nutrient-sensing capabilities of placenta and trophoblast invasiveness. These genes also implicate the Coronavirus-pathogenesis pathway and showed increased expression in placentae from a small sample of SARS-CoV-2-positive pregnancies. Investigating placental risk genes for schizophrenia and candidate mechanisms may lead to opportunities for prevention that would not be suggested by study of the brain alone.

The survival curves of E2F4>0 and E2F4

Background: The peripheral blood neutrophil-to-lymphocyte ratio (NLR) is a cytologic marker of both inflammation and poor outcomes in patients with cancer. DNA methylation is a key element of the epigenetic program defining different leukocyte subtypes and may provide an alternative to cytology in assessing leukocyte profiles. Our aim was to create a bioinformatic tool to estimate NLR using DNA methylation, and to assess its diagnostic and prognostic performance in human populations.Methods: We developed a DNA methylation–derived NLR (mdNLR) index based on normal isolated leukocyte methylation libraries and established cell-mixture deconvolution algorithms. The method was applied to cancer case–control studies of the bladder, head and neck, ovary, and breast, as well as publicly available data on cancer-free subjects.Results: Across cancer studies, mdNLR scores were either elevated in cases relative to controls, or associated with increased hazard of death. High mdNLR values (>5) were strong indicators of poor survival. In addition, mdNLR scores were elevated in males, in nonHispanic white versus Hispanic ethnicity, and increased with age. We also observed a significant interaction between cigarette smoking history and mdNLR on cancer survival.Conclusions: These results mean that our current understanding of mature leukocyte methylomes is sufficient to allow researchers and clinicians to apply epigenetically based analyses of NLR in clinical and epidemiologic studies of cancer risk and survival.Impact: As cytologic measurements of NLR are not always possible (i.e., archival blood), mdNLR, which is computed from DNA methylation signatures alone, has the potential to expand the scope of epigenome-wide association studies. Cancer Epidemiol Biomarkers Prev; 26(3); 328–38. ©2016 AACR.

PDF file - 14K, Differentially expressed miRNAs in tumor vs normal as determined by SAM method (Q

Results from a Cox-regression model fit to the HNSCC data set.

Validation analysis comparing mdNLR with cytological NLR.

J non-overlapping L-DMRs derived from Illumina HM27 reference leukocyte methylation data.

Supplementary Table S1 from Global Hypomethylation Identifies Loci Targeted for Hypermethylation in Head and Neck Cancer

PDF file, 437KB, Supplementary Table 1: Characteristics of the leukocyte subtype study population.Supplementary Table 2: Characteristics of the study population in the HNSCC data set. Supplementary Table 3: Characteristics of the study population in the Bladder cancer data set. Supplementary Table 4: The top 50 differentially methylated regions (DMRs) among the leukocyte subtypes (false discovery rate q-values < 0.001 for all). Supplementary Figure 1: Diagram illustrating Semi-Supervised Recursively Partitioned Mixture Models (SS-RPMM). Supplementary Figure 2: Diagram representing the analytic workflow the HNSCC data set. Supplementary Figure 3: Diagrams representing the analytic workflow the ovarian cancer data set. Supplementary Figure 4: Diagrams representing the analytic workflow the bladder cancer data set. Supplementary Figure 5: Results from the SS-RPMM analysis of the Ovarian cancer data set.

J non-overlapping L-DMRs derived from the Illumina HM450 reference leukocyte methylation data.

Purpose: The involvement of microRNAs in cancer and their potential as biomarkers of diagnosis and prognosis are becoming increasingly appreciated. We sought to identify microRNAs altered in head and neck squamous cell carcinoma (HNSCC) and to determine whether microRNA expression is predictive of disease.Experimental Design: RNA isolated from fresh-frozen primary tumors, fresh-frozen nondiseased head and neck epithelial tissues, and HNSCC cell lines was profiled for the expression of 662 microRNAs by microarray. The microRNAs that were both differentially expressed on the array and by quantitative reverse transcription-PCR were subsequently validated by quantitative reverse transcription-PCR using a total of 99 HNSCC samples and 14 normal epithelia.Results: A marked difference in microRNA expression pattern was observed between tumors and cell lines. Eighteen microRNAs were significantly altered in their expression between normal tissues and tumors. Four of these microRNAs were validated in the larger sample series, and each showed significant differential expression (P < 0.0001). Furthermore, an expression ratio of miR-221:miR-375 showed a high sensitivity (0.92) and specificity (0.93) for disease prediction.Conclusions: These data suggest that cultured tumor cell lines are inappropriate for microRNA biomarker identification and that the pattern of microRNA expression in primary head and neck tissues is reflective of disease status, with certain microRNAs exhibiting strong predictive potential. These results indicate that miR-221 and miR-375 should be evaluated further as diagnostic biomarkers because they may hold utility in defining broadly responsive prevention and treatment strategies for HNSCC.

Purpose: The human epigenome is profoundly altered in cancers, with a characteristic loss of methylation in repetitive regions and concomitant accumulation of gene promoter methylation. The degree to which these processes are coordinated is unclear so we investigated both in head and neck squamous cell carcinomas.Experimental Design: Global methylation was measured using the luminometric methylation assay (LUMA) and pyrosequencing of LINE-1Hs and AluYb8 repetitive elements in a series of 138 tumors. We also measured methylation of more than 27,000 CpG loci with the Illumina HumanMethylation27 Microarray (n = 91).Results:LINE-1 methylation was significantly associated with LUMA and Infinium loci methylation (Spearman's ρ = 0.52/ρ = 0.56, both P < 0.001) but not that of AluYb8. Methylation of LINE-1, AluYb8, and Infinium loci differed by tumor site (each Kruskal–Wallis, P < 0.05). Also, LINE-1 and LUMA methylation were associated with HPV16 E6 serology (each Mann–Whitney, P < 0.05). Comparing LINE-1 methylation to gene-associated methylation, we identified a distinct subset of CpG loci with significant hypermethylation associated with LINE-1 hypomethylation. An investigation of sequence features for these CpG loci revealed that they were significantly less likely to reside in repetitive elements (Gene Set Enrichment Analysis, P < 0.02), enriched in CpG islands (P < 0.001) and were proximal to transcription factor–binding sites (P < 0.05). We validated the top CpG loci that had significant hypermethylation associated with LINE-1 hypomethylation (at EVI2A, IFRD1, KLHL6, and PTPRCAP) by pyrosequencing independent tumors.Conclusions: These data indicate that global hypomethylation and gene-specific methylation processes are associated in a sequence-dependent manner, and that clinical characteristics and exposures leading to HNSCC may be influencing these processes. Clin Cancer Res; 17(11); 3579–89. ©2011 AACR.

PDF file - 71K, Quantitative real-time PCR was used to confirm differential expression of six miRNAs identified as aberrantly expressed in the microarray. (A) Global normalized signal of six miRNAs found to be significantly differentially expressed by SAM method. (B) Relative expression of same six miRNAs determined by real-time PCR. * indicates P < 0.01.

Results from a Cox-regression model fit to the Bladder cancer data set.

Supplementary Figures S1-S4 from Global Hypomethylation Identifies Loci Targeted for Hypermethylation in Head and Neck Cancer

PDF file - 94K, Specificity analysis for survival association with PcG|MIR|TFBS locus methylation

PDF file - 62K, Concordance of the detecting markers in subset of subjects with complete data and HPV16 serological markers, Eastern Massachusetts, 1999-2003

PDF file - 44K, Comparison of hyper- and hypomethylated CpG loci among each of the patient methylation subgroups

PDF file - 35K, ROC curves for HPV assays. AUC=Area under the Curve. P=0.024 from the DeLong's tests comprising the AUCs of E7 and DNA (MPG); P=0.05 comparing the AUCs of E7 and L1 (MS)

Supplementary Figure 1 from Integrated Profiling Reveals a Global Correlation between Epigenetic and Genetic Alterations in Mesothelioma

Supplementary Figure Legend from Integrated Profiling Reveals a Global Correlation between Epigenetic and Genetic Alterations in Mesothelioma

PDF file - 63K, The association between selected markers and overall survival of HNSSC patients stratified by tumor sites, Eastern Massachusetts, 1999-2003

Supplementary Figures 1-2 from MicroRNA Responses to Cellular Stress

Supplementary Methods, Figures 1-6 from Fundamental Differences in Cell Cycle Deregulation in Human Papillomavirus–Positive and Human Papillomavirus–Negative Head/Neck and Cervical Cancers

Supplementary Tables 1-6 from Differentiation of Lung Adenocarcinoma, Pleural Mesothelioma, and Nonmalignant Pulmonary Tissues Using DNA Methylation Profiles

PDF file - 5K, Primers Used In Pyrosequencing Validation

PDF file - 64K, Characteristics among the whole cases and those with DNA or P16 detected, Eastern Massachusetts, 1999-2003

PDF file - 95K, Specificity analysis for survival association with neighboring gene-locus methylation

XLS file - 566K, Differentially-methylated CpG Loci In Each Patient Methylation Subgroup

Human papillomaviruses (HPV) are associated with nearly all cervical cancers, 20% to 30% of head and neck cancers (HNC), and other cancers. Because HNCs also arise in HPV-negative patients, this type of cancer provides unique opportunities to define similarities and differences of HPV-positive versus HPV-negative cancers arising in the same tissue. Here, we describe genome-wide expression profiling of 84 HNCs, cervical cancers, and site-matched normal epithelial samples in which we used laser capture microdissection to enrich samples for tumor-derived versus normal epithelial cells. This analysis revealed that HPV+ HNCs and cervical cancers differed in their patterns of gene expression yet shared many changes compared with HPV− HNCs. Some of these shared changes were predicted, but many others were not. Notably, HPV+ HNCs and cervical cancers were found to be up-regulated in their expression of a distinct and larger subset of cell cycle genes than that observed in HPV− HNC. Moreover, HPV+ cancers overexpressed testis-specific genes that are normally expressed only in meiotic cells. Many, although not all, of the hallmark differences between HPV+ HNC and HPV− HNC were a direct consequence of HPV and in particular the viral E6 and E7 oncogenes. This included a novel association of HPV oncogenes with testis-specific gene expression. These findings in primary human tumors provide novel biomarkers for early detection of HPV+ and HPV− cancers, and emphasize the potential value of targeting E6 and E7 function, alone or combined with radiation and/or traditional chemotherapy, in the treatment of HPV+ cancers. [Cancer Res 2007;67(10):4605–19]

Supplementary Figure 2 from Epigenetic Profiles Distinguish Pleural Mesothelioma from Normal Pleura and Predict Lung Asbestos Burden and Clinical Outcome

Supplementary Table 1 from Epigenetic Profiles Distinguish Pleural Mesothelioma from Normal Pleura and Predict Lung Asbestos Burden and Clinical Outcome

PDF file - 65K, The association between selected markers and overall survival of HNSSC patients with and without adjustment for tumor stages, Eastern Massachusetts, 1999-2003

Supplementary Table 5 from Integrated Profiling Reveals a Global Correlation between Epigenetic and Genetic Alterations in Mesothelioma

Supplementary Table 1 from Integrated Profiling Reveals a Global Correlation between Epigenetic and Genetic Alterations in Mesothelioma

PDF file - 74K, The association between presence of HPV DNA detected by varying positive thresholds and overall survival of HNSSC patients stratified by tumor sites, Eastern Massachusetts, 1999-2003