Papers by Victoria Cortessis
Biomedicines
Gestational trophoblastic diseases (GTDs) have not been investigated for their epigenetic marks a... more Gestational trophoblastic diseases (GTDs) have not been investigated for their epigenetic marks and consequent transcriptomic changes. Here, we analyzed genome-wide DNA methylation and transcriptome data to reveal the epigenetic basis of disease pathways that may lead to benign or malignant GTDs. RNA-Seq, mRNA microarray, and Human Methylation 450 BeadChip data from complete moles and choriocarcinoma cells were bioinformatically analyzed. Paraffin-embedded tissues from complete moles and control placentas were used for tissue microarray construction, DNMT3B immunostaining and immunoscoring. We found that DNA methylation increases with disease severity in GTDs. Differentially expressed genes are mainly upregulated in moles while predominantly downregulated in choriocarcinoma. DNA methylation principally influences the gene expression of villous trophoblast differentiation-related or predominantly placenta-expressed genes in moles and choriocarcinoma cells. Affected genes in these sub...
International Journal of Molecular Sciences, 2019
Gene expression studies of molar pregnancy have been limited to a small number of candidate loci.... more Gene expression studies of molar pregnancy have been limited to a small number of candidate loci. We analyzed high-dimensional RNA and protein data to characterize molecular features of complete hydatidiform moles (CHMs) and corresponding pathologic pathways. CHMs and first trimester placentas were collected, histopathologically examined, then flash-frozen or paraffin-embedded. Frozen CHMs and control placentas were subjected to RNA-Seq, with resulting data and published placental RNA-Seq data subjected to bioinformatics analyses. Paraffin-embedded tissues from CHMs and control placentas were used for tissue microarray (TMA) construction, immunohistochemistry, and immunoscoring for galectin-14. Of the 14,022 protein-coding genes expressed in all samples, 3,729 were differentially expressed (DE) in CHMs, of which 72% were up-regulated. DE genes were enriched in placenta-specific genes (OR = 1.88, p = 0.0001), of which 79% were down-regulated, imprinted genes (OR = 2.38, p = 1.54 × 10...
JNCI Cancer Spectrum, 2019
BackgroundEarly exposure to estrogen-like compounds has been implicated in the etiology of testic... more BackgroundEarly exposure to estrogen-like compounds has been implicated in the etiology of testicular cancer, but individual level epidemiologic data addressing this hypothesis are scarce. The synthetic estrogen diethylstilbestrol (DES) was administered during pregnancy from 1948 to 1971, but sequelae of in utero exposure have been more extensively characterized in females than in males.MethodsBy systematic review, we sought to identify all epidemiologic research relating testicular cancer to a history of in utero exposure to diethylstilbestrol. Identified studies were critically appraised to assemble a set of nonredundant data in which any in utero exposure to DES was compared between men with incident testicular cancer and cancer-free men. These data were synthesized using random effects meta-analysis to estimate the summary association between in utero DES exposure and testicular cancer.ResultsBy meta-analysis of data from the six qualifying studies, the summary odds ratio estima...
Heritability analysis suggests that genome-wide association studies (GWAS) have the potential to ... more Heritability analysis suggests that genome-wide association studies (GWAS) have the potential to improve genetic risk prediction for complex diseases. Polygenic risk-score (PRS) is a widely used modelling technique that requires only availability of summary-level data from the discovery samples. We propose two modifications to improve the performance of PRS. First, we propose threshold dependent winners curse adjustments for marginal association coefficients that are used to weight the SNPs in PRS. Second, to exploit various external functional/annotation knowledge that might identify subset of SNPs highly enriched for association signals, we consider using variable thresholds for SNPs selection. We applied our methods to the GWAS summary-level data of fourteen complex diseases. Our analysis shows that while a simple winners curse correction uniformly leads to enhancement of performance of the models across traits, incorporation of functional SNPs was beneficial for only selected tr...
American journal of epidemiology, Jan 15, 2014
IARC scientific publications, 2004
We propose an approach to modelling the joint effects of multiple genes involved in metabolic act... more We propose an approach to modelling the joint effects of multiple genes involved in metabolic activation and detoxification of environmental exposures. A physiologically based pharmacokinetic (PBPK) model is used, in which the various person-specific metabolic rates are related to measurements of the genotypes and/or phenotypes at the various stages of the relevant pathways. Markov chain Monte Carlo (MCMC) methods are used to fit the model. We illustrate the approach by application to case-control data on colorectal polyps in relation to consumption of well-done red meat and tobacco smoking via pathways involving heterocyclic amines (regulated by the genes CYP1A2, NAT1 and NAT2) and polycyclic aromatic hydrocarbons (regulated by the genes CYP1A1, EPHX1 (also called mEH) and GSTM3). In this chapter, we focus on the biochemical basis for our conceptual models, deferring detailed mathematical description of the models and simulation results to a separate paper.
Cancer research, Jan 15, 2014
A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 wi... more A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r(2) ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09-1.27, P = 4.67 × 10(-5)] versus OR = 1.01 (95% CI, 0.93-1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E pr...
Human molecular genetics, Jan 15, 2014
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers ... more Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); a...
PLoS ONE, 2007
Background. Male-factor infertility is a common condition, and etiology is unknown for a high pro... more Background. Male-factor infertility is a common condition, and etiology is unknown for a high proportion of cases. Abnormal epigenetic programming of the germline is proposed as a possible mechanism compromising spermatogenesis of some men currently diagnosed with idiopathic infertility. During germ cell maturation and gametogenesis, cells of the germ line undergo extensive epigenetic reprogramming. This process involves widespread erasure of somatic-like patterns of DNA methylation followed by establishment of sex-specific patterns by de novo DNA methylation. Incomplete reprogramming of the male germ line could, in theory, result in both altered sperm DNA methylation and compromised spermatogenesis. Methodology/ Principal Finding. We determined concentration, motility and morphology of sperm in semen samples collected by male members of couples attending an infertility clinic. Using MethyLight and Illumina assays we measured methylation of DNA isolated from purified sperm from the same samples. Methylation at numerous sequences was elevated in DNA from poor quality sperm. Conclusions. This is the first report of a broad epigenetic defect associated with abnormal semen parameters. Our results suggest that the underlying mechanism for these epigenetic changes may be improper erasure of DNA methylation during epigenetic reprogramming of the male germ line.
The Journal of Clinical Endocrinology & Metabolism, 2007
Context: Many studies have investigated the association between male infertility and trinucleotid... more Context: Many studies have investigated the association between male infertility and trinucleotide repeat polymorphisms in the androgen receptor (AR) gene, but no comprehensive meta-analysis of all published studies has been conducted. Objective: Our goals were to summarize published data on associations between AR CAG and GGC repeat lengths and male infertility and investigate sources of variation between study results. Data Sources: We searched for reports published before October 2006 using Medline, PubMed, and Web of Science. Study Selection: All selected studies included the following: a case group with infertility as measured by semen parameters, a control group of known or presumed fertile men, and measurement of CAG and/or GGC repeat lengths among cases and controls. Thirty-nine reports were selected based on these criteria, and 33 were ultimately included in the meta-analysis. Data Extraction: One investigator extracted data on sample size, mean and SD of trinucleotide repeat length, and study characteristics. Data Synthesis: Estimates of the standardized mean difference (95% confidence interval) were 0.19 (0.09-0.29) for the 33 studies and 0.31 (0.14-0.47) for a subset of 13 studies that used more stringent case and control selection criteria. Thus, in both groups, cases had statistically significantly longer CAG repeat length than controls. Publication date appeared to be a significant source of variation between studies. Conclusions: This meta-analysis provides support for an association between increased androgen receptor CAG length and idiopathic male infertility, suggesting that even subtle disruptions in the androgen axis may compromise male fertility.
The Journal of Clinical Endocrinology & Metabolism, 2012
Context: Cryptorchidism is the most frequent congenital malformation among males, the major estab... more Context: Cryptorchidism is the most frequent congenital malformation among males, the major established risk factor for testicular germ cell tumors, and a presumed infertility risk factor. Androgens are essential for testicular descent, and functional genetic polymorphisms in the androgen receptor gene (AR) are postulated to influence cryptorchidism risk. Objective: The aim of the study was to investigate whether the CAG repeat length polymorphism in exon 1 of the AR is associated with cryptorchidism risk. Design and Setting: We conducted a family-based genotype-risk association study employing the transmission disequilibrium test for genotypic variants transmitted on the X-chromosome at a university-affiliated regional children's hospital. Participants: We studied 127 Hispanic boys with persistent cryptorchidism and comorbidities described in detail and their biological mothers. Intervention: Genotypes defined by number of CAG repeats were measured for each member of participating son-mother pairs. Main Outcome Measure: Associations between CAG tract length genotype and cryptorchidism risk were estimated using matched-pairs logistic regression. Results: Cryptorchidism risk was significantly associated with shorter CAG repeats [CAG Յ 19 vs. CAG Ն 20, odds ratio (OR) ϭ 0.44; 95% confidence interval (CI), 0.23-0.88]. This association was restricted to cryptorchidism with accompanying comorbidities, which was primarily hernia [CAG Յ 19 vs. CAG Ն 20, OR ϭ 0.35 (95% CI, 0.16-0.78)], and was strongest for bilateral cryptorchidism [CAG Յ 19 vs. CAG Ն 20, OR ϭ 0.09 (95% CI, 0.010-0.78)]. Conclusions: Androgen receptor genotypes encoding moderate functional variation may influence cryptorchidism risk, particularly among boys with bilateral nondescent or congenital hernia, and may explain in part the elevated risk of testicular seminoma experienced by ex-cryptorchid boys. Mechanistic research is warranted to examine both classical and nonclassical mechanisms through which androgens may influence risk of cryptorchidism and related conditions.
International Journal of Cancer, 2011
There is little information regarding associations between suspected bladder cancer risk factors ... more There is little information regarding associations between suspected bladder cancer risk factors and tumor subtypes at diagnosis. Some, but not all, studies have found that bladder cancer among smokers is often more invasive than it is among nonsmokers. This population‐based case‐control study was conducted in Los Angeles, California, involving 1,586 bladder cancer patients and their individually matched controls. Logistic regression was used to conduct separate analyses according to tumor subtypes defined by stage and grade. Cigarette smoking increased risk of both superficial and invasive bladder cancer, but the more advanced the stage, the stronger the effect. The odds ratios associated with regular smokers were 2.2 (95% confidence intervals, 1.8–2.8), 2.7 (2.1–3.6) and 3.7 (2.5–5.5) for low‐grade superficial, high‐grade superficial and invasive tumors respectively. This pattern was consistently observed regardless of the smoking exposure index under examination. Women had higher...
International Journal of Cancer, 2014
Tobacco smoking is a bladder cancer risk factor and a source of carcinogens that induce DNA damag... more Tobacco smoking is a bladder cancer risk factor and a source of carcinogens that induce DNA damage to urothelial cells. Using data and samples from 988 cases and 1,004 controls enrolled in the Los Angeles County Bladder Cancer Study and the Shanghai Bladder Cancer Study we investigated associations between bladder cancer risk and 632 tagSNPs that comprehensively capture genetic variation in 28 DNA repair genes from four DNA repair pathways: base excision repai, nucleotide excision repair (NER), non-homologous end-joining (NHEJ), and homologous recombination repair (HHR). Odds ratios (ORs) and 95% confidence intervals (CIs) for each tagSNP were corrected for multiple testing for all SNPs within each gene using pACT, and for genes within each pathway and across pathways with Bonferroni. Gene and pathway summary estimates were obtained using ARTP. We observed an association between bladder cancer and POLB rs7832529 (BER) (p ACT = 0.003; p pathway = 0.021) among all, and SNPs in XPC (NER) and OGG1 (BER) among Chinese men and women, respectively. The NER pathway showed an overall association with risk among Chinese males (ARTP NER p = 0.034). The XRCC6 SNP rs2284082 (NHEJ), also in LD with SREBF2, showed an interaction with smoking (Smoking status interaction p gene = 0.001, p pathway = 0.008, p overall = 0.034). Our findings support a role in bladder carcinogenesis for regions that map close to or within BER (POLB, OGG1) and NER
Human Molecular Genetics, 2005
Human Molecular Genetics, 2013
Genome-wide association studies (GWASs) have identified multiple common genetic variants associat... more Genome-wide association studies (GWASs) have identified multiple common genetic variants associated with an increased risk of testicular germ cell tumors (TGCTs). A previous GWAS reported a possible TGCT susceptibility locus on chromosome 1q23 in the UCK2 gene, but failed to reach genome-wide significance following replication. We interrogated this region by conducting a meta-analysis of two independent GWASs including a total of 940 TGCT cases and 1559 controls for 122 single-nucleotide polymorphisms
Human Heredity, 1992
We present a Monte Carlo approach to estimation of the recombination fraction theta and the profi... more We present a Monte Carlo approach to estimation of the recombination fraction theta and the profile likelihood for a dichotomous trait and a single marker gene with 2 alleles. The method is an application of a technique known as 'Gibbs sampling', in which random samples of each of the unknowns (here genotypes, theta and nuisance parameters, including the allele frequencies and the penetrances) are drawn from their posterior distributions, given the data and the current values of all the other unknowns. Upon convergence, the resulting samples derive from the marginal distribution of all the unknowns, given only the data, so that the uncertainty in the specification of the nuisance parameters is reflected in the variance of the posterior distribution of theta. Prior knowledge about the distribution of theta and the nuisance parameters can be incorporated using a Bayesian approach, but adoption of a flat prior for theta and point priors for the nuisance parameters would correspond to the standard likelihood approach. The method is easy to program, runs quickly on a microcomputer, and could be generalized to multiple alleles, multipoint linkage, continuous phenotypes and more complex models of disease etiology. The basic approach is illustrated by application to data on cholesterol levels and an a low-density lipoprotein receptor gene in a single large pedigree.
Human Heredity, 2003
Many chronic diseases are the result of a complex sequence of biochemical reactions involving exp... more Many chronic diseases are the result of a complex sequence of biochemical reactions involving exposures to various environmental agents, metabolized by a number of different genes. Routine epidemiologic analyses of such associations have tended to rely on standard contingency table or logistic regression methods, typically focusing on one variable at a time or pairwise combinations. We consider two statistical alternatives to this approach, one based on Bayesian model averaging, one based on pharmacokinetic modeling of the biochemical pathways. These approaches are illustrated using data from a case-control study of colorectal polyps in relation to tobacco smoking and consumption of well done red meat, both viewed as sources of heterocyclic amines and polycyclic aromatic hydrocarbons. The new analyses are structured in a manner that attempts to take advantage of prior knowledge of the metabolism of these classes of compounds and the various genes that regulate these pathways.
Nature genetics, 2010
We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan o... more We conducted a multi-stage, genome-wide association study of bladder cancer with a primary scan of 591,637 SNPs in 3,532 affected individuals (cases) and 5,120 controls of European descent from five studies followed by a replication strategy, which included 8,382 cases and 48,275 controls from 16 studies. In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1: rs1014971, (P = 8 × 10⁻¹²) maps to a non-genic region of chromosome 22q13.1, rs8102137 (P = 2 × 10⁻¹¹) on 19q12 maps to CCNE1 and rs11892031 (P = 1 × 10⁻⁷) maps to the UGT1A cluster on 2q37.1. We confirmed four previously identified genome-wide associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P = 4 × 10⁻¹¹) and a tag SNP for NAT2 acetylation status (P = 4 × 10⁻¹¹), and found interactions with smoking in both regions. Our findings on common variants associated with bladder cance...
Genes, Chromosomes and Cancer, 2008
Carcinogenesis, 2010
Genome-wide association studies have associated common variations at chromosomes 5p15 and 15q25 w... more Genome-wide association studies have associated common variations at chromosomes 5p15 and 15q25 with lung cancer risk. The 5p15 locus has also been associated with increased bladder cancer risk in a recent report. The 15q25 locus has been associated with nicotine dependence and self-reported number of cigarettes smoked per day in some studies and it was proposed that its association with lung cancer may be mediated through differences in smoking behavior. Here, we investigated the roles of variations at 5p15 (rs401681, rs402710, rs2736098 and rs2736100) and 15q25 (rs1051730 and rs8034191) in bladder cancer etiology in two case-control studies conducted separately in Los Angeles County, CA, USA (498 cases and 588 controls) and in Shanghai, China (506 cases and 530 controls). We replicated the association between the 5p15 locus and bladder cancer among non-Hispanic whites (NHW) in Los Angeles [for rs2736100, per C allele odds ratio (OR) 5 1.23; 95% confidence interval (CI), 1.02-1.48; P 5 0.029] and among Chinese in Shanghai (OR 5 1.22; 95% CI, 1.02-1.47; P 5 0.033). Both rs1051730 and rs8034191 at 15q25 were rare among Chinese. Among NHW, a significant association was found between rs8034191 and bladder cancer which persisted after adjustment for cigarette smoking status, number of cigarettes smoked per day and number of years of smoking (per C allele OR 5 1.26; 95% CI, 1.04-1.54; P 5 0.017). Our results support 5p15 and 15q25 as susceptibility regions for bladder cancer risk.
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Papers by Victoria Cortessis