Browsing by Author "Moorman, Patricia G"

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Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer.
(PLoS One, 2010-04-08) Schildkraut, Joellen M; Iversen, Edwin S; Wilson, Melanie A; Clyde, Merlise A; Moorman, Patricia G; Palmieri, Rachel T; Whitaker, Regina; Bentley, Rex C; Marks, Jeffrey R; Berchuck, Andrew
BACKGROUND: We analyzed the association between 53 genes related to DNA repair and p53-mediated damage response and serous ovarian cancer risk using case-control data from the North Carolina Ovarian Cancer Study (NCOCS), a population-based, case-control study. METHODS/PRINCIPAL FINDINGS: The analysis was restricted to 364 invasive serous ovarian cancer cases and 761 controls of white, non-Hispanic race. Statistical analysis was two staged: a screen using marginal Bayes factors (BFs) for 484 SNPs and a modeling stage in which we calculated multivariate adjusted posterior probabilities of association for 77 SNPs that passed the screen. These probabilities were conditional on subject age at diagnosis/interview, batch, a DNA quality metric and genotypes of other SNPs and allowed for uncertainty in the genetic parameterizations of the SNPs and number of associated SNPs. Six SNPs had Bayes factors greater than 10 in favor of an association with invasive serous ovarian cancer. These included rs5762746 (median OR(odds ratio)(per allele) = 0.66; 95% credible interval (CI) = 0.44-1.00) and rs6005835 (median OR(per allele) = 0.69; 95% CI = 0.53-0.91) in CHEK2, rs2078486 (median OR(per allele) = 1.65; 95% CI = 1.21-2.25) and rs12951053 (median OR(per allele) = 1.65; 95% CI = 1.20-2.26) in TP53, rs411697 (median OR (rare homozygote) = 0.53; 95% CI = 0.35 - 0.79) in BACH1 and rs10131 (median OR( rare homozygote) = not estimable) in LIG4. The six most highly associated SNPs are either predicted to be functionally significant or are in LD with such a variant. The variants in TP53 were confirmed to be associated in a large follow-up study. CONCLUSIONS/SIGNIFICANCE: Based on our findings, further follow-up of the DNA repair and response pathways in a larger dataset is warranted to confirm these results.
Open Access
Associations between genetic variants of KIF5B, FMN1, and MGAT3 in the cadherin pathway and pancreatic cancer risk.
(Cancer medicine, 2020-11-16) Zhao, Lingling; Liu, Hongliang; Luo, Sheng; Moorman, Patricia G; Walsh, Kyle M; Li, Wei; Wei, Qingyi
Because the cadherin-mediated signaling pathway promotes cancer progression, we assessed associations between genetic variants in 109 cadherin-related genes and risk of pancreatic cancer (PanC) by using genotyping data from publically available genome-wide association studies (GWAS) datasets comprising 15,423 individuals of European ancestry. After initial single-locus analyses and subsequent meta-analysis with multiple testing correction for 29,963 single-nucleotide polymorphisms (SNPs), 11 SNPs remained statistically significant (p < 0.05). In the stepwise logistic regression analysis, three independent PanC risk-associated SNPs (KIF5B rs211304 C > G, FMN1 rs117648907 C > T, and MGAT3 rs34943118 T > C) remained statistically significant (p < 0.05), with odds ratios of 0.89 (95% confidence interval = 0.82-0.95 and p = 6.93 × 10-4 ), 1.33 (1.13-1.56 and 2.11 × 10-4 ), and 1.11 (1.05-1.17 and 8.10 × 10-5 ), respectively. Combined analysis of unfavorable genotypes of these three independent SNPs showed an upward trend in the genotype-risk association (ptrend < 0.001). Expression quantitative trait loci analyses indicated that the rs211304 G and rs34943118 C alleles were associated with increased mRNA expression levels of KIF5B and MGAT3, respectively (all p < 0.05). Additional bioinformatics prediction suggested that these three SNPs may affect enhancer histone marks that likely have an epigenetic effect on the genes. Our findings provide biological clues for these PanC risk-associated SNPs in cadherin-related genes in European ancestry populations, possibly by regulating the expression of the affected genes. However, our findings need to be validated in additional population, molecular and mechanistic investigations.
Open Access
Engaging African Americans in Research: The Recruiter's Perspective.
(Ethnicity & disease, 2017-01) Barrett, Nadine J; Ingraham, Kearston L; Vann Hawkins, Tracey; Moorman, Patricia G
To examine barriers recruiters encounter when enrolling African American study participants, identify motivating factors to increase research participation, and provide recommendations to facilitate successful minority recruitment.Recruiters are often the first point of contact between the research study and potential African American participants. While challenges in enrolling African Americans into clinical and epidemiologic research has been reported in numerous studies the non-physician recruiter's role as a determinant of overall participation rates has received minimal attention.We conducted four 90-minute teleconference focus groups with 18 recruiters experienced in enrolling African Americans for clinical and epidemiologic studies at five academic/medical institutions. Participants represented diverse racial and ethnic backgrounds and were asked to reflect on barriers preventing African Americans from participating in research studies, factors that motivated participation, and recommendations to increase participation of African Americans in research. Multi-coder and thematic data analysis was implemented using the Braun and Clarke method.Prominent concerns in recruitment of African Americans in research include fear and mistrust and inflexible research protocols. The participants suggest that improved recruitment could be achieved through cross-cultural and skillset building training opportunities for recruiters, greater community engagement among researchers, and better engagement with clinic staff and research teams.
Open Access
Genetic Variants in RUNX3, AMD1 and MSRA in the Methionine Metabolic Pathway and Survival in Non-small Cell Lung Cancer Patients.
(International journal of cancer, 2019-01-16) Chen, Ka; Liu, Hongliang; Liu, Zhensheng; Luo, Sheng; Patz, Edward F; Moorman, Patricia G; Su, Li; Shen, Sipeng; Christiani, David C; Wei, Qingyi
Abnormal methionine dependence in cancer cells has led to methionine restriction as a potential therapeutic strategy. We hypothesized that genetic variants involved in methionine-metabolic genes are associated with survival in non-small cell lung cancer (NSCLC) patients. Therefore, we investigated associations of 16,378 common single-nucleotide polymorphisms (SNPs) in 97 methionine-metabolic pathway genes with overall survival (OS) in NSCLC patients using genotyping data from two published genome-wide association study (GWAS) datasets. In the single-locus analysis, 1,005 SNPs were significantly associated with NSCLC OS (P < 0.05 and false-positive report probability < 0.2) in the discovery dataset. Three SNPs (RUNX3 rs7553295G>T, AMD1 rs1279590G>A and MSRA rs73534533C>A) were replicated in the validation dataset and their meta-analysis showed that adjusted hazards ratio [HR] of 0.82 [95% confidence interval (CI) =0.75-0.89] and Pmeta =2.86 x 10-6 , 0.81 (0.73-0.91) and Pmeta =4.63 x 10-4 , and 0.77 (0.68-0.89) and Pmeta =2.07 x 10-4 , respectively). A genetics score of protective genotypes of these three SNPs revealed an increased OS in a dose-response manner (Ptrend <.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between these genotypes and gene mRNA expression levels. Moreover, differential expression analysis further supported a tumor-suppressive effect of MSRA, with lower mRNA levels in both lung squamous carcinoma and adenocarcinoma (P <.0001 and <.0001, respectively) than in adjacent normal tissues. Additionally, low mutation rates of these three genes indicated the critical roles of these functional SNPs in cancer progression. Taken together, these genetic variants of methionine-metabolic pathway genes may be promising predictors of survival in NSCLC patients. This article is protected by copyright. All rights reserved.
Open Access
Genetic variants of genes in the NER pathway associated with risk of breast cancer: A large-scale analysis of 14 published GWAS datasets in the DRIVE study.
(International journal of cancer, 2019-09) Ge, Jie; Liu, Hongliang; Qian, Danwen; Wang, Xiaomeng; Moorman, Patricia G; Luo, Sheng; Hwang, Shelley; Wei, Qingyi
A recent hypothesis-free pathway-level analysis of genome-wide association study (GWAS) datasets suggested that the overall genetic variation measured by single nucleotide polymorphisms (SNPs) in the nucleotide excision repair (NER) pathway genes was associated with breast cancer (BC) risk, but no detailed SNP information was provided. To substantiate this finding, we performed a larger meta-analysis of 14 previously published GWAS datasets in the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) study with 53,107 subjects of European descent. Using a hypothesis-driven approach, we selected 138 candidate genes from the NER pathway using the "Molecular Signatures Database (MsigDB)" and "PathCards". All SNPs were imputed using IMPUTE2 with the 1000 Genomes Project Phase 3. Logistic regression was used to estimate BC risk, and pooled ORs for each SNP were obtained from the meta-analysis using the false discovery rate for multiple test correction. RegulomeDB, HaploReg, SNPinfo and expression quantitative trait loci (eQTL) analysis were used to assess the SNP functionality. We identified four independent SNPs associated with BC risk, BIVM-ERCC5 rs1323697_C (OR = 1.06, 95% CI = 1.03-1.10), GTF2H4 rs1264308_T (OR = 0.93, 95% CI = 0.89-0.97), COPS2 rs141308737_C deletion (OR = 1.06, 95% CI = 1.03-1.09) and ELL rs1469412_C (OR = 0.93, 95% CI = 0.90-0.96). Their combined genetic score was also associated with BC risk (OR = 1.12, 95% CI = 1.08-1.16, ptrend < 0.0001). The eQTL analysis revealed that BIVM-ERCC5 rs1323697 C and ELL rs1469412 C alleles were correlated with increased mRNA expression levels of their genes in 373 lymphoblastoid cell lines (p = 0.022 and 2.67 × 10-22 , respectively). These SNPs might have roles in the BC etiology, likely through modulating their corresponding gene expression.
Open Access
Novel genetic variants in genes of the Fc gamma receptor-mediated phagocytosis pathway predict non-small cell lung cancer survival.
(Translational lung cancer research, 2020-06) Qian, Danwen; Liu, Hongliang; Zhao, Lingling; Wang, Xiaomeng; Luo, Sheng; Moorman, Patricia G; Patz, Edward F; Su, Li; Shen, Sipeng; Christiani, David C; Wei, Qingyi
Background:Both antibody-dependent cellular cytotoxicity and phagocytosis activate innate immunity, and the Fc gamma receptor (FCGR)-mediated phagocytosis is an integral part of the process. We assessed associations between single-nucleotide polymorphisms (SNPs) in FCGR-related genes and survival of patients with non-small cell lung cancer (NSCLC). Methods:We evaluated associations between 24,734 (SNPs) in 97 FCGR-related genes and survival of 1,185 patients with NSCLC using a published genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial and validated the results in another independent dataset of 894 NSCLC patients. Results:In the single-locus analysis with Bayesian false discovery probability (BFDP) for multiple testing correction, we found 1,084 SNPs to be significantly associated overall survival (OS) (P<0.050 and BFDP ≤0.80), of which two independent SNPs (PLCG2 rs9673682 T>G and PLPP1 rs115613985 T>A) were further validated in another GWAS dataset of 894 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study, with combined allelic hazards ratios for OS of 0.87 [95% confidence interval (CI): 0.81-0.94 and P=5.90×10-4] and 1.18 (95% CI: 1.08-1.29 and 1.32×10-4, respectively). Expression quantitative trait loci analysis showed that the rs9673682 G allele was significantly correlated with increased mRNA expression levels of PLCG2 in 373 transformed lymphoblastoid cell-lines (P=7.20×10-5). Additional evidence from differential expression analysis further supported a tumor-suppressive effect of PLCG2 on OS of patients with lung cancer, with lower mRNA expression levels in both lung squamous carcinoma and adenocarcinoma than in adjacent normal tissues. Conclusions:Genetic variants in PLCG2 of the FCGR-mediated phagocytosis pathway may be promising predictors of NSCLC survival, possibly through modulating gene expression, but additional investigation of the molecular mechanisms of PLPP1 rs115613985 is warranted.
Open Access
Novel genetic variants in HDAC2 and PPARGC1A of the CREB-binding protein pathway predict survival of non-small-cell lung cancer.
(Molecular carcinogenesis, 2019-11-12) Tang, Dongfang; Zhao, Yu Chen; Qian, Danwen; Liu, Hongliang; Luo, Sheng; Patz, Edward F; Moorman, Patricia G; Su, Li; Shen, Sipeng; Christiani, David C; Glass, Carolyn; Gao, Wen; Wei, Qingyi
The CREB-binding protein (CBP) pathway plays an important role in transcription and activity of acetyltransferase that acetylates lysine residues of histones and nonhistone proteins. In the present study, we hypothesized that genetic variants in the CBP pathway genes played a role in survival of non-small-cell lung cancer (NSCLC). We tested this hypothesis using the genotyping data from the genome-wide association study (GWAS) dataset from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In the single-locus analysis, we evaluated associations between 13 176 (1107 genotyped and 12 069 imputed) single-nucleotide polymorphisms (SNPs) in 72 genes and survival of 1185 patients with NSCLC. The identified 106 significant SNPs in the discovery were further validated in additional genotyping data from another GWAS dataset of 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study. The combined results of two datasets showed that two independent, potentially functional SNPs (i.e., HDAC2 rs13213007G>A and PPARGC1A rs60571065T>A) were significantly associated with NSCLC overall survival, with a combined hazards ratio (HR) of 1.26 (95% confidence interval (CI), 1.09-1.45; P = .002) and 1.23 (1.04-1.47; P = .017), respectively. Furthermore, we performed an expression quantitative trait loci analysis and found that the survival-associated HDAC2 rs13213007A allele (GA+AA), but not PPARGC1A rs60571065A allele (TA+AA), was significantly associated with increased messenger RNA expression levels of HDAC2 in 373 lymphoblastoid cell lines. These results indicate that the HDAC2 rs13213007A allele is a potential predictor of NSCLC survival, likely by altering the HDAC2 expression.
Open Access
Potentially functional genetic variants in the complement-related immunity gene-set are associated with non-small cell lung cancer survival.
(International journal of cancer, 2019-04) Qian, Danwen; Liu, Hongliang; Wang, Xiaomeng; Ge, Jie; Luo, Sheng; Patz, Edward F; Moorman, Patricia G; Su, Li; Shen, Sipeng; Christiani, David C; Wei, Qingyi
The complement system plays an important role in the innate and adaptive immunity, complement components mediate tumor cytolysis of antibody-based immunotherapy, and complement activation in the tumor microenvironment may promote tumor progression or inhibition, depending on the mechanism of action. In the present study, we conducted a two-phase analysis of two independently published genome-wide association studies (GWASs) for associations between genetic variants in a complement-related immunity gene-set and overall survival of non-small cell lung cancer (NSCLC). The GWAS dataset from Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was used as the discovery, and multivariate Cox proportional hazards regression with false-positive report probability for multiple test corrections were performed to evaluate associations between 14,699 single-nucleotide polymorphisms (SNPs) in 111 genes and survival of 1,185 NSCLC patients. The identified significant SNPs in a single-locus analysis were further validated with 984 NSCLC patients in the GWAS dataset from the Harvard Lung Cancer Susceptibility (HLCS) Study. The results showed that two independent, potentially functional SNPs in two genes (VWF rs73049469 and ITGB2 rs3788142) were significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 1.22 [95% confidence interval (CI) = 1.07-1.40, P = 0.002] and 1.16 (1.07-1.27, 6.45 × 10-4 ), respectively. Finally, we performed expression quantitative trait loci (eQTL) analysis and found that survival-associated genotypes of VWF rs73049469 were also significantly associated with mRNA expression levels of the gene. These results indicated that genetic variants of the complement-related immunity genes might be predictors of NSCLC survival, particularly for the short-term survival, possibly by modulating the expression of genes involved in the host immunity.
Open Access
Potentially functional genetic variants in the TNF/TNFR signaling pathway genes predict survival of patients with non-small cell lung cancer in the PLCO cancer screening trial.
(Molecular carcinogenesis, 2019-04-15) Guo, Yi; Feng, Yun; Liu, Hongliang; Luo, Sheng; Clarke, Jeffrey W; Moorman, Patricia G; Su, Li; Shen, Sipeng; Christiani, David C; Wei, Qingyi
The tumor necrosis factor (TNF)/TNF receptor (TNFR) pathway is known to influence survival of patients with cancer. We hypothesize that single nucleotide polymorphisms (SNPs) in the TNF/TNFR pathway genes related to apoptosis are associated with survival of patients with non-small cell lung cancer (NSCLC). We used 1185 patients with NSCLC in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and 984 patients with NSCLC in the Harvard Lung Cancer Susceptibility Study as the discovery and validation datasets, respectively. We selected 6788 SNPs in 71 genes in the TNF/TNFR signaling pathway and extracted their genotyping data from the PLCO genowide-association study (GWAS) dataset. We performed Cox proportional hazards regression analysis to evaluate associations between the identified SNPs and survival and validated the significant SNPs, which were further analyzed for their functional relevance. We found that genotypes of two validated SNPs, IKBKAP rs4978754 CT + TT and TNFRSF1B rs677844 TC + CC, as well as their combined genotypes predicted a better overall survival (P = 0.004, 0.002 and <0.001, respectively). These two validated SNPs were predicted by the RegulomeDB score to be potentially functional. In addition, IKBKAP mRNA expression levels were significantly higher, while TNFRSF1B mRNA expression levels were significantly lower in lung cancer tissues than in adjacent normal tissues (P < 0.001). The Cancer Genome Atlas (TCGA)-based expression quantitative trait loci analysis showed that IKBKAP rs4978754 and TNFRSF1B rs677844 genotypes were significantly associated with their corresponding mRNA expression levels in lung cancer tissues in a recessive model (P = 0.035 and 0.045, respectively). Therefore, we identified two potentially functional SNPs (IKBKAP rs4978754 C > T and TNFRSF1B rs677844 T > C) to be associated with survival of patients with NSCLC.
Open Access
Single-nucleotide polymorphisms of stemness genes predicted to regulate RNA splicing, microRNA and oncogenic signaling are associated with prostate cancer survival.
(Carcinogenesis, 2018-07) Freedman, Jennifer A; Wang, Yanru; Li, Xuechan; Liu, Hongliang; Moorman, Patricia G; George, Daniel J; Lee, Norman H; Hyslop, Terry; Wei, Qingyi; Patierno, Steven R
Prostate cancer (PCa) is a clinically and molecularly heterogeneous disease, with variation in outcomes only partially predicted by grade and stage. Additional tools to distinguish indolent from aggressive disease are needed. Phenotypic characteristics of stemness correlate with poor cancer prognosis. Given this correlation, we identified single-nucleotide polymorphisms (SNPs) of stemness-related genes and examined their associations with PCa survival. SNPs within stemness-related genes were analyzed for association with overall survival of PCa in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Significant SNPs predicted to be functional were selected for linkage disequilibrium analysis and combined and stratified analyses. Identified SNPs were evaluated for association with gene expression. SNPs of CD44 (rs9666607), ABCC1 (rs35605 and rs212091) and GDF15 (rs1058587) were associated with PCa survival and predicted to be functional. A role for rs9666607 of CD44 and rs35605 of ABCC1 in RNA splicing regulation, rs212091 of ABCC1 in miRNA binding site activity and rs1058587 of GDF15 in causing an amino acid change was predicted. These SNPs represent potential novel prognostic markers for overall survival of PCa and support a contribution of the stemness pathway to PCa patient outcome.