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Article ; Online: Moving from one to many: insights from the growing list of pleiotropic cancer risk genes.

Bien, Stephanie A / Peters, Ulrike

2019 Volume 120, Issue 12, Page(s) 1087–1089

Abstract: Pleiotropy, a phenomenon in which a single gene affects multiple phenotypes, is becoming very common among different cancer types and cancer-related phenotypes, such as those in hormonal, cardiometabolic and inflammatory/immune conditions. The discovery ... ...

Abstract	Pleiotropy, a phenomenon in which a single gene affects multiple phenotypes, is becoming very common among different cancer types and cancer-related phenotypes, such as those in hormonal, cardiometabolic and inflammatory/immune conditions. The discovery of pleiotropic associations can improve our understanding of cancer and help to target investigation of genes with greater clinical relevance.
MeSH term(s)	Genetic Pleiotropy ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Humans ; Neoplasms/genetics ; Penetrance ; Phenotype
Language	English
Publishing date	2019-05-21
Publishing country	England
Document type	Editorial ; Research Support, N.I.H., Extramural
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-019-0475-9
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Article ; Online: Tumor-associated antigen-specific T cells with nivolumab are safe and persist in vivo in relapsed/refractory Hodgkin lymphoma.

Dave, Hema / Terpilowski, Madeline / Mai, Mimi / Toner, Keri / Grant, Melanie / Stanojevic, Maja / Lazarski, Christopher / Shibli, Abeer / Bien, Stephanie A / Maglo, Philip / Hoq, Fahmida / Schore, Reuven / Glenn, Martha / Hu, Boyu / Hanley, Patrick J / Ambinder, Richard / Bollard, Catherine M

Blood advances

2021 Volume 6, Issue 2, Page(s) 473–485

Abstract: Hodgkin lymphoma (HL) Reed Sternberg cells express tumor-associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA-specific T cells (TAA-Ts) targeting WT1, PRAME, and Survivin were safe and associated ... ...

Abstract	Hodgkin lymphoma (HL) Reed Sternberg cells express tumor-associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA-specific T cells (TAA-Ts) targeting WT1, PRAME, and Survivin were safe and associated with prolonged time to progression in solid tumors. Hence, we evaluated whether TAA-Ts when given alone or with nivolumab were safe and could elicit antitumor effects in vivo in patients with relapsed/refractory (r/r) HL. Ten patients were infused with TAA-Ts (8 autologous and 2 allogeneic) for active HL (n = 8) or as adjuvant therapy after hematopoietic stem cell transplant (n = 2). Six patients received nivolumab priming before TAA-Ts and continued until disease progression or unacceptable toxicity. All 10 products recognized 1 or more TAAs and were polyfunctional. Patients were monitored for safety for 6 weeks after the TAA-Ts and for response until disease progression. The infusions were safe with no clear dose-limiting toxicities. Patients receiving TAA-Ts as adjuvant therapy remain in continued remission at 3+ years. Of the 8 patients with active disease, 1 patient had a complete response and 7 had stable disease at 3 months, 3 of whom remain with stable disease at 1 year. Antigen spreading and long-term persistence of TAA-Ts in vivo were observed in responding patients. Nivolumab priming impacted TAA-T recognition and persistence. In conclusion, treatment of patients with r/r HL with TAA-Ts alone or in combination with nivolumab was safe and produced promising results. This trial was registered at www.clinicaltrials.gov as #NCT022039303 and #NCT03843294.
MeSH term(s)	Antigens, Neoplasm ; Disease Progression ; Hodgkin Disease/drug therapy ; Humans ; Nivolumab/therapeutic use ; T-Lymphocytes/pathology
Chemical Substances	Antigens, Neoplasm ; Nivolumab (31YO63LBSN)
Language	English
Publishing date	2021-09-03
Publishing country	United States
Document type	Clinical Trial ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2021005343
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Article ; Online: The Future of Genomic Studies Must Be Globally Representative: Perspectives from PAGE.

Bien, Stephanie A / Wojcik, Genevieve L / Hodonsky, Chani J / Gignoux, Christopher R / Cheng, Iona / Matise, Tara C / Peters, Ulrike / Kenny, Eimear E / North, Kari E

Annual review of genomics and human genetics

2019 Volume 20, Page(s) 181–200

Abstract: The past decade has seen a technological revolution in human genetics that has empowered population-level investigations into genetic associations with phenotypes. Although these discoveries rely on genetic variation across individuals, association ... ...

Abstract	The past decade has seen a technological revolution in human genetics that has empowered population-level investigations into genetic associations with phenotypes. Although these discoveries rely on genetic variation across individuals, association studies have overwhelmingly been performed in populations of European descent. In this review, we describe limitations faced by single-population studies and provide an overview of strategies to improve global representation in existing data sets and future human genomics research via diversity-focused, multiethnic studies. We highlight the successes of individual studies and meta-analysis consortia that have provided unique knowledge. Additionally, we outline the approach taken by the Population Architecture Using Genomics and Epidemiology (PAGE) study to develop best practices for performing genetic epidemiology in multiethnic contexts. Finally, we discuss how limiting investigations to single populations impairs findings in the clinical domain for both rare-variant identification and genetic risk prediction.
MeSH term(s)	Bias ; Continental Population Groups/genetics ; Databases, Factual ; Ethnic Groups/genetics ; Genetic Variation ; Genome, Human ; Genome-Wide Association Study ; Genotype ; Human Genetics/trends ; Humans ; Metagenomics/trends ; Molecular Epidemiology/trends ; Phenotype
Language	English
Publishing date	2019-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2037670-4
ISSN	1545-293X ; 1527-8204
ISSN (online)	1545-293X
ISSN	1527-8204
DOI	10.1146/annurev-genom-091416-035517
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Article ; Online: Genetic associations of breast and prostate cancer are enriched for regulatory elements identified in disease-related tissues.

Chen, Hongjie / Kichaev, Gleb / Bien, Stephanie A / MacDonald, James W / Wang, Lu / Bammler, Theo K / Auer, Paul / Pasaniuc, Bogdan / Lindström, Sara

Human genetics

2019 Volume 138, Issue 10, Page(s) 1091–1104

Abstract: Although genome-wide association studies (GWAS) have identified hundreds of risk loci for breast and prostate cancer, only a few studies have characterized the GWAS association signals across functional genomic annotations with a particular focus on ... ...

Abstract	Although genome-wide association studies (GWAS) have identified hundreds of risk loci for breast and prostate cancer, only a few studies have characterized the GWAS association signals across functional genomic annotations with a particular focus on single nucleotide polymorphisms (SNPs) located in DNA regulatory elements. In this study, we investigated the enrichment pattern of GWAS signals for breast and prostate cancer in genomic functional regions located in normal tissue and cancer cell lines. We quantified the overall enrichment of SNPs with breast and prostate cancer association p values < 1 × 10
MeSH term(s)	Biomarkers, Tumor ; Breast Neoplasms/genetics ; Cell Line, Tumor ; Computational Biology/methods ; Female ; Genetic Association Studies ; Genetic Predisposition to Disease ; Genetic Variation ; Genome-Wide Association Study ; Humans ; Male ; Molecular Sequence Annotation ; Organ Specificity ; Prostatic Neoplasms/genetics ; Regulatory Sequences, Nucleic Acid
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2019-06-22
Publishing country	Germany
Document type	Journal Article
ZDB-ID	223009-4
ISSN	1432-1203 ; 0340-6717
ISSN (online)	1432-1203
ISSN	0340-6717
DOI	10.1007/s00439-019-02041-5
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Article ; Online: A general framework for functionally informed set-based analysis: Application to a large-scale colorectal cancer study.

Dong, Xinyuan / Su, Yu-Ru / Barfield, Richard / Bien, Stephanie A / He, Qianchuan / Harrison, Tabitha A / Huyghe, Jeroen R / Keku, Temitope O / Lindor, Noralane M / Schafmayer, Clemens / Chan, Andrew T / Gruber, Stephen B / Jenkins, Mark A / Kooperberg, Charles / Peters, Ulrike / Hsu, Li

PLoS genetics

2020 Volume 16, Issue 8, Page(s) e1008947

Abstract: Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. ... ...

Abstract	Genome-wide association studies (GWAS) have successfully identified tens of thousands of genetic variants associated with various phenotypes, but together they explain only a fraction of heritability, suggesting many variants have yet to be discovered. Recently it has been recognized that incorporating functional information of genetic variants can improve power for identifying novel loci. For example, S-PrediXcan and TWAS tested the association of predicted gene expression with phenotypes based on GWAS summary statistics by leveraging the information on genetic regulation of gene expression and found many novel loci. However, as genetic variants may have effects on more than one gene and through different mechanisms, these methods likely only capture part of the total effects of these variants. In this paper, we propose a summary statistics-based mixed effects score test (sMiST) that tests for the total effect of both the effect of the mediator by imputing genetically predicted gene expression, like S-PrediXcan and TWAS, and the direct effects of individual variants. It allows for multiple functional annotations and multiple genetically predicted mediators. It can also perform conditional association analysis while adjusting for other genetic variants (e.g., known loci for the phenotype). Extensive simulation and real data analyses demonstrate that sMiST yields p-values that agree well with those obtained from individual level data but with substantively improved computational speed. Importantly, a broad application of sMiST to GWAS is possible, as only summary statistics of genetic variant associations are required. We apply sMiST to a large-scale GWAS of colorectal cancer using summary statistics from ∼120, 000 study participants and gene expression data from the Genotype-Tissue Expression (GTEx) project. We identify several novel and secondary independent genetic loci.
MeSH term(s)	Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Computational Biology ; Gene Expression Regulation, Neoplastic/genetics ; Genetic Predisposition to Disease ; Genetic Variation/genetics ; Genome-Wide Association Study ; Genotype ; Humans ; Models, Statistical ; Phenotype ; Polymorphism, Single Nucleotide/genetics ; Quantitative Trait Loci/genetics
Language	English
Publishing date	2020-08-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1008947
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Article ; Online: A large-scale transcriptome-wide association study (TWAS) of 10 blood cell phenotypes reveals complexities of TWAS fine-mapping.

Tapia, Amanda L / Rowland, Bryce T / Rosen, Jonathan D / Preuss, Michael / Young, Kris / Graff, Misa / Choquet, Hélène / Couper, David J / Buyske, Steve / Bien, Stephanie A / Jorgenson, Eric / Kooperberg, Charles / Loos, Ruth J F / Morrison, Alanna C / North, Kari E / Yu, Bing / Reiner, Alexander P / Li, Yun / Raffield, Laura M

Genetic epidemiology

2021 Volume 46, Issue 1, Page(s) 3–16

Abstract: Hematological measures are important intermediate clinical phenotypes for many acute and chronic diseases and are highly heritable. Although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, ... ...

Abstract	Hematological measures are important intermediate clinical phenotypes for many acute and chronic diseases and are highly heritable. Although genome-wide association studies (GWAS) have identified thousands of loci containing trait-associated variants, the causal genes underlying these associations are often uncertain. To better understand the underlying genetic regulatory mechanisms, we performed a transcriptome-wide association study (TWAS) to systematically investigate the association between genetically predicted gene expression and hematological measures in 54,542 Europeans from the Genetic Epidemiology Research on Aging cohort. We found 239 significant gene-trait associations with hematological measures; we replicated 71 associations at p < 0.05 in a TWAS meta-analysis consisting of up to 35,900 Europeans from the Women's Health Initiative, Atherosclerosis Risk in Communities Study, and BioMe Biobank. Additionally, we attempted to refine this list of candidate genes by performing conditional analyses, adjusting for individual variants previously associated with hematological measures, and performed further fine-mapping of TWAS loci. To facilitate interpretation of our findings, we designed an R Shiny application to interactively visualize our TWAS results by integrating them with additional genetic data sources (GWAS, TWAS from multiple reference panels, conditional analyses, known GWAS variants, etc.). Our results and application highlight frequently overlooked TWAS challenges and illustrate the complexity of TWAS fine-mapping.
MeSH term(s)	Blood Cells ; Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study/methods ; Humans ; Phenotype ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Transcriptome
Language	English
Publishing date	2021-11-15
Publishing country	United States
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	605785-8
ISSN	1098-2272 ; 0741-0395
ISSN (online)	1098-2272
ISSN	0741-0395
DOI	10.1002/gepi.22436
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Article ; Online: Corrigendum to: Colorectal cancer susceptibility variants and risk of conventional adenomas and serrated polyps: results from three cohort studies.

Hang, Dong / Joshi, Amit D / He, Xiaosheng / Chan, Andrew T / Jovani, Manol / Gala, Manish K / Ogino, Shuji / Kraft, Peter / Turman, Constance / Peters, Ulrike / Bien, Stephanie A / Lin, Yi / Hu, Zhibin / Shen, Hongbing / Wu, Kana / Giovannucci, Edward L / Song, Mingyang

International journal of epidemiology

2019 Volume 49, Issue 1, Page(s) 352

Language	English
Publishing date	2019-05-23
Publishing country	England
Document type	Journal Article ; Published Erratum
ZDB-ID	187909-1
ISSN	1464-3685 ; 0300-5771
ISSN (online)	1464-3685
ISSN	0300-5771
DOI	10.1093/ije/dyz112
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Article ; Online: Colorectal cancer susceptibility variants and risk of conventional adenomas and serrated polyps: results from three cohort studies.

International journal of epidemiology

2019 Volume 49, Issue 1, Page(s) 259–269

Abstract: Background: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain ... ...

Abstract	Background: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown. Methods: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis. Results: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584). Conclusions: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.
MeSH term(s)	Adenoma/genetics ; Aged ; Cohort Studies ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/pathology ; Follow-Up Studies ; Genome-Wide Association Study ; Genotype ; Humans ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; Polyps/genetics ; Polyps/pathology ; Prospective Studies ; Risk Factors
Language	English
Publishing date	2019-03-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	187909-1
ISSN	1464-3685 ; 0300-5771
ISSN (online)	1464-3685
ISSN	0300-5771
DOI	10.1093/ije/dyz096
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Article ; Online: Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancer.

Papadimitriou, Nikos / Kim, Andre / Kawaguchi, Eric S / Morrison, John / Diez-Obrero, Virginia / Albanes, Demetrius / Berndt, Sonja I / Bézieau, Stéphane / Bien, Stephanie A / Bishop, D Timothy / Bouras, Emmanouil / Brenner, Hermann / Buchanan, Daniel D / Campbell, Peter T / Carreras-Torres, Robert / Chan, Andrew T / Chang-Claude, Jenny / Conti, David V / Devall, Matthew A /

Dimou, Niki / Drew, David A / Gruber, Stephen B / Harrison, Tabitha A / Hoffmeister, Michael / Huyghe, Jeroen R / Joshi, Amit D / Keku, Temitope O / Kundaje, Anshul / Küry, Sébastien / Le Marchand, Loic / Lewinger, Juan Pablo / Li, Li / Lynch, Brigid M / Moreno, Victor / Newton, Christina C / Obón-Santacana, Mireia / Ose, Jennifer / Pellatt, Andrew J / Peoples, Anita R / Platz, Elizabeth A / Qu, Conghui / Rennert, Gad / Ruiz-Narvaez, Edward / Shcherbina, Anna / Stern, Mariana C / Su, Yu-Ru / Thomas, Duncan C / Thomas, Claire E / Tian, Yu / Tsilidis, Konstantinos K / Ulrich, Cornelia M / Um, Caroline Y / Visvanathan, Kala / Wang, Jun / White, Emily / Woods, Michael O / Schmit, Stephanie L / Macrae, Finlay / Potter, John D / Hopper, John L / Peters, Ulrike / Murphy, Neil / Hsu, Li / Gunter, Marc J / Gauderman, W James

EBioMedicine

2024 Volume 104, Page(s) 105146

Abstract: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations.: Methods: A ... ...

Abstract	Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. Findings: The 3-DF joint test revealed two significant loci with p-value <5 × 10 Interpretation: We identified 2 loci associated with fibre and fruit intake that also modify the association of these dietary factors with CRC risk. Potential mechanisms include chronic inflammatory intestinal disorders, and gut function. However, further studies are needed for mechanistic validation and replication of findings. Funding: National Institutes of Health, National Cancer Institute. Full funding details for the individual consortia are provided in acknowledgments.
Language	English
Publishing date	2024-05-14
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2024.105146
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Article ; Online: Ancestry-specific associations identified in genome-wide combined-phenotype study of red blood cell traits emphasize benefits of diversity in genomics.

BMC genomics

2020 Volume 21, Issue 1, Page(s) 228

Abstract: Background: Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite ... ...

Abstract	Background: Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. Results: We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p < 5E-9), with lead SNPs at nine loci significantly associated with three or more RBC traits. A majority of the lead SNPs were common (MAF > 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP. Conclusion: This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations.
MeSH term(s)	Black or African American/genetics ; Erythrocytes/metabolism ; Female ; Genetics, Population ; Genome-Wide Association Study/methods ; Hispanic or Latino/genetics ; Humans ; Male ; Multifactorial Inheritance ; Phenotype ; Polymorphism, Single Nucleotide ; Quantitative Trait, Heritable ; Sequence Analysis, DNA ; United States/ethnology ; White People/genetics
Language	English
Publishing date	2020-03-14
Publishing country	England
Document type	Journal Article
ZDB-ID	2041499-7
ISSN	1471-2164 ; 1471-2164
ISSN (online)	1471-2164
ISSN	1471-2164
DOI	10.1186/s12864-020-6626-9
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