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1. Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia

Author

Mary L. McMaster, Sonja I. Berndt, Jianqing Zhang, Susan L. Slager, Shengchao Alfred Li, Claire M. Vajdic, Karin E. Smedby, Huihuang Yan, Brenda M. Birmann, Elizabeth E. Brown, Alex Smith, Geffen Kleinstern, Mervin M. Fansler, Christine Mayr, Bin Zhu, Charles C. Chung, Ju-Hyun Park, Laurie Burdette, Belynda D. Hicks, Amy Hutchinson, Lauren R. Teras, Hans-Olov Adami, Paige M. Bracci, James McKay, Alain Monnereau, Brian K. Link, Roel C. H. Vermeulen, Stephen M. Ansell, Ann Maria, W. Ryan Diver, Mads Melbye, Akinyemi I. Ojesina, Peter Kraft, Paolo Boffetta, Jacqueline Clavel, Edward Giovannucci, Caroline M. Besson, Federico Canzian, Ruth C. Travis, Paolo Vineis, Elisabete Weiderpass, Rebecca Montalvan, Zhaoming Wang, Meredith Yeager, Nikolaus Becker, Yolanda Benavente, Paul Brennan, Lenka Foretova, Marc Maynadie, Alexandra Nieters, Silvia de Sanjose, Anthony Staines, Lucia Conde, Jacques Riby, Bengt Glimelius, Henrik Hjalgrim, Nisha Pradhan, Andrew L. Feldman, Anne J. Novak, Charles Lawrence, Bryan A. Bassig, Qing Lan, Tongzhang Zheng, Kari E. North, Lesley F. Tinker, Wendy Cozen, Richard K. Severson, Jonathan N. Hofmann, Yawei Zhang, Rebecca D. Jackson, Lindsay M. Morton, Mark P. Purdue, Nilanjan Chatterjee, Kenneth Offit, James R. Cerhan, Stephen J. Chanock, Nathaniel Rothman, Joseph Vijai, Lynn R. Goldin, Christine F. Skibola, and Neil E. Caporaso

Subjects
Science
Abstract

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a non-Hodgkin-type B cell lymphoma. Here, the authors identify two risk loci for WM/LPL in a two-stage GWAS involving a family-oversampling approach and provide evidence for a functional role of the non-coding SNP rs116446171.

Published
2018
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2. Genetically Determined Height and Risk of Non-hodgkin Lymphoma

Author

Amy Moore, Eleanor Kane, Zhaoming Wang, Orestis A. Panagiotou, Lauren R. Teras, Alain Monnereau, Nicole Wong Doo, Mitchell J. Machiela, Christine F. Skibola, Susan L. Slager, Gilles Salles, Nicola J. Camp, Paige M. Bracci, Alexandra Nieters, Roel C. H. Vermeulen, Joseph Vijai, Karin E. Smedby, Yawei Zhang, Claire M. Vajdic, Wendy Cozen, John J. Spinelli, Henrik Hjalgrim, Graham G. Giles, Brian K. Link, Jacqueline Clavel, Alan A. Arslan, Mark P. Purdue, Lesley F. Tinker, Demetrius Albanes, Giovanni M. Ferri, Thomas M. Habermann, Hans-Olov Adami, Nikolaus Becker, Yolanda Benavente, Simonetta Bisanzi, Paolo Boffetta, Paul Brennan, Angela R. Brooks-Wilson, Federico Canzian, Lucia Conde, David G. Cox, Karen Curtin, Lenka Foretova, Susan M. Gapstur, Hervé Ghesquières, Martha Glenn, Bengt Glimelius, Rebecca D. Jackson, Qing Lan, Mark Liebow, Marc Maynadie, James McKay, Mads Melbye, Lucia Miligi, Roger L. Milne, Thierry J. Molina, Lindsay M. Morton, Kari E. North, Kenneth Offit, Marina Padoan, Alpa V. Patel, Sara Piro, Vignesh Ravichandran, Elio Riboli, Silvia de Sanjose, Richard K. Severson, Melissa C. Southey, Anthony Staines, Carolyn Stewart, Ruth C. Travis, Elisabete Weiderpass, Stephanie Weinstein, Tongzhang Zheng, Stephen J. Chanock, Nilanjan Chatterjee, Nathaniel Rothman, Brenda M. Birmann, James R. Cerhan, and Sonja I. Berndt

Subjects
non-Hodgkin lymphoma, height, genetics, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00–1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01–1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.

Published
2020
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3. Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia

Author

Philip J. Law, Sonja I. Berndt, Helen E. Speedy, Nicola J. Camp, Georgina P. Sava, Christine F. Skibola, Amy Holroyd, Vijai Joseph, Nicola J. Sunter, Alexandra Nieters, Silvia Bea, Alain Monnereau, David Martin-Garcia, Lynn R. Goldin, Guillem Clot, Lauren R. Teras, Inés Quintela, Brenda M. Birmann, Sandrine Jayne, Wendy Cozen, Aneela Majid, Karin E. Smedby, Qing Lan, Claire Dearden, Angela R. Brooks-Wilson, Andrew G. Hall, Mark P. Purdue, Tryfonia Mainou-Fowler, Claire M. Vajdic, Graham H. Jackson, Pierluigi Cocco, Helen Marr, Yawei Zhang, Tongzhang Zheng, Graham G. Giles, Charles Lawrence, Timothy G. Call, Mark Liebow, Mads Melbye, Bengt Glimelius, Larry Mansouri, Martha Glenn, Karen Curtin, W Ryan Diver, Brian K. Link, Lucia Conde, Paige M. Bracci, Elizabeth A. Holly, Rebecca D. Jackson, Lesley F. Tinker, Yolanda Benavente, Paolo Boffetta, Paul Brennan, Marc Maynadie, James McKay, Demetrius Albanes, Stephanie Weinstein, Zhaoming Wang, Neil E. Caporaso, Lindsay M. Morton, Richard K. Severson, Elio Riboli, Paolo Vineis, Roel C. H. Vermeulen, Melissa C. Southey, Roger L. Milne, Jacqueline Clavel, Sabine Topka, John J. Spinelli, Peter Kraft, Maria Grazia Ennas, Geoffrey Summerfield, Giovanni M. Ferri, Robert J. Harris, Lucia Miligi, Andrew R. Pettitt, Kari E. North, David J. Allsup, Joseph F. Fraumeni, James R. Bailey, Kenneth Offit, Guy Pratt, Henrik Hjalgrim, Chris Pepper, Stephen J. Chanock, Chris Fegan, Richard Rosenquist, Silvia de Sanjose, Angel Carracedo, Martin J. S. Dyer, Daniel Catovsky, Elias Campo, James R. Cerhan, James M. Allan, Nathanial Rothman, Richard Houlston, and Susan Slager

Subjects
Science
Abstract

Chronic lymphocytic leukaemia has a hereditary component, much of which remains to be identified. Here, the authors perform a genome-wide association study and find new risk loci for the disease, which are associated with genes involved in immune function.

Published
2017
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4. Nonsyndromic cleft lip with or without cleft palate and cancer: Evaluation of a possible common genetic background through the analysis of GWAS data

Author

Eva Dunkhase, Kerstin U. Ludwig, Michael Knapp, Christine F. Skibola, Jane C. Figueiredo, Fay Julie Hosking, Eva Ellinghaus, Maria Teresa Landi, Hongxia Ma, Hidewaki Nakagawa, Jong-Won Kim, Jiali Han, Ping Yang, Anne C. Böhmer, Manuel Mattheisen, Markus M. Nöthen, and Elisabeth Mangold

Subjects
Cleft lip, Cleft palate, Genome-wide association study, Single nucleotide polymorphism, Cancer, Genetics, QH426-470
Abstract

Previous research suggests a genetic overlap between nonsyndromic cleft lip with or without cleft palate (NSCL/P) and cancer. The aim of the present study was to identify common genetic risk loci for NSCL/P and cancer entities that have been reported to co-occur with orofacial clefting. This was achieved through the investigation of large genome-wide association study datasets. Investigations of 12 NSCL/P single nucleotide polymorphisms (SNPs) in 32 cancer datasets, and 204 cancer SNPs in two NSCL/P datasets, were performed. The SNPs rs13041247 (20q12) and rs6457327 (6p21.33) showed suggestive evidence for an association with both NSCL/P and a specific cancer entity. These loci harbor genes of biological relevance to oncogenesis (MAFB and OCT4, respectively). This study is the first to characterize possible pleiotropic risk loci for NSCL/P and cancer in a systematic manner. The data represent a starting point for future research by identifying a genetic link between NSCL/P and cancer.

Published
2016
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5. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

Author

Sonja I. Berndt, Nicola J. Camp, Christine F. Skibola, Joseph Vijai, Zhaoming Wang, Jian Gu, Alexandra Nieters, Rachel S. Kelly, Karin E. Smedby, Alain Monnereau, Wendy Cozen, Angela Cox, Sophia S. Wang, Qing Lan, Lauren R. Teras, Moara Machado, Meredith Yeager, Angela R. Brooks-Wilson, Patricia Hartge, Mark P. Purdue, Brenda M. Birmann, Claire M. Vajdic, Pierluigi Cocco, Yawei Zhang, Graham G. Giles, Anne Zeleniuch-Jacquotte, Charles Lawrence, Rebecca Montalvan, Laurie Burdett, Amy Hutchinson, Yuanqing Ye, Timothy G. Call, Tait D. Shanafelt, Anne J. Novak, Neil E. Kay, Mark Liebow, Julie M. Cunningham, Cristine Allmer, Henrik Hjalgrim, Hans-Olov Adami, Mads Melbye, Bengt Glimelius, Ellen T. Chang, Martha Glenn, Karen Curtin, Lisa A. Cannon-Albright, W Ryan Diver, Brian K. Link, George J. Weiner, Lucia Conde, Paige M. Bracci, Jacques Riby, Donna K. Arnett, Degui Zhi, Justin M. Leach, Elizabeth A. Holly, Rebecca D. Jackson, Lesley F. Tinker, Yolanda Benavente, Núria Sala, Delphine Casabonne, Nikolaus Becker, Paolo Boffetta, Paul Brennan, Lenka Foretova, Marc Maynadie, James McKay, Anthony Staines, Kari G. Chaffee, Sara J. Achenbach, Celine M. Vachon, Lynn R. Goldin, Sara S. Strom, Jose F. Leis, J. Brice Weinberg, Neil E. Caporaso, Aaron D. Norman, Anneclaire J. De Roos, Lindsay M. Morton, Richard K. Severson, Elio Riboli, Paolo Vineis, Rudolph Kaaks, Giovanna Masala, Elisabete Weiderpass, María- Dolores Chirlaque, Roel C. H. Vermeulen, Ruth C. Travis, Melissa C. Southey, Roger L. Milne, Demetrius Albanes, Jarmo Virtamo, Stephanie Weinstein, Jacqueline Clavel, Tongzhang Zheng, Theodore R. Holford, Danylo J. Villano, Ann Maria, John J. Spinelli, Randy D. Gascoyne, Joseph M. Connors, Kimberly A. Bertrand, Edward Giovannucci, Peter Kraft, Anne Kricker, Jenny Turner, Maria Grazia Ennas, Giovanni M. Ferri, Lucia Miligi, Liming Liang, Baoshan Ma, Jinyan Huang, Simon Crouch, Ju-Hyun Park, Nilanjan Chatterjee, Kari E. North, John A. Snowden, Josh Wright, Joseph F. Fraumeni, Kenneth Offit, Xifeng Wu, Silvia de Sanjose, James R. Cerhan, Stephen J. Chanock, Nathaniel Rothman, and Susan L. Slager

Subjects
Science
Abstract

Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPPassociated with risk of this disease.

Published
2016
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6. Supplemental Table from HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author

Christine F. Skibola, Patricia Hartge, Nathaniel Rothman, Stephen J. Chanock, Peter Kraft, Yawei Zhang, Anne Kricker, Eve Roman, Martyn T. Smith, Angela Brooks-Wilson, Qing Lan, Richard K. Severson, Scott Davis, Anthony Staines, Lenka Foretova, Paulo Bofetta, Gilles Salles, Hervé Ghesquières, David G. Cox, Alain Monnereau, Jacqueline Clavel, Karen Curtin, Martha Glenn, Nicola J. Camp, Lucia Conde, Bengt Glimelius, Mads Melbye, Hans-Olov Adami, Mark P. Purdue, Alan A. Arslan, Jacob Musinsky, Kenneth Offit, Roger L. Milne, Melissa C. Southey, Graham G. Giles, Nicole Wong Doo, Andrew L. Feldman, Giancarlo Latte, Maria Grazia Ennas, Corrado Magnani, Brian K. Link, Marie-Hélène Delfau-Larue, James McKay, Paul Brennan, Yolanda Benavente, Elio Riboli, Rudolph Kaaks, Ruth C. Travis, Stephanie J. Lax, W. Ryan Diver, Lauren R. Teras, Stephanie J. Weinstein, Demetrius Albanes, Pierluigi Cocco, Marc Maynadie, Dennis Weisenburger, Eleanor Kane, Elizabeth A. Holly, Nikolaus Becker, Christopher R. Flowers, Brenda M. Birmann, Tongzhang Zheng, John J. Spinelli, Jennifer Turner, Elizabeth E. Brown, Wendy Cozen, Silvia de Sanjose, Alexandra Nieters, Martha S. Linet, Claire M. Vajdic, Ora Paltiel, Roel Vermeulen, Lindsay M. Morton, Joseph Vijai, Henrik Hjalgrim, Karin E. Smedby, James R. Cerhan, Jenna Voutsinas, Paige M. Bracci, Susan L. Slager, Sonja I. Berndt, Mary Carrington, and Sophia S. Wang

Abstract

SUPPLEMENTAL TABLE: Effect of homozygosity at the three HLA class I loci -A, -B and -C and five HLA class I loci -DRB1, DQA1, DQB1, DPA1, and DPB1 on susceptibility to four NHL subtypes (DLBCL, FL, CLL/SLL, and MZL) stratified by GWAS platform (analyses adjusted for sex, age, and ancestry/principal components)

Published
2023
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7. Data from HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author

Christine F. Skibola, Patricia Hartge, Nathaniel Rothman, Stephen J. Chanock, Peter Kraft, Yawei Zhang, Anne Kricker, Eve Roman, Martyn T. Smith, Angela Brooks-Wilson, Qing Lan, Richard K. Severson, Scott Davis, Anthony Staines, Lenka Foretova, Paulo Bofetta, Gilles Salles, Hervé Ghesquières, David G. Cox, Alain Monnereau, Jacqueline Clavel, Karen Curtin, Martha Glenn, Nicola J. Camp, Lucia Conde, Bengt Glimelius, Mads Melbye, Hans-Olov Adami, Mark P. Purdue, Alan A. Arslan, Jacob Musinsky, Kenneth Offit, Roger L. Milne, Melissa C. Southey, Graham G. Giles, Nicole Wong Doo, Andrew L. Feldman, Giancarlo Latte, Maria Grazia Ennas, Corrado Magnani, Brian K. Link, Marie-Hélène Delfau-Larue, James McKay, Paul Brennan, Yolanda Benavente, Elio Riboli, Rudolph Kaaks, Ruth C. Travis, Stephanie J. Lax, W. Ryan Diver, Lauren R. Teras, Stephanie J. Weinstein, Demetrius Albanes, Pierluigi Cocco, Marc Maynadie, Dennis Weisenburger, Eleanor Kane, Elizabeth A. Holly, Nikolaus Becker, Christopher R. Flowers, Brenda M. Birmann, Tongzhang Zheng, John J. Spinelli, Jennifer Turner, Elizabeth E. Brown, Wendy Cozen, Silvia de Sanjose, Alexandra Nieters, Martha S. Linet, Claire M. Vajdic, Ora Paltiel, Roel Vermeulen, Lindsay M. Morton, Joseph Vijai, Henrik Hjalgrim, Karin E. Smedby, James R. Cerhan, Jenna Voutsinas, Paige M. Bracci, Susan L. Slager, Sonja I. Berndt, Mary Carrington, and Sophia S. Wang

Abstract

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Published
2023
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8. Supplementary Tables 1 and 2 from Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium

Author

Eve Roman, Tongzhang Zheng, Yawei Zhang, Sophia S. Wang, Susan L. Slager, Silvia de Sanjosé, Lindsay Morton, Mads Melbye, Mark Liebow, Alex G. Smith, Stephen M. Ansell, Tracy J. Lightfoot, Anne J. Novak, Marc Maynadié, Elizabeth A. Holly, Karin Ekström Smedby, Laura Costas, James R. Cerhan, Paige M. Bracci, Christine F. Skibola, and Eleanor Kane

Abstract

Supplementary Tables 1 and 2. Joint associations and relative excess risks due to interaction between BMI and cytokine polymorphisms for lymphoid neoplasms

Published
2023
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9. Data from Non-Hodgkin Lymphoma, Body Mass Index, and Cytokine Polymorphisms: A Pooled Analysis from the InterLymph Consortium

Author

Eve Roman, Tongzhang Zheng, Yawei Zhang, Sophia S. Wang, Susan L. Slager, Silvia de Sanjosé, Lindsay Morton, Mads Melbye, Mark Liebow, Alex G. Smith, Stephen M. Ansell, Tracy J. Lightfoot, Anne J. Novak, Marc Maynadié, Elizabeth A. Holly, Karin Ekström Smedby, Laura Costas, James R. Cerhan, Paige M. Bracci, Christine F. Skibola, and Eleanor Kane

Abstract

Background: Excess adiposity has been associated with lymphomagenesis, possibly mediated by increased cytokine production causing a chronic inflammatory state. The relationship between obesity, cytokine polymorphisms, and selected mature B-cell neoplasms is reported.Method: Data on 4,979 cases and 4,752 controls from nine American/European studies from the InterLymph consortium (1988–2008) were pooled. For diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), joint associations of body mass index (from self-reported height and weight) and 12 polymorphisms in cytokines IL1A (rs1800587), IL1B (rs16944, rs1143627), IL1RN (rs454078), IL2 (rs2069762), IL6 (rs1800795, rs1800797), IL10 (rs1800890, rs1800896), TNF (rs1800629), LTA (rs909253), and CARD15 (rs2066847) were investigated using unconditional logistic regression. BMI-polymorphism interaction effects were estimated using the relative excess risk due to interaction (RERI).Results: Obesity (BMI ≥ 30 kg/m2) was associated with DLBCL risk [OR = 1.33; 95% confidence interval (CI), 1.02–1.73], as was TNF-308GA+AA (OR = 1.24; 95% CI, 1.07–1.44). Together, being obese and TNF-308GA+AA increased DLBCL risk almost 2-fold relative to those of normal weight and TNF-308GG (OR = 1.93; 95% CI, 1.27–2.94), with a RERI of 0.41 (95% CI, −0.05–0.84; Pinteraction = 0.13). For FL and CLL/SLL, no associations with obesity or TNF-308GA+AA, either singly or jointly, were observed. No evidence of interactions between obesity and the other polymorphisms were detected.Conclusions: Our results suggest that cytokine polymorphisms do not generally interact with BMI to increase lymphoma risk but obesity and TNF-308GA+AA may interact to increase DLBCL risk.Impact: Studies using better measures of adiposity are needed to further investigate the interactions between obesity and TNF-308G>A in the pathogenesis of lymphoma. Cancer Epidemiol Biomarkers Prev; 24(7); 1061–70. ©2015 AACR.

Published
2023
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10. Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways

Author

Qing Lan, Alexandra Nieters, Mark P. Purdue, Christine F. Skibola, Lauren R. Teras, Angela Brooks-Wilson, Kenneth Offit, Anne Zeleniuch-Jacquotte, Joseph Vijai, Simon Crouch, Vivekananda Sarangi, Graham G. Giles, James R. Cerhan, Sophia S. Wang, Nathaniel Rothman, James McKay, Mads Melbye, Karin E. Smedby, Yan W. Asmann, Xifeng Wu, Pierluigi Cocco, Gilles Salles, Hervé Ghesquières, Rebecca D. Jackson, Peter Kraft, Brenda M. Birmann, Huihuang Yan, Sonja I. Berndt, Stephen J. Chanock, Claire M. Vajdic, Demetrius Albanes, Michelle A.T. Hildebrandt, Susan L. Slager, Yuanqing Ye, Geffen Kleinstern, Alain Monnereau, Yawei Zhang, and Roel Vermeulen

Subjects
Linkage disequilibrium, Lymphoma, B-Cell, Genotype, Receptors, Cell Surface, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, 03 medical and health sciences, 0302 clinical medicine, Gene Frequency, Odds Ratio, Genetics, medicine, Genetic predisposition, Humans, SNP, Genetic Predisposition to Disease, Promoter Regions, Genetic, Molecular Biology, Genetics (clinical), 030304 developmental biology, 0303 health sciences, General Medicine, medicine.disease, Minor allele frequency, 030220 oncology & carcinogenesis, B7-2 Antigen, Chromosomes, Human, Pair 3, Diffuse large B-cell lymphoma, Genome-Wide Association Study
Abstract

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

Published
2019
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11. B-Cell NHL Subtype Risk Associated with Autoimmune Conditions and PRS

Author

Sophia S. Wang, Claire M. Vajdic, Martha S. Linet, Susan L. Slager, Jenna Voutsinas, Alexandra Nieters, Delphine Casabonne, James R. Cerhan, Wendy Cozen, Graciela Alarcón, Otoniel Martínez-Maza, Elizabeth E. Brown, Paige M. Bracci, Jennifer Turner, Henrik Hjalgrim, Parveen Bhatti, Yawei Zhang, Brenda M. Birmann, Christopher R. Flowers, Ora Paltiel, Elizabeth A. Holly, Eleanor Kane, Dennis D. Weisenburger, Marc Maynadié, Pierluigi Cocco, Lenka Foretova, Elizabeth Crabb Breen, Qing Lan, Angela Brooks-Wilson, Anneclaire J. De Roos, Martyn T. Smith, Eve Roman, Paolo Boffetta, Anne Kricker, Tongzhang Zheng, Christine F. Skibola, Jacqueline Clavel, Alain Monnereau, Stephen J. Chanock, Nathaniel Rothman, Yolanda Benavente, Patricia Hartge, Karin E. Smedby, Beckman Research Institute of the City of Hope, University of New South Wales [Sydney] (UNSW), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Mayo Clinic [Rochester], Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Epidemiología y Salud Pública (CIBERESP), University of California [Irvine] (UCI), University of California, University of Alabama at Birmingham [ Birmingham] (UAB), University of California [Los Angeles] (UCLA), University of California [San Francisco] (UCSF), Macquarie University [Sydney], Statens Serum Institut [Copenhagen], British Columbia Cancer Research Centre [British Columbia, Canada], Chinese Academy of Medical Sciences [Beijing, China] (CAMS), Peking Union Medical College [Beijing, China], Harvard Medical School [Boston] (HMS), Emory University [Atlanta, GA], Hadassah Hebrew University Medical Center [Jerusalem], University of York [York, UK], City of Hope Comprehensive Cancer Center [Duarte], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University of Cagliari, Masaryk Memorial Cancer Institute (RECAMO), Simon Fraser University (SFU.ca), Drexel University, University of California [Berkeley], Stony Brook University [SUNY] (SBU), State University of New York (SUNY), University of Bologna, The University of Sydney, Brown University, Centre for Research in Earth and Space Science [Toronto] (CRESS), York University [Toronto], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer environnement (EPICENE ), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER, Karolinska Institutet [Stockholm], European Commission, European Regional Development Fund, and National Cancer Institute

Subjects
B-Lymphocytes, Malalties autoimmunitàries, Epidemiology, Autoimmune diseases, Genomics, Article, Autoimmune Diseases, Genòmica, Oncology, immune system diseases, hemic and lymphatic diseases, Case-Control Studies, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Lymphoma, Large B-Cell, Diffuse, Lymphoma, Follicular, Genome-Wide Association Study
Abstract

Background: A previous International Lymphoma Epidemiology (InterLymph) Consortium evaluation of joint associations between five immune gene variants and autoimmune conditions reported interactions between B-cell response-mediated autoimmune conditions and the rs1800629 genotype on risk of B-cell non–Hodgkin lymphoma (NHL) subtypes. Here, we extend that evaluation using NHL subtype-specific polygenic risk scores (PRS) constructed from loci identified in genome-wide association studies of three common B-cell NHL subtypes. Methods: In a pooled analysis of NHL cases and controls of Caucasian descent from 14 participating InterLymph studies, we evaluated joint associations between B-cell–mediated autoimmune conditions and tertile (T) of PRS for risk of diffuse large B-cell lymphoma (DLBCL; n = 1,914), follicular lymphoma (n = 1,733), and marginal zone lymphoma (MZL; n = 407), using unconditional logistic regression. Results: We demonstrated a positive association of DLBCL PRS with DLBCL risk [T2 vs. T1: OR = 1.24; 95% confidence interval (CI), 1.08–1.43; T3 vs. T1: OR = 1.81; 95% CI, 1.59–2.07; P-trend (Ptrend) < 0.0001]. DLBCL risk also increased with increasing PRS tertile among those with an autoimmune condition, being highest for those with a B-cell–mediated autoimmune condition and a T3 PRS [OR = 6.46 vs. no autoimmune condition and a T1 PRS, Ptrend < 0.0001, P-interaction (Pinteraction) = 0.49]. Follicular lymphoma and MZL risk demonstrated no evidence of joint associations or significant Pinteraction. Conclusions: Our results suggest that PRS constructed from currently known subtype-specific loci may not necessarily capture biological pathways shared with autoimmune conditions. Impact: Targeted genetic (PRS) screening among population subsets with autoimmune conditions may offer opportunities for identifying those at highest risk for (and early detection from) DLBCL.

Published
2021
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12. Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes

Author

Joseph Vijai, Henrik Hjalgrim, Roger L. Milne, Simonetta Bisanzi, Rebecca D. Jackson, Graham G. Giles, Mark Liebow, John J. Spinelli, Stephanie J. Weinstein, Wendy Cozen, Susan M. Gapstur, Michael Dean, Paolo Boffetta, Pierluigi Cocco, Paige M. Bracci, Nicola J. Camp, Amy Moore, Herve Ghesquieres, Federico Canzian, James McKay, Thomas M. Habermann, Nikolaus Becker, Kari E. North, Demetrius Albanes, Alain Monnereau, Marc Maynadié, Lesley F. Tinker, Christine F. Skibola, Vignesh Ravichandran, Susan L. Slager, Karin E. Smedby, Ruth C. Travis, Jacqueline Clavel, Lucia Miligi, Melissa C. Southey, Mary Carrington, Claire M. Vajdic, Karen Curtin, David G. Cox, Roel Vermeulen, Elio Riboli, Eleanor Kane, Weiyin Zhou, Nathaniel Rothman, Mitchell J. Machiela, Yolanda Benavente, Alan A. Arslan, Meredith Yeager, Paul Brennan, Tongzhang Zheng, Elisabete Weiderpass, Moara Machado, Qing Lan, Alpa V. Patel, James R. Cerhan, Sonja I. Berndt, Neil E. Caporaso, Silvia de Sanjosé, Stephen J. Chanock, Nicole Wong Doo, Lauren R. Teras, Sara Piro, Lenka Foretova, Chi Gao, Gilles Salles, Immaculata De Vivo, Alexandra Nieters, Bengt Glimelius, Sophia S. Wang, Richard K. Severson, Mads Melbye, Hans-Olov Adami, Yawei Zhang, Carolyn Stewart, Lucia Conde, Brenda M. Birmann, Angela Brooks-Wilson, Thierry Jo Molina, Kenneth Offit, Brian K. Link, Martha Glenn, Anthony Staines, Moore, Amy, Machiela, Mitchell J, Machado, Moara, Wang, Sophia S, Kane, Eleanor, Slager, Susan L, Zhou, Weiyin, Carrington, Mary, Lan, Qing, Milne, Roger L, Birmann, Brenda M, Adami, Hans-Olov, Albanes, Demetriu, Arslan, Alan A, Becker, Nikolau, Benavente, Yolanda, Bisanzi, Simonetta, Boffetta, Paolo, Bracci, Paige M, Brennan, Paul, Brooks-Wilson, Angela R, Canzian, Federico, Caporaso, Neil, Clavel, Jacqueline, Cocco, Pierluigi, Conde, Lucia, Cox, David G, Cozen, Wendy, Curtin, Karen, De Vivo, Immaculata, de Sanjose, Silvia, Foretova, Lenka, Gapstur, Susan M, Ghesquières, Hervè, Giles, Graham G, Glenn, Martha, Glimelius, Bengt, Gao, Chi, Habermann, Thomas M, Hjalgrim, Henrik, Jackson, Rebecca D, Liebow, Mark, Link, Brian K, Maynadie, Marc, McKay, Jame, Melbye, Mad, Miligi, Lucia, Molina, Thierry J, Monnereau, Alain, Nieters, Alexandra, North, Kari E, Offit, Kenneth, Patel, Alpa V, Piro, Sara, Ravichandran, Vignesh, Riboli, Elio, Salles, Gille, Severson, Richard K, Skibola, Christine F, Smedby, Karin E, Southey, Melissa C, Spinelli, John J, Staines, Anthony, Stewart, Carolyn, Teras, Lauren R, Tinker, Lesley F, Travis, Ruth C, Vajdic, Claire M, Vermeulen, Roel C H, Vijai, Joseph, Weiderpass, Elisabete, Weinstein, Stephanie, Doo, Nicole Wong, Zhang, Yawei, Zheng, Tongzhang, Chanock, Stephen J, Rothman, Nathaniel, Cerhan, James R, Dean, Michael, Camp, Nicola J, Yeager, Meredith, and Berndt, Sonja I

Subjects
Genetics, Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Follicular lymphoma, Single-nucleotide polymorphism, Runs of Homozygosity, Biology, medicine.disease, marginal zone lymphoma, Article, follicular lymphoma, immune system diseases, hemic and lymphatic diseases, Genetic variation, medicine, chronic lymphocytic leukemia, homozygosity, Diffuse large B-cell lymphoma, Inbreeding, Non-Hodgkin lymphoma, Genetic association
Abstract

Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10 -6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL ( P = 1.0) or MZL ( P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10 -5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

Published
2021
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13. HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author

Roel Vermeulen, Paulo Bofetta, Nicole Wong Doo, Mark P. Purdue, Eleanor Kane, Gilles Salles, Bengt Glimelius, Christine F. Skibola, Tongzhang Zheng, Graham G. Giles, Scott Davis, Pierluigi Cocco, Karin E. Smedby, Melissa C. Southey, Alexandra Nieters, Elizabeth A. Holly, Corrado Magnani, Paul Brennan, Stephanie J. Lax, David G. Cox, Lindsay M. Morton, Nikolaus Becker, Qing Lan, Elio Riboli, Herve Ghesquieres, Rudolph Kaaks, Jennifer Turner, Martha S. Linet, Anne Kricker, Stephanie J. Weinstein, Christopher R. Flowers, Alain Monnereau, Silvia de Sanjosé, Mary Carrington, John J. Spinelli, Patricia Hartge, Nathaniel Rothman, Yolanda Benavente, Susan L. Slager, Martha Glenn, Richard K. Severson, Ora Paltiel, Yawei Zhang, Ruth C. Travis, Demetrius Albanes, Nicola J. Camp, Paige M. Bracci, Jacqueline Clavel, James R. Cerhan, Marc Maynadié, Maria Grazia Ennas, Marie Hélène Delfau-Larue, Peter Kraft, Henrik Hjalgrim, Roger L. Milne, Alan A. Arslan, Jacob Musinsky, Martyn T. Smith, Anthony Staines, Lauren R. Teras, Jenna M. Voutsinas, Lenka Foretova, Sophia S. Wang, Hans-Olov Adami, Andrew L. Feldman, Wendy Cozen, Angela Brooks-Wilson, Kenneth Offit, Brian K. Link, Brenda M. Birmann, Sonja I. Berndt, Stephen J. Chanock, James McKay, Dennis D. Weisenburger, Claire M. Vajdic, Giancarlo Latte, Karen Curtin, W. Ryan Diver, Mads Melbye, Lucia Conde, Elizabeth E. Brown, Joseph Vijai, Eve Roman, Wang, Sophia S., Carrington, Mary, Berndt, Sonja I., Slager, Susan L., Bracci, Paige M., Voutsinas, Jenna, Cerhan, James R., Smedby, Karin E., Hjalgrim, Henrik, Vijai, Joseph, Morton, Lindsay M., Vermeulen, Roel, Paltiel, Ora, Vajdic, Claire M., Linet, Martha S., Nieters, Alexandra, de Sanjose, Silvia, Cozen, Wendy, Brown, Elizabeth E., Turner, Jennifer, Spinelli, John J., Zheng, Tongzhang, Birmann, Brenda M., Flowers, Christopher R., Becker, Nikolau, Holly, Elizabeth A., Kane, Eleanor, Weisenburger, Denni, Maynadie, Marc, Cocco, Pierluigi, Albanes, Demetriu, Weinstein, Stephanie J., Teras, Lauren R., Diver, W. Ryan, Lax, Stephanie J., Travis, Ruth C., Kaaks, Rudolph, Riboli, Elio, Benavente, Yolanda, Brennan, Paul, McKay, Jame, Delfau-Larue, Marie-Hélène, Link, Brian K., Magnani, Corrado, Ennas, Maria Grazia, Latte, Giancarlo, Feldman, Andrew L., Doo, Nicole Wong, Giles, Graham G., Southey, Melissa C., Milne, Roger L., Offit, Kenneth, Musinsky, Jacob, Arslan, Alan A., Purdue, Mark P., Adami, Hans-Olov, Melbye, Mad, Glimelius, Bengt, Conde, Lucia, Camp, Nicola J., Glenn, Martha, Curtin, Karen, Clavel, Jacqueline, Monnereau, Alain, Cox, David G., Ghesquières, Hervé, Salles, Gille, Boffetta, Paolo, Foretova, Lenka, Staines, Anthony, Davis, Scott, Severson, Richard K., Lan, Qing, Brooks-Wilson, Angela, Smith, Martyn T., Roman, Eve, Kricker, Anne, Zhang, Yawei, Kraft, Peter, Chanock, Stephen J., Rothman, Nathaniel, Hartge, Patricia, and Skibola, Christine F.

Subjects
Male, 0301 basic medicine, Heterozygote, Cancer Research, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Chronic lymphocytic leukemia, EPIDEMIOLOGIC RESEARCH, Genome-wide association study, Human leukocyte antigen, Biology, CLASSIFICATION, ANTIGENS, Article, Genetic Heterogeneity, 03 medical and health sciences, immune system diseases, hemic and lymphatic diseases, Internal medicine, medicine, INTERLYMPH, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Prospective Studies, GENOME-WIDE ASSOCIATION, Allele, HLA Complex, Science & Technology, Hematology, CHRONIC LYMPHOCYTIC-LEUKEMIA, Genetic heterogeneity, Lymphoma, Non-Hodgkin, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, HETEROZYGOTE ADVANTAGE, medicine.disease, 3. Good health, Lymphoma, 030104 developmental biology, Oncology, Case-Control Studies, Immunology, B-VIRUS INFECTION, Female, Life Sciences & Biomedicine, NEOPLASMS, Genome-Wide Association Study
Abstract

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Published
2018
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14. Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population

Author

Lucia Conde, Allan H. Smith, Craig Steinmaus, Nicholas K. Akers, Catterina Ferreccio, Martyn T. Smith, Rosemarie de la Rosa, Luoping Zhang, David A. Kalman, Christine F. Skibola, and Kevin Zhang

Subjects
0301 basic medicine, medicine.medical_specialty, Methyltransferase, Epidemiology, Health, Toxicology and Mutagenesis, Metabolite, Population, chemistry.chemical_element, Single-nucleotide polymorphism, Mutagen, 010501 environmental sciences, Biology, medicine.disease_cause, 01 natural sciences, DNA methyltransferase, 03 medical and health sciences, chemistry.chemical_compound, Internal medicine, medicine, education, Lung cancer, Genetics (clinical), Arsenic, 0105 earth and related environmental sciences, Genetics, education.field_of_study, medicine.disease, 030104 developmental biology, Endocrinology, chemistry
Abstract

Inter-individual differences in arsenic metabolism have been linked to arsenic-related disease risks. Arsenic (+3) methyltransferase (AS3MT) is the primary enzyme involved in arsenic metabolism, and we previously demonstrated in vitro that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) also methylates the toxic inorganic arsenic (iAs) metabolite, monomethylarsonous acid (MMA), to the less toxic dimethylarsonic acid (DMA). Here, we evaluated whether AS3MT and N6AMT1 gene polymorphisms alter arsenic methylation and impact iAs-related cancer risks. We assessed AS3MT and N6AMT1 polymorphisms and urinary arsenic metabolites (%iAs, %MMA, %DMA) in 722 subjects from an arsenic-cancer case-control study in a uniquely exposed area in northern Chile. Polymorphisms were genotyped using a custom designed multiplex, ligation-dependent probe amplification (MLPA) assay for 6 AS3MT SNPs and 14 tag SNPs in the N6AMT1 gene. We found several AS3MT polymorphisms associated with both urinary arsenic metabolite profiles and cancer risk. For example, compared to wildtypes, individuals carrying minor alleles in AS3MT rs3740393 had lower %MMA (mean difference = −1.9%, 95% CI: −3.3, −0.4), higher %DMA (mean difference = 4.0%, 95% CI: 1.5, 6.5), and lower odds ratios for bladder (OR = 0.3; 95% CI: 0.1–0.6) and lung cancer (OR = 0.6; 95% CI: 0.2–1.1). Evidence of interaction was also observed for both lung and bladder cancer between these polymorphisms and elevated historical arsenic exposures. Clear associations were not seen for N6AMT1. These results are the first to demonstrate a direct association between AS3MT polymorphisms and arsenic-related internal cancer risk. This research could help identify subpopulations that are particularly vulnerable to arsenic-related disease. Environ. Mol. Mutagen., 2017. © 2017 Wiley Periodicals, Inc.

Published
2017
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15. Argininosuccinate Synthase 1 is a Metabolic Regulator of Colorectal Cancer Pathogenicity

Author

Daniel K. Nomura, Leslie A. Bateman, Carlo M. Contreras, Wan-min Ku, Christine F. Skibola, and Martin J. Heslin

Subjects
0301 basic medicine, Colorectal cancer, Metabolite, Cell, Argininosuccinate Synthase, Mouse model of colorectal and intestinal cancer, Biology, Bioinformatics, Biochemistry, 03 medical and health sciences, chemistry.chemical_compound, Metabolomics, Downregulation and upregulation, medicine, Humans, Enzyme Inhibitors, Cancer, General Medicine, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, chemistry, Metabolome, Cancer research, Molecular Medicine, Signal transduction, Colorectal Neoplasms, Signal Transduction
Abstract

Like many cancer types, colorectal cancers have dysregulated metabolism that promotes their pathogenic features. In this study, we used the activity-based protein profiling chemoproteomic platform to profile cysteine-reactive metabolic enzymes that are upregulated in primary human colorectal tumors. We identified argininosuccinate synthase 1 (ASS1) as an upregulated target in primary human colorectal tumors and show that pharmacological inhibition or genetic ablation of ASS1 impairs colorectal cancer pathogenicity. Using metabolomic profiling, we show that ASS1 inhibition leads to reductions in the levels of oncogenic metabolite fumarate, leading to impairments in glycolytic metabolism that supports colorectal cancer cell pathogenicity. We show here that ASS1 inhibitors may represent a novel therapeutic approach for attenuating colorectal cancer through compromising critical metabolic and metabolite signaling pathways and demonstrate the utility of coupling chemoproteomic and metabolomic strategies to map novel metabolic regulators of cancer.

Published
2017
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16. Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes

Author

Paul Brennan, M. G. Ennas, Qing Lan, Sasha Bernatsky, Alan A. Arslan, Peter Kraft, Lohith Madireddy, Roel Vermeulen, Kenan Onel, Graham G. Giles, John J. Spinelli, Eleanor Kane, Bengt Glimelius, Alexandra Nieters, David V. Conti, Christine F. Skibola, Pouya Khankhanian, Amy Moore, Ruth C. Travis, Mads Melbye, Sonja I. Berndt, Mark Liebow, Lauren R. Teras, Pierluigi Cocco, Lennox Din, Alain Monnereau, Mark P. Purdue, Lenka Foretova, Stephen J. Chanock, Stephen M. Ansell, Angela Brooks-Wilson, Wendy Cozen, Kenneth Offit, Demetrius Albanes, Anne J. Novak, Melissa C. Southey, Paolo Boffetta, Nicola J. Camp, James R. Cerhan, Rudolph Kaaks, Silvia de Sanjosé, Karen Curtin, Sophia S. Wang, James McKay, Nicole Wong Doo, Hans-Olov Adami, Tongzhang Zheng, Claire M. Vajdic, Nisha Pradhan, Giacomo Muzi, Gilles Salles, Nathaniel Rothman, Yolanda Benavente, Marc Maynadié, Brian K. Link, Delphine Casabonne, Hervé Ghesquières, Joseph Vijai, Karin E. Smedby, Paige M. Bracci, David G. Cox, Brenda M. Birmann, Lucia Miligi, Carolyn Stewart, Lucia Conde, Leonid Padyukov, Eve Roman, Richard K. Severson, Jorge R. Oksenberg, Immaculata De Vivo, Yawei Zhang, Corrado Magnani, Jacqueline Clavel, Lindsay M. Morton, Corinne Haioun, Jonathan N. Hofmann, Karen H. Costenbader, Pierre-Antoine Gourraud, Mohammad Sheikh, Stephanie J. Weinstein, Susan L. Slager, Paolo Vineis, Nikitha Kosaraju, Zachary Taub, Henrik Hjalgrim, Roger L. Milne, Morris Din, Martha Glenn, Nikolaus Becker, Timothy J. Vyse, Thomas M. Mack, Anthony Staines, Department of Medicine, Clinical Epidemiology, McGill University Health Center [Montreal] (MUHC), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Emory University [Atlanta, GA], Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, International Agency for Cancer Research (IACR), Department of Public Health, Vientiane Municipality, Registre des hémopathies malignes de Côte d'Or, Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, GRAPHOS - IFROSS Recherche, Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon, Faculty of Medicine, Section of Rheumatology, Imperial College London, Karolinska Institutet [Stockholm], Epidémiologie environnementale des cancers, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Uppsala Universitet [Uppsala], Carver College of Medicine, University of Iowa, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Cancer Epidemiology and Genetics, National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Health Sciences, University of York [York, UK], Service de Radio-Oncologie [Lyon], Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), University of Melbourne, Centre Léon Bérard [Lyon], Mayo Clinic [Rochester], Occupational and Environmental Epidemiology Branch [Bethesda, Maryland], Division of Cancer Epidemiology and Genetics [Bethesda, Maryland], National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), Memorial Sloane Kettering Cancer Center [New York], Huntsman Cancer Institute, Clinical Genetics Service, ISPO - Cancer Prevention and Research Institute, Unit of Environmental and Occupational Epidemiology, Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], B.B. Brodie Department of Neuroscience, Department of Pathology, Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Unit of Environment Cancer Epidemiology, IARC, University of Torino and CPO-Piemonte, Università degli studi di Torino (UNITO), Department of Epidemiology, Harvard School of Public Health, Wayne State University [Detroit], Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Cancer Epidemiology Centre, Cancer Council Victoria, Cancer Epidemiology Unit, University of Oxford [Oxford], De la Molécule aux Nanos-objets : Réactivité, Interactions et Spectroscopies (MONARIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Catalan Institute of Oncology (ICO), Department of Neurology [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Norris Comprehensive Cancer Center, Masaryk University [Brno] (MUNI), Università degli studi di Torino = University of Turin (UNITO), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Imperial College London, University of Oxford, Din L., Sheikh M., Kosaraju N., Smedby K.E., Bernatsky S., Berndt S.I., Skibola C.F., Nieters A., Wang S., McKay J.D., Cocco P., Maynadie M., Foretova L., Staines A., Mack T.M., de Sanjose S., Vyse T.J., Padyukov L., Monnereau A., Arslan A.A., Moore A., Brooks-Wilson A.R., Novak A.J., Glimelius B., Birmann B.M., Link B.K., Stewart C., Vajdic C.M., Haioun C., Magnani C., Conti D.V., Cox D.G., Casabonne D., Albanes D., Kane E., Roman E., Muzi G., Salles G., Giles G.G., Adami H.-O., Ghesquieres H., De Vivo I., Clavel J., Cerhan J.R., Spinelli J.J., Hofmann J., Vijai J., Curtin K., Costenbader K.H., Onel K., Offit K., Teras L.R., Morton L., Conde L., Miligi L., Melbye M., Ennas M.G., Liebow M., Purdue M.P., Glenn M., Southey M.C., Din M., Rothman N., Camp N.J., Wong Doo N., Becker N., Pradhan N., Bracci P.M., Boffetta P., Vineis P., Brennan P., Kraft P., Lan Q., Severson R.K., Vermeulen R.C.H., Milne R.L., Kaaks R., Travis R.C., Weinstein S.J., Chanock S.J., Ansell S.M., Slager S.L., Zheng T., Zhang Y., Benavente Y., Taub Z., Madireddy L., Gourraud P.-A., Oksenberg J.R., Cozen W., Hjalgrim H., Khankhanian P., and Le Bihan, Sylvie

Subjects
Oncology, Male, Multifactorial Inheritance, Lymphoma, Epidemiology, Chronic lymphocytic leukemia, Follicular lymphoma, Genome-wide association study, Disease, Neurodegenerative, meta-analysi, immune system diseases, HLA Antigens, Risk Factors, hemic and lymphatic diseases, 2.1 Biological and endogenous factors, HLA Antigen, Aetiology, Genetics (clinical), Cancer, Allele, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Lymphoma, Non-Hodgkin, non-Hodgkin lymphoma, 030305 genetics & heredity, Single Nucleotide, Hematology, Middle Aged, 3. Good health, Public Health and Health Services, Female, Human, medicine.medical_specialty, autoimmune disease, genome-wide association study, meta-analysis, Alleles, Autoimmune Diseases, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Non-Hodgkin, Article, 03 medical and health sciences, Rare Diseases, Internal medicine, Genetic variation, medicine, Genetics, Polymorphism, 030304 developmental biology, Autoimmune disease, business.industry, Multiple sclerosis, Risk Factor, Arthritis, Inflammatory and immune system, Human Genome, medicine.disease, Brain Disorders, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Published
2019
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17. Infectious mononucleosis, immune genotypes, and non-Hodgkin lymphoma (NHL): an InterLymph Consortium study

Author

Susan L. Slager, Jun Wang, Eleanor Kane, Alexandra Nieters, Elizabeth E. Brown, Cindy M. Chang, Wendy Cozen, Joshua Millstein, Niquelle Brown Wadé, Karin E. Smedby, Ruth F. Jarrett, Sophia S. Wang, David V. Conti, Henrik Hjalgrim, Silvia de Sanjosé, Yawei Zhang, John J. Spinelli, Paige M. Bracci, and Christine F. Skibola

Subjects
Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Mononucleosis, Adolescent, Genotype, Logistic regression, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Risk Factors, Internal medicine, Epidemiology, medicine, T-cell lymphoma, Humans, 030212 general & internal medicine, Infectious Mononucleosis, Gene–environment interaction, Aged, Aged, 80 and over, business.industry, Lymphoma, Non-Hodgkin, Bayes Theorem, Odds ratio, Middle Aged, medicine.disease, Confidence interval, 3. Good health, Lymphoma, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Self Report, business
Abstract

We explored the interaction between non-Hodgkin lymphoma (NHL), infectious mononucleosis (IM) history, and immune-related genotypes in a pooled case–control analysis. A total of 7,926 NHL patients and 10,018 controls from 12 case–control studies were included. Studies were conducted during various time periods between 1988 and 2008, and participants were 17–96 years of age at the time of ascertainment/recruitment. Self-reported IM history and immune response genotypes were provided by the InterLymph Data Coordinating Center at Mayo Clinic. Odds ratios (OR) were estimated using multivariate logistic regression, and interactions were estimated using the empirical Bayes method. PACT was used to account for multiple comparisons. There was evidence of an interaction effect between IM history and two variants on T-cell lymphoma (TCL) risk: rs1143627 in interleukin-1B (IL1B) (pinteraction = 0.04, ORinteraction = 0.09, 95% confidence interval [CI] 0.01, 0.87) and rs1800797 in interleukin-6 (IL6) (pinteraction = 0.03, ORinteraction = 0.08, 95% CI 0.01, 0.80). Neither interaction effect withstood adjustment for multiple comparisons. There were no statistically significant interactions between immune response genotypes and IM on other NHL subtypes. Genetic risk variants in IL1B and IL6 may affect the association between IM and TCL, possibly by influencing T-cell activation, growth, and differentiation in the presence of IM, thereby decreasing risk of immune cell proliferation.

Published
2019

18. Chemoproteomic Screening of Covalent Ligands Reveals UBA5 As a Novel Pancreatic Cancer Target

Author

Carlo M. Contreras, Tucker R. Huffman, Ashley N. Ives, David Akopian, David K. Miyamoto, Allison M. Roberts, Daniel K. Nomura, Christine F. Skibola, Leslie A. Bateman, Martin J. Heslin, and Michael Rape

Subjects
Proteomics, 0301 basic medicine, Ubiquitin-activating enzyme, Druggability, Antineoplastic Agents, Ubiquitin-Activating Enzymes, Biology, Ligands, Polymerase Chain Reaction, 01 natural sciences, Biochemistry, 03 medical and health sciences, Pancreatic cancer, medicine, Humans, chemistry.chemical_classification, 010405 organic chemistry, Ligand, General Medicine, medicine.disease, Small molecule, 0104 chemical sciences, Pancreatic Neoplasms, 030104 developmental biology, Enzyme, Mechanism of action, chemistry, Gene Knockdown Techniques, Molecular Medicine, medicine.symptom
Abstract

Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy. Through this coupled approach, we have discovered a covalent ligand DKM 2-93 that impairs pancreatic cancer cell survival and in vivo tumor growth through covalently modifying the catalytic cysteine of the ubiquitin-like modifier activating enzyme 5 (UBA5), thereby inhibiting its activity as a protein that activates the ubiquitin-like protein UFM1 to UFMylate proteins. We show that UBA5 is a novel pancreatic cancer therapeutic target and show DKM 2-93 as a relatively selective lead inhibitor of UBA5. Our results underscore the utility of coupling the screening of covalent ligand libraries with isoTOP-ABPP platforms for mining the proteome for druggable hotspots for cancer therapy.

Published
2017
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19. Serum protein profiling in diffuse large B-cell lymphoma

Author

Jianqing Zhang, Paige M. Bracci, Jacques Riby, Christine F. Skibola, and James A. Mobley

Subjects
0301 basic medicine, Oncology, Pathology, medicine.medical_specialty, Clinical Biochemistry, Lipopolysaccharide Receptors, Enzyme-Linked Immunosorbent Assay, Pilot Projects, Proteomics, Mass Spectrometry, 03 medical and health sciences, 0302 clinical medicine, hemic and lymphatic diseases, Internal medicine, Humans, Medicine, Clinical significance, Prospective cohort study, Chromatography, High Pressure Liquid, Aged, Aged, 80 and over, Extracellular Matrix Proteins, Cluster of differentiation, Adiponectin, business.industry, Blood Proteins, Middle Aged, medicine.disease, Lymphoma, 030104 developmental biology, Case-Control Studies, 030220 oncology & carcinogenesis, Biomarker (medicine), Lymphoma, Large B-Cell, Diffuse, Peptides, business, Diffuse large B-cell lymphoma, Heparan Sulfate Proteoglycans
Abstract

Purpose The aim of this pilot study was to conduct a non-targeted exploratory proteomics profiling analysis on sera obtained from patients diagnosed with diffuse large B-cell lymphoma (DLBCL) with the goal of identifying disease-specific biomarkers. Experimental design Sera from 87 participants (57 chemotherapy-naive diffuse DLBCL patients, 30 controls frequency-matched by age group and World Health Organization (WHO) BMI categories) that were part of a large San Francisco Bay Area case-control study of non-Hodgkin lymphoma were analyzed by liquid chromatography combined with tandem mass spectrometry. Results Thirty-five proteins (p-adjusted

Published
2016
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20. Nonsyndromic cleft lip with or without cleft palate and cancer: Evaluation of a possible common genetic background through the analysis of GWAS data

Author

Jiali Han, Jong-Won Kim, Hongxia Ma, Manuel Mattheisen, Anne C. Böhmer, Maria Teresa Landi, Eva Ellinghaus, Elisabeth Mangold, Fay J. Hosking, Christine F. Skibola, Hidewaki Nakagawa, Michael Knapp, Eva Dunkhase, Kerstin U. Ludwig, Ping Yang, Jane C. Figueiredo, and Markus M. Nöthen

Subjects
0301 basic medicine, Genome-wide association study, lcsh:QH426-470, Gwas data, Single-nucleotide polymorphism, Biology, medicine.disease_cause, Biochemistry, 03 medical and health sciences, Genetics, medicine, Genetic risk, Cancer, Cleft lip, Regular Article, medicine.disease, 3. Good health, Single nucleotide polymorphism, lcsh:Genetics, 030104 developmental biology, MAFB, Cleft palate, Molecular Medicine, Carcinogenesis, Biotechnology
Abstract

Previous research suggests a genetic overlap between nonsyndromic cleft lip with or without cleft palate (NSCL/P) and cancer. The aim of the present study was to identify common genetic risk loci for NSCL/P and cancer entities that have been reported to co-occur with orofacial clefting. This was achieved through the investigation of large genome-wide association study datasets. Investigations of 12 NSCL/P single nucleotide polymorphisms (SNPs) in 32 cancer datasets, and 204 cancer SNPs in two NSCL/P datasets, were performed. The SNPs rs13041247 (20q12) and rs6457327 (6p21.33) showed suggestive evidence for an association with both NSCL/P and a specific cancer entity. These loci harbor genes of biological relevance to oncogenesis (MAFB and OCT4, respectively). This study is the first to characterize possible pleiotropic risk loci for NSCL/P and cancer in a systematic manner. The data represent a starting point for future research by identifying a genetic link between NSCL/P and cancer.

Published
2016

21. Lipid trait variants and the risk of non-hodgkin lymphoma subtypes: a mendelian randomization study

Author

Nicola J. Camp, Eleanor Kane, Sonja I. Berndt, Paige M. Bracci, Geffen Kleinstern, Stephen J. Chanock, Alain Monnereau, Henrik Hjalgrim, Roel Vermeulen, Mark P. Purdue, Neil E. Caporaso, Pierluigi Cocco, Lauren R. Teras, James McKay, James R. Cerhan, Susan L. Slager, Graham G. Giles, Sophia S. Wang, Brenda M. Birmann, Gilles Salles, Claire M. Vajdic, Angela Brooks-Wilson, Christine F. Skibola, Nathaniel Rothman, Yawei Zhang, Yolanda Benavente, Demetrius Albanes, Alexandra Nieters, Qing Lan, Anne Zeleniuch-Jacquotte, Hervé Ghesquières, Joseph Vijai, and Karin E. Smedby

Subjects
0301 basic medicine, Oncology, Limfomes, medicine.medical_specialty, Risk factors in diseases, Epidemiology, Chronic lymphocytic leukemia, Quantitative Trait Loci, Follicular lymphoma, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, immune system diseases, Internal medicine, hemic and lymphatic diseases, Mendelian randomization, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, Lymphoma, Follicular, Triglycerides, Factors de risc en les malalties, business.industry, Confounding, Lymphoma, B-Cell, Marginal Zone, Mendelian Randomization Analysis, Lipid Metabolism, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Lipids, Lymphoma, Causality, Lipoproteins, LDL, Cholesterol, 030104 developmental biology, Lípids, 030220 oncology & carcinogenesis, Trait, Hodgkin lymphoma, Lymphomas, Lymphoma, Large B-Cell, Diffuse, Lipoproteins, HDL, business, Genome-Wide Association Study
Abstract

Background: Lipid traits have been inconsistently linked to risk of non-Hodgkin lymphoma (NHL). We examined the association of genetically predicted lipid traits with risk of diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), and marginal zone lymphoma (MZL) using Mendelian randomization (MR) analysis. Methods: Genome-wide association study data from the InterLymph Consortium were available for 2,661 DLBCLs, 2,179 CLLs, 2,142 FLs, 824 MZLs, and 6,221 controls. SNPs associated (P < 5 × 10−8) with high-density lipoprotein (HDL, n = 164), low-density lipoprotein (LDL, n = 137), total cholesterol (TC, n = 161), and triglycerides (TG, n = 123) were used as instrumental variables (IV), explaining 14.6%, 27.7%, 16.8%, and 12.8% of phenotypic variation, respectively. Associations between each lipid trait and NHL subtype were calculated using the MR inverse variance–weighted method, estimating odds ratios (OR) per standard deviation and 95% confidence intervals (CI). Results: HDL was positively associated with DLBCL (OR = 1.14; 95% CI, 1.00–1.30) and MZL (OR = 1.09; 95% CI, 1.01–1.18), while TG was inversely associated with MZL risk (OR = 0.90; 95% CI, 0.83–0.99), all at nominal significance (P < 0.05). A positive trend was observed for HDL with FL risk (OR = 1.08; 95% CI, 0.99–1.19; P = 0.087). No associations were noteworthy after adjusting for multiple testing. Conclusions: We did not find evidence of a clear or strong association of these lipid traits with the most common NHL subtypes. While these IVs have been previously linked to other cancers, our findings do not support any causal associations with these NHL subtypes. Impact: Our results suggest that prior reported inverse associations of lipid traits are not likely to be causal and could represent reverse causality or confounding.

Published
2020

22. Correction to: Infectious mononucleosis, immune genotypes, and non-Hodgkin lymphoma (NHL): an InterLymph Consortium study

Author

Wendy Cozen, Henrik Hjalgrim, David V. Conti, Silvia de Sanjosé, John J. Spinelli, Yawei Zhang, Elizabeth E. Brown, Niquelle Brown Wadé, Karin E. Smedby, Paige M. Bracci, Jun Wang, Alexandra Nieters, Christine F. Skibola, Sophia S. Wang, Cindy M. Chang, Joshua Millstein, Ruth F. Jarrett, Eleanor Kane, and Susan L. Slager

Subjects
Cancer Research, medicine.medical_specialty, Hematology, Mononucleosis, business.industry, medicine.disease, Dermatology, Article, Immune system, Oncology, Internal medicine, Genotype, medicine, Hodgkin lymphoma, business
Abstract

PURPOSE: We explored the interaction between non-Hodgkin lymphoma (NHL), infectious mononucleosis (IM) history, and immune-related genotypes in a pooled case–control analysis. METHODS: A total of 7,926 NHL patients and 10,018 controls from 12 case–control studies were included. Studies were conducted during various time periods between 1988 and 2008, and participants were 17–96 years of age at the time of ascertainment/recruitment. Self-reported IM history and immune response genotypes were provided by the InterLymph Data Coordinating Center at Mayo Clinic. Odds ratios (OR) were estimated using multivariate logistic regression, and interactions were estimated using the empirical Bayes method. PACT was used to account for multiple comparisons. RESULTS: There was evidence of an interaction effect between IM history and two variants on T-cell lymphoma (TCL) risk: rs1143627 in interleukin-1B (IL1B) (p(interaction) = 0.04, OR(interaction) = 0.09, 95% confidence interval [CI] 0.01, 0.87) and rs1800797 in interleukin-6 (IL6) (p(interaction) = 0.03, OR(interaction) = 0.08, 95% CI 0.01, 0.80). Neither interaction effect withstood adjustment for multiple comparisons. There were no statistically significant interactions between immune response genotypes and IM on other NHL subtypes. CONCLUSIONS: Genetic risk variants in IL1B and IL6 may affect the association between IM and TCL, possibly by influencing T-cell activation, growth, and differentiation in the presence of IM, thereby decreasing risk of immune cell proliferation.

Published
2020
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23. Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Author

Kari G. Chaffee, Sonja I. Berndt, Alexandra Nieters, Lindsay M. Morton, Stephen J. Chanock, Neil E. Caporaso, Delphine Casabonne, Karin E. Smedby, Aaron D. Norman, Celine M. Vachon, James McKay, Pierluigi Cocco, Christine F. Skibola, Timothy G. Call, Nicola J. Camp, Martha Glenn, Jacqueline Clavel, Mark Liebow, Paolo Boffetta, James B. Johnston, John J. Spinelli, James R. Cerhan, Lynn R. Goldin, Hans-Olov Adami, Nathaniel Rothman, Yolanda Benavente, J. Brice Weinberg, Paul Brennan, Paige M. Bracci, Marc Maynadié, Dennis P. Robinson, Geffen Kleinstern, Silvia de Sanjosé, Susan L. Slager, Tait D. Shanafelt, Lucia Conde, Bengt Glimelius, Richard K. Severson, Jose F. Leis, Wendy Cozen, Claire M. Vajdic, Angela Brooks-Wilson, Mads Melbye, Henrik Hjalgrim, Karen Curtin, Neil E. Kay, Curtis A. Hanson, Alain Monnereau, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Catalan Institute of Oncology, Department of Epidemiology, Catalan Institute of Oncology (ICO), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], Uppsala Universitet [Uppsala], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Registre des hémopathies malignes de Côte d'Or, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), International Agency for Cancer Research (IACR), Mayo Clinic [Rochester], Laboratoire Interdisciplinaire de Spectroscopie Electronique (LISE), Facultés Universitaires Notre Dame de la Paix (FUNDP), Registre des hémopathies malignes de la Gironde, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Cancer environnement (EPICENE ), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe 7 : EPICEA - Epidémiologie des cancers de l'enfant et de l'adolescent (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Huntsman Cancer Institute, Norris Comprehensive Cancer Center, Wayne State University [Detroit], Division of Cancer Epidemiology and Genetics, National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Emory University [Atlanta, GA], Cancer Center Karolinska [Karolinska Institutet] (CCK), Department of Psychiatry, Facultés Universitaires Notre Dame de la Paix (FUNDP) - Namur, Institut Bergonié - CRLCC Bordeaux, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kleinstern, Geffen, Camp, Nicola J., Goldin, Lynn R., Vachon, Celine M., Vajdic, Claire M., De Sanjose, Silvia, Weinberg, J. Brice, Benavente, Yolanda, Casabonne, Delphine, Liebow, Mark, Nieters, Alexandra, Hjalgrim, Henrik, Melbye, Mad, Glimelius, Bengt, Adami, Hans-Olov, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, Jame, Cocco, Pier Luigi, Shanafelt, Tait D., Call, Timothy G., Norman, Aaron D., Hanson, Curti, Robinson, Denni, Chaffee, Kari G., Brooks-Wilson, Angela R., Monnereau, Alain, Clavel, Jacqueline, Glenn, Martha, Curtin, Karen, Conde, Lucia, Bracci, Paige M., Morton, Lindsay M., Cozen, Wendy, Severson, Richard K., Chanock, Stephen J., Spinelli, John J., Johnston, James B., Rothman, Nathaniel, Skibola, Christine F., Leis, Jose F., Kay, Neil E., Smedby, Karin E., Berndt, Sonja I., Cerhan, James R., Caporaso, Neil, and Slager, Susan L.

Subjects
Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Lymphocytosis, Clinical Trials and Observations, Chronic lymphocytic leukemia, Immunology, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, immune system diseases, Internal medicine, hemic and lymphatic diseases, Genotype, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, 10. No inequality, Aged, Aged, 80 and over, B-Lymphocytes, business.industry, Confounding, Cell Biology, Hematology, Odds ratio, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, 030104 developmental biology, Genetic epidemiology, Genetic Loci, 030220 oncology & carcinogenesis, Monoclonal B-cell lymphocytosis, Female, medicine.symptom, business
Abstract

IF 15.132 (2017); International audience; Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

Published
2018
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24. The potential relevance of the endocannabinoid, 2-arachidonoylglycerol, in diffuse large B-cell lymphoma

Author

Paige M. Bracci, Leon Bernal-Mizrachi, Jacques Riby, Daniel Medina-Cleghorn, Alan Hubbard, Lucia Conde, Daniel K. Nomura, Jianqing Zhang, and Christine F. Skibola

Subjects
0301 basic medicine, obesity, Cancer Research, medicine.medical_specialty, 2-AG, Population, lymphoma, Disease, Overweight, Gastroenterology, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, hemic and lymphatic diseases, Internal medicine, medicine, endocannabinoids, education, education.field_of_study, business.industry, medicine.disease, Obesity, 3. Good health, Lymphoma, 030104 developmental biology, Oncology, DLBCL, 030220 oncology & carcinogenesis, Immunology, Etiology, medicine.symptom, business, Diffuse large B-cell lymphoma, Research Paper
Abstract

Diffuse large B-cell lymphoma is an aggressive, genetically heterogenerous disease and the most common type of non-Hodgkin lymphoma among adults. To gain further insights into the etiology of DLBCL and to discover potential disease-related factors, we performed a serum lipid analysis on a subset of individuals from a population-based NHL case-control study. An untargeted mass-spectrometry-based metabolomics platform was used to analyze serum samples from 100 DLBCL patients and 100 healthy matched controls. Significantly elevated levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), were detected in the serum of DLBCL patients (121%, P < 0.05). In the male controls, elevated 2-AG levels were observed in those who were overweight (BMI ≥ 25 - < 30 kg/m2; 108%, P < 0.01) and obese (BMI ≥ 30 kg/m(2); 118%, P < 0.001) compared to those with a BMI < 25 kg/m(2). DLBCL cell lines treated with exogenous 2-AG across a range of concentrations, exhibited heterogenous responses: proliferation rates were markedly higher in 4 cell lines by 22%-68% (P < 0.001) and lower in 8 by 20%-75% (P < 0.001). The combined findings of elevated 2-AG levels in DLBCL patients and the proliferative effects of 2-AG on a subset of DLBCL cell lines suggests that 2-AG may play a potential role in the pathogenesis or progression of a subset of DLBCLs.

Published
2016
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25. Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia

Author

Laurie Burdette, Lindsay M. Morton, Neil E. Caporaso, Sonja I. Berndt, Paolo Vineis, Stephen J. Chanock, Stephen M. Ansell, Elisabete Weiderpass, James McKay, Charles C. Chung, Nisha Pradhan, James R. Cerhan, Peter Kraft, Alexandra Nieters, Lauren R. Teras, Lenka Foretova, Paul Brennan, Lesley F. Tinker, Susan L. Slager, Nilanjan Chatterjee, Jianqing Zhang, Caroline Besson, Mark P. Purdue, Zhaoming Wang, Shengchao Alfred Li, Bengt Glimelius, Paige M. Bracci, Qing Lan, Mervin M. Fansler, Jacqueline Clavel, Hans-Olov Adami, Ruth C. Travis, Karin E. Smedby, Christine F. Skibola, Silvia de Sanjosé, Edward Giovannucci, Akinyemi I. Ojesina, Huihuang Yan, Richard K. Severson, Jonathan N. Hofmann, Paolo Boffetta, Lynn R. Goldin, Yawei Zhang, Belynda Hicks, Bryan A. Bassig, Charles E. Lawrence, Andrew L. Feldman, Nathaniel Rothman, Jacques Riby, Yolanda Benavente, Nikolaus Becker, Geffen Kleinstern, Marc Maynadié, Meredith Yeager, Henrik Hjalgrim, Rebecca D. Jackson, Joseph Vijai, Tongzhang Zheng, Roel Vermeulen, Amy K. Hutchinson, Brenda M. Birmann, Bin Zhu, Kenneth Offit, Brian K. Link, Alex Smith, Anthony Staines, Christine Mayr, Federico Canzian, Lucia Conde, Rebecca Montalvan, Elizabeth E. Brown, Wendy Cozen, Anne J. Novak, Claire M. Vajdic, Ju-Hyun Park, W. Ryan Diver, Mary L. McMaster, Mads Melbye, Ann Maria, Kari E. North, Alain Monnereau, McMaster, Mary L., Berndt, Sonja I., Zhang, Jianqing, Slager, Susan L., Li, Shengchao Alfred, Vajdic, Claire M., Smedby, Karin E., Yan, Huihuang, Birmann, Brenda M., Brown, Elizabeth E., Smith, Alex, Kleinstern, Geffen, Fansler, Mervin M., Mayr, Christine, Zhu, Bin, Chung, Charles C., Park, Ju-Hyun, Burdette, Laurie, Hicks, Belynda D., Hutchinson, Amy, Teras, Lauren R., Adami, Hans-Olov, Bracci, Paige M., McKay, Jame, Monnereau, Alain, Link, Brian K., Vermeulen, Roel C. H., Ansell, Stephen M., Maria, Ann, Diver, W. Ryan, Melbye, Mad, Ojesina, Akinyemi I., Kraft, Peter, Boffetta, Paolo, Clavel, Jacqueline, Giovannucci, Edward, Besson, Caroline M., Canzian, Federico, Travis, Ruth C., Vineis, Paolo, Weiderpass, Elisabete, Montalvan, Rebecca, Wang, Zhaoming, Yeager, Meredith, Becker, Nikolau, Benavente, Yolanda, Brennan, Paul, Foretova, Lenka, Maynadie, Marc, Nieters, Alexandra, de Sanjose, Silvia, Staines, Anthony, Conde, Lucia, Riby, Jacque, Glimelius, Bengt, Hjalgrim, Henrik, Pradhan, Nisha, Feldman, Andrew L., Novak, Anne J., Lawrence, Charle, Bassig, Bryan A., Lan, Qing, Zheng, Tongzhang, North, Kari E., Tinker, Lesley F., Cozen, Wendy, Severson, Richard K., Hofmann, Jonathan N., Zhang, Yawei, Jackson, Rebecca D., Morton, Lindsay M., Purdue, Mark P., Chatterjee, Nilanjan, Offit, Kenneth, Cerhan, James R., Chanock, Stephen J., Rothman, Nathaniel, Vijai, Joseph, Goldin, Lynn R., Skibola, Christine F., Caporaso, Neil E., National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), International Agency for Cancer Research (IACR), Equipe 7 : EPICEA - Epidémiologie des cancers de l'enfant et de l'adolescent (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Department of Internal Medicine [Iowa City], Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Mayo Clinic [Rochester], Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Tisch Cancer Institute, Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Centre de recherche en épidémiologie et santé des populations (CESP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany, Catalan Institute of Oncology (ICO-IDIBELL), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Masaryk Memorial Cancer Institute, Masaryk Memorial Cancer Institute (RECAMO), Registre des hématopathies malignes de Côte d'Or (RHEMCO), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Carolina Center for Genome Sciences, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Keck School of Medicine [Los Angeles], University of Southern California (USC), Wayne State University [Detroit], Yale School of Public Health (YSPH), Ohio State University [Columbus] (OSU), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Memorial Sloane Kettering Cancer Center [New York], Emory University [Atlanta, GA], Department of Medical and Clinical Genetics, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Paul Brousse-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), One Health Chemisch, dIRAS RA-2, Sub Atmospheric physics and chemistry, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Sorbonne Paris Cité (USPC), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Genotyping Techniques, Inheritance Patterns, Genome-wide association study, enhanced green fluorescent protein, Lymphoplasmacytic Lymphoma, 0302 clinical medicine, Genes, Reporter, genetics, B-cell lymphoma, lcsh:Science, Malalties del sistema limfàtic, 1184 Genetics, developmental biology, physiology, Waldenstrom macroglobulinemia, Leucèmia, chromosome 14, reporter gene, 3. Good health, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Chromosomes, Human, Pair 6, NON-HODGKIN-LYMPHOMA, GERMINAL CENTER B, Human, Science, Green Fluorescent Protein, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Physics and Astronomy (all), LYMPHOPLASMACYTIC LYMPHOMA/WALDENSTROM MACROGLOBULINEMIA, Genetic predisposition, inheritance, Humans, Family, GENOME-WIDE ASSOCIATION, reproducibility, Inheritance Pattern, Cancer och onkologi, Science & Technology, Biochemistry, Genetics and Molecular Biology (all), VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, CHRONIC LYMPHOCYTIC-LEUKEMIA, nutritional and metabolic diseases, Molecular Sequence Annotation, medicine.disease, Chromosomes Human Pair 6, Lymphoma, 030104 developmental biology, Cancer and Oncology, Immunology, molecular genetics, lcsh:Q, HIGH-RESOLUTION, 0301 basic medicine, General Physics and Astronomy, Genome-wide association studies, HEK293 Cell, immune system diseases, single nucleotide polymorphism, Risk Factors, Chromosomes Human Pair 14, hemic and lymphatic diseases, Lymphatic diseases, EXPRESSION PATTERNS, FAMILIAL AGGREGATION, Multidisciplinary, Leukemia, Chemistry (all), MicroRNA, Waldenstroem macroglobulinemia, Multidisciplinary Sciences, HEK293 cell line, miRNAs, Waldenstrom Macroglobulinemia, Green Fluorescent Proteins, Reproducibility of Result, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Malignancy, Polymorphism, Single Nucleotide, Chromosomes, Cancer epidemiology, MD Multidisciplinary, medicine, chromosome 6, Genetic Predisposition to Disease, RAL GTPASES, Cell Proliferation, Chromosomes, Human, Pair 14, Base Sequence, Risk Factor, B-CELL LYMPHOMA, Reproducibility of Results, nucleotide sequence, General Chemistry, Heritability, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, MicroRNAs, HEK293 Cells, Genotyping Technique, genetic predisposition, metabolism
Abstract

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10−54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10−19). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy., Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a non-Hodgkin-type B cell lymphoma. Here, the authors identify two risk loci for WM/LPL in a two-stage GWAS involving a family-oversampling approach and provide evidence for a functional role of the non-coding SNP rs116446171.

Published
2018
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26. Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma

Author

Mariagrazia Zucca, Thomas M. Habermann, Lauren R. Teras, Joseph Vijai, Lenka Foretova, Simon Crouch, Anneclaire J. De Roos, Jacqueline Clavel, Lindsay M. Morton, Melissa C. Southey, W. Ryan Diver, Patrick M. Gaffney, James McKay, Eve Roman, Sophia S. Wang, Mark P. Purdue, Hans-Olov Adami, Gilles Salles, Jarmo Virtamo, Yan W. Asmann, Angela Brooks-Wilson, Thierry Jo Molina, Andrew D. Zelenetz, Ahmet Dogan, Kenneth Offit, Peter Kraft, Gianluca Severi, Zhaoming Wang, Tongzhang Zheng, Sonja I. Berndt, Brian K. Link, Sasha Bernatsky, Theodore R. Holford, Emanuele Angelucci, Paige M. Bracci, Martyn T. Smith, Stephen J. Chanock, Brenda M. Birmann, Hervé Ghesquières, Stephen M. Ansell, Paolo Vineis, Mads Melbye, Kari E. North, Jenny Turner, Jacques Riby, Charles E. Lawrence, Alain Monnereau, Nikolaus Becker, Lucia Conde, James R. Cerhan, Susan L. Slager, Demetrius Albanes, Henrik Hjalgrim, Hervé Tilly, Héctor A. Velásquez García, Rebecca D. Jackson, Ann E. Clarke, Elizabeth A. Holly, Robert J. Klein, Paolo Boffetta, Mark Liebow, Karin E. Smedby, Marco Rais, David G. Cox, Patricia Hartge, Rosalind Ramsey-Goldman, Rachel S. Kelly, Lesley F. Tinker, Christine F. Skibola, Wendy Cozen, Tracy Lightfoot, Anne J. Novak, Heiner Boeing, Roel Vermeulen, Claire M. Vajdic, Bengt Glimelius, Kimberly A. Bertrand, Marc Maynadie, Eleanor Kane, Nathaniel Rothman, Yolanda Benavente, Paul Brennan, Anne Tjønneland, John J. Spinelli, Qing Lan, Anne Kricker, Alex Smith, Anthony Staines, Graham G. Giles, Carrie A. Thompson, Thomas E. Witzig, Stephanie J. Weinstein, Karen H. Cotenbader, Corinne Haioun, Anne Zeleniuch-Jacquotte, Simonetta Di Lollo, Alexandra Nieters, Rudolph Kaaks, Silvia de Sanjosé, Richard K. Severson, Yawei Zhang, Research Institute of the McGill University Health Centre, 1650 Cedar Avenue, Oklahoma Medical Research Foundation, Registre des hémopathies malignes de Côte d'Or, Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université Bourgogne Franche-Comté ( UBFC ), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), University of Calgary, Bernatsky, S. and García, H.A.V. and Spinelli, J.J. and Gaffney, P. and Smedby, K.E. and Ramsey-Goldman, R. and Wang, S.S. and Adami, H.-O. and Albanes, D. and Angelucci, E. and Ansell, S.M. and WAsmann, Y. and Becker, N. and Benavente, Y. and Berndt, S.I. and Bertrand, K.A. and Birmann, B.M. and Boeing, H. and Boffetta, P. and Bracci, P.M. and Brennan, P. and Brooks-Wilson, A.R. and Cerhan, J.R. and Chanock, S.J. and Clavel, J. and Conde, L. and Cotenbader, K.H. and Cox, D.G. and Cozen, W. and Crouch, S. and De Roos, A.J. and De Sanjose, S. and Di Lollo, S. and Diver, W.R. and Dogan, A. and Foretova, L. and Ghesquières, H. and Giles, G.G. and Glimelius, B. and Habermann, T.M. and Haioun, C. and Hartge, P. and Hjalgrim, H. and Holford, T.R. and Holly, E.A. and Jackson, R.D. and Kaaks, R. and Kane, E. and Kelly, R.S. and Klein, R.J. and Kraft, P. and Kricker, A. and Lan, Q. and Lawrence, C. and Liebow, M. and Lightfoot, T. and Link, B.K. and Maynadie, M. and McKay, J. and Melbye, M. and Molina, T.J. and Monnereau, A. and Morton, L.M. and Nieters, A. and North, K.E. and Novak, A.J. and Offit, K. and Purdue, M.P. and Rais, M. and Riby, J. and Roman, E. and Rothman, N. and Salles, G. and Severi, G. and Severson, R.K. and Skibola, C.F. and Slager, S.L. and Smith, A. and Smith, M.T. and Southey, M.C. and Staines, A. and Teras, L.R. and Thompson, C.A. and Tilly, H. and Tinker, L.F. and Tjonneland, A. and Turner, J. and Vajdic, C.M. and Vermeulen, R.C.H. and Vijai, J. and Vineis, P. and Virtamo, J. and Wang, Z. and Weinstein, S. and Witzig, T.E. and Zelenetz, A. and Zeleniuch-Jacquotte, A. and Zhang, Y. and Zheng, T. and Zucca, M. and Clarke, A.E., McGill University Health Center [Montreal] (MUHC), Oklahoma Medical Research Foundation (OMRF), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-2, and dIRAS RA-I&I RA

Subjects
Oncology, medicine.medical_specialty, Immunology, Single-nucleotide polymorphism, Genome-wide association study, [SDV.CAN]Life Sciences [q-bio]/Cancer, lymphoma, Human leukocyte antigen, Bioinformatics, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Internal medicine, medicine, SNP, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, General Medicine, medicine.disease, Systemic lupus, Lupus Nephritis, Risk of diffuse large B-cell lymphoma, 3. Good health, Lymphoma, 030220 oncology & carcinogenesis, business, Diffuse large B-cell lymphoma, IRF5, malignancy
Abstract

Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genomewide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE. © 2017 BMJ Publishing Group. All rights reserved.

Published
2017
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27. Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in reticulon 4 that impairs ER morphology and cancer pathogenicity

Author

Wan-min Ku, Tucker R. Huffman, Allison M. Roberts, Truc B. Nguyen, Yana Petri, James A. Olzmann, Christine F. Skibola, Daniel K. Nomura, Carlo M. Contreras, Leslie A. Bateman, Martin J. Heslin, and David K. Miyamoto

Subjects
0301 basic medicine, Proteomics, Nuclear Envelope, Nogo Proteins, Druggability, Antineoplastic Agents, Computational biology, Endoplasmic Reticulum, Ligands, 01 natural sciences, Catalysis, Article, 03 medical and health sciences, Materials Chemistry, 2.1 Biological and endogenous factors, Humans, Chemoproteomics, Cysteine, Aetiology, Cancer, Acrylamide, 010405 organic chemistry, Chemistry, Endoplasmic reticulum, Prevention, Organic Chemistry, Metals and Alloys, General Chemistry, Molecular biology, Endoplasmic reticulum tubular network formation, 0104 chemical sciences, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, Colo-Rectal Cancer, 030104 developmental biology, 5.1 Pharmaceuticals, Proteome, Chemical Sciences, Ceramics and Composites, Development of treatments and therapeutic interventions, Digestive Diseases, Colorectal Neoplasms, Chemical genetics, Reticulon 4, Biotechnology
Abstract

Chemical genetics has arisen as a powerful approach for identifying novel anti-cancer agents. However, a major bottleneck of this approach is identifying the targets of lead compounds that arise from screens. Here, we coupled the synthesis and screening of fragment-based cysteine-reactive covalent ligands with activity-based protein profiling (ABPP) chemoproteomic approaches to identify compounds that impair colorectal cancer pathogenicity and map the druggable hotspots targeted by these hits. Through this coupled approach, we discovered a cysteine-reactive acrylamide DKM 3-30 that significantly impaired colorectal cancer cell pathogenicity through targeting C1101 on reticulon 4 (RTN4). While little is known about the role of RTN4 in colorectal cancer, this protein has been established as a critical mediator of endoplasmic reticulum tubular network formation. We show here that covalent modification of C1101 on RTN4 by DKM 3-30 or genetic knockdown of RTN4 impairs endoplasmic reticulum and nuclear envelope morphology as well as colorectal cancer pathogenicity. We thus put forth RTN4 as a potential novel colorectal cancer therapeutic target and reveal a unique druggable hotspot within RTN4 that can be targeted by covalent ligands to impair colorectal cancer pathogenicity. Our results underscore the utility of coupling the screening of fragment-based covalent ligands with isoTOP-ABPP platforms for mining the proteome for novel druggable nodes that can be targeted for cancer therapy.

Published
2017

28. Associations between arsenic (+3 oxidation state) methyltransferase (AS3MT) and N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) polymorphisms, arsenic metabolism, and cancer risk in a chilean population

Author

Rosemarie, de la Rosa, Craig, Steinmaus, Nicholas K, Akers, Lucia, Conde, Catterina, Ferreccio, David, Kalman, Kevin R, Zhang, Christine F, Skibola, Allan H, Smith, Luoping, Zhang, and Martyn T, Smith

Subjects
Male, Site-Specific DNA-Methyltransferase (Adenine-Specific), Polymorphism, Genetic, Methyltransferases, Middle Aged, Linkage Disequilibrium, Article, Arsenic, Treatment Outcome, Gene Frequency, Risk Factors, Neoplasms, Humans, Female, Genetic Predisposition to Disease, Chile, Oxidation-Reduction, Aged
Abstract

Inter-individual differences in arsenic metabolism have been linked to arsenic-related disease risks. Arsenic (+3) methyltransferase (AS3MT) is the primary enzyme involved in arsenic metabolism, and we previously demonstrated in vitro that N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) also methylates the toxic inorganic arsenic (iAs) metabolite, monomethylarsonous acid (MMA), to the less toxic dimethylarsonic acid (DMA). Here, we evaluated whether AS3MT and N6AMT1 gene polymorphisms alter arsenic methylation and impact iAs-related cancer risks. We assessed AS3MT and N6AMT1 polymorphisms and urinary arsenic metabolites (%iAs, %MMA, %DMA) in 722 subjects from an arsenic-cancer case-control study in a uniquely exposed area in northern Chile. Polymorphisms were genotyped using a custom designed multiplex, ligation-dependent probe amplification (MLPA) assay for 6 AS3MT SNPs and 14 tag SNPs in the N6AMT1 gene. We found several AS3MT polymorphisms associated with both urinary arsenic metabolite profiles and cancer risk. For example, compared to wildtypes, individuals carrying minor alleles in AS3MT rs3740393 had lower %MMA (mean difference = -1.9%, 95% CI: -3.3, -0.4), higher %DMA (mean difference = 4.0%, 95% CI: 1.5, 6.5), and lower odds ratios for bladder (OR = 0.3; 95% CI: 0.1-0.6) and lung cancer (OR = 0.6; 95% CI: 0.2-1.1). Evidence of interaction was also observed for both lung and bladder cancer between these polymorphisms and elevated historical arsenic exposures. Clear associations were not seen for N6AMT1. These results are the first to demonstrate a direct association between AS3MT polymorphisms and arsenic-related internal cancer risk. This research could help identify subpopulations that are particularly vulnerable to arsenic-related disease. Environ. Mol. Mutagen. 58:411-422, 2017. © 2017 Wiley Periodicals, Inc.

Published
2017

29. Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region

Author

Joseph Vijai, W. Ryan Diver, Degui Zhi, Brenda M. Birmann, Henrik Hjalgrim, Bruce K. Armstrong, Gianluca Severi, Pierluigi Cocco, Joseph F. Fraumeni, Xifeng Wu, Graham G. Giles, Eleanor Kane, Herve Ghesquieres, Eve Roman, Edward Giovannucci, Mads Melbye, Rudolph Kaaks, Lindsay M. Morton, Nicholas K. Akers, Elizabeth A. Holly, Liming Liang, Patrizio Mazza, Kari E. North, John J. Spinelli, Carrie A. Thompson, Bodil Ohlsson, Yuanqing Ye, Anneclaire J. De Roos, Stephen J. Chanock, Theodore R. Holford, Paul Brennan, Jianjun Liu, Roel Vermeulen, Thomas E. Witzig, Angela Brooks-Wilson, Mark P. Purdue, Ahmet Dogan, Gilles Salles, Kenneth Offit, Lucia Conde, Laurie Burdett, George J. Weiner, Anne Kricker, James McKay, Peter Kraft, Sonja I. Berndt, Attilio Gabbas, Rebecca Montalvan, Rebecca D. Jackson, Baoshan Ma, Zhaoming Wang, Patricia Hartge, Danylo J. Villano, Marc Maynadie, Mortimer J. Lacher, Lauren R. Teras, Susan L. Slager, Lenka Foretova, Rachel S. Kelly, Martha S. Linet, Brian K. Link, Jarmo Virtamo, Charles C. Chung, Anne Zeleniuch-Jacquotte, Martyn T. Smith, Tracy Lightfoot, Jacques Riby, Paolo Boffetta, Meredith Yeager, Brian C.-H. Chiu, Grzegorz S. Nowakowski, Yolanda Benavente, Bengt Glimelius, Mark Liebow, Saioa Chamosa, Charles E. Lawrence, Karin E. Smedby, Nikolaus Becker, Thomas M. Habermann, Jacqueline Clavel, Qing Lan, Alexandra Nieters, Maryjean Schenk, Sophia S. Wang, Demetrius Albanes, Lesley F. Tinker, Alex Smith, Anthony Staines, Amy Hutchinson, Wendy Cozen, Hans-Olov Adami, Anne J. Novak, Christine F. Skibola, Ann Maria, Elisabete Weiderpass, Kimberly A. Bertrand, James R. Cerhan, Maria Grazia Ennas, Claire M. Vajdic, Jinyan Huang, Paul I.W. de Bakker, Paige M. Bracci, Tongzhang Zheng, Ruth C. Travis, Paolo Vineis, Jia Nee Foo, Jennifer Turner, Alain Monnereau, Silvia de Sanjosé, Nathaniel Rothman, Yawei Zhang, Jian Gu, Skibola, C.F., Berndt, S.I., Vijai, J., Conde, L., Wang, Z., Yeager, M., De Bakker, P.I.W., Birmann, B.M., Vajdic, C.M., Foo, J.-N., Bracci, P.M., Vermeulen, R.C.H., Slager, S.L., De Sanjose, S., Wang, S.S., Linet, M.S., Salles, G., Lan, Q., Severi, G., Hjalgrim, H., Lightfoot, T., Melbye, M., Gu, J., Ghesquières, H., Link, B.K., Morton, L.M., Holly, E.A., Smith, A., Tinker, L.F., Teras, L.R., Kricker, A., Becker, N., Purdue, M.P., Spinelli, J.J., Zhang, Y., Giles, G.G., Vineis, P., Monnereau, A., Bertrand, K.A., Albanes, D., Zeleniuch-Jacquotte, A., Gabbas, A., Chung, C.C., Burdett, L., Hutchinson, A., Lawrence, C., Montalvan, R., Liang, L., Huang, J., Ma, B., Liu, J., Adami, H.-O., Glimelius, B., Ye, Y., Nowakowski, G.S., Dogan, A., Thompson, C.A., Habermann, T.M., Novak, A.J., Liebow, M., Witzig, T.E., Weiner, G.J., Schenk, M., Hartge, P., De Roos, A.J., Cozen, W., Zhi, D., Akers, N.K., Riby, J., Smith, M.T., Lacher, M., Villano, D.J., Maria, A., Roman, E., Kane, E., Jackson, R.D., North, K.E., Diver, W.R., Turner, J., Armstrong, B.K., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., Staines, A., McKay, J., Brooks-Wilson, A.R., Zheng, T., Holford, T.R., Chamosa, S., Kaaks, R., Kelly, R.S., Ohlsson, B., Travis, R.C., Weiderpass, E., Clavel, J., Giovannucci, E., Kraft, P., Virtamo, J., Mazza, P., Cocco, P., Ennas, M.G., Chiu, B.C.H., Fraumeni, J.F., Jr., Nieters, A., Offit, K., Wu, X., Cerhan, J.R., Smedby, K.E., Chanock, S.J., and Rothman, N.

Subjects
EXPRESSION, Follicular lymphoma, Single-nucleotide polymorphism, Genome-wide association study, Human leukocyte antigen, Biology, VARIANTS, Polymorphism, Single Nucleotide, follicular lymphoma, HLA Antigens, Polymorphism (computer science), Report, CLASS-I, RESOURCE, Biomarkers, Tumor, Genetics, medicine, Chromosomes, Human, Humans, TOOL, Genetic Predisposition to Disease, Genetics(clinical), PEPTIDE, Allele, Lymphoma, Follicular, Alleles, Genetics (clinical), Genetic association, SNPS, RISK, Genome-wide association, Haplotype, medicine.disease, HLA, Haplotypes, Case-Control Studies, UNIVERSITY, SET, Genome-Wide Association Study
Abstract

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10 -20) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10 -11) near ETS1; 3q28 (rs6444305, p = 1.10 × 10 -10) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10 -10) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10 -8) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRß1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10 -67 to 2.67 × 10 -70). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10 -16) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10 -9). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk. © 2014 by The American Society of Human Genetics. All rights reserved.

Published
2016

30. A Fucus vesiculosus extract inhibits estrogen receptor activation and induces cell death in female cancer cell lines

Author

Christine F. Skibola, William E. Grizzle, Jacques Riby, Jianqing Zhang, Lucia Conde, and Xiangqin Cui

Subjects
0301 basic medicine, Cell signaling, medicine.medical_specialty, Programmed cell death, Antineoplastic Agents, Hormonal, Cell Survival, Estrogen receptor, Gene Expression, Apoptosis, mTORC1, 03 medical and health sciences, 0302 clinical medicine, Aromatase, Internal medicine, Fucoidan, Cell Line, Tumor, medicine, Autophagy, Humans, Viability assay, Protein kinase B, PI3K signaling, biology, Anti-estrogenic activity, General Medicine, Seaweed, Enzyme Activation, 030104 developmental biology, Endocrinology, Complementary and alternative medicine, Receptors, Estrogen, 030220 oncology & carcinogenesis, Caspases, Fucus, biology.protein, Cancer research, Female, Biomarkers, Research Article
Abstract

Background We previously reported the anti-estrogenic activity of the brown seaweed, Fucus vesiculosus. The present study aimed to further investigate its anti-estrogenic modes of action and to assess other potentially biologically relevant anti-tumorigenic effects in estrogen receptor (ER)-dependent and -independent female cancer cell lines. Methods The CALUX® assay was used to determine the effect of a F. vesiculosus extract (FVE) on activation of the ER. Aromatase enzymatic activity was measured to determine the potential effect of FVE on estradiol (E2) biosynthesis. Transcriptional activity profiling of 248 genes involved in cancer, immunity, hormonal regulation, protein phosphorylation, transcription, metabolism, and cellular structure was conducted using the NanoString nCounter® analysis system in FVE-treated breast, ovarian and endometrial cancer cell lines. The effects of FVE on cell viability, morphology, membrane integrity, mitochondrial toxicity, induction of apoptotic and autophagic markers, and cell signaling were also analyzed. Results In co-treatments with 12.5 pM (EC50) E2, FVE (2 %) reduced ER activation by 50 %, exhibiting potent ER antagonistic effects. FVE inhibited aromatase activity in an in vitro assay (IC50 2.0 %). ER-dependent and -independent cancer cell lines showed significantly decreased viability that correlated with increasing FVE concentrations and altered morphological features suggestive of apoptosis and autophagy. Expression of genes that were significantly altered by FVE (p

Published
2016

31. Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes

Author

Henrik Hjalgrim, Joseph Vijai, Bengt Glimelius, Kimberly A. Bertrand, Immaculata De Vivo, Eve Roman, Martha Glenn, Nathaniel Rothman, Yolanda Benavente, Zhaoming Wang, Ju-Hyun Park, Anneclaire J. De Roos, John J. Spinelli, Demetrius Albanes, Paul Brennan, Emanuele Angelucci, Mariagrazia Zucca, Qing Lan, Kari E. North, Paige M. Bracci, Mark P. Purdue, Marco Rais, Melissa C. Southey, Alain Monnereau, Ahmet Dogan, Graham G. Giles, Robert J. Klein, Peter Kraft, Lesley F. Tinker, Laurie Burdett, Lucia Conde, Carrie A. Thompson, James McKay, Martyn T. Smith, Göran Roos, Yan W. Asmann, Dennis D. Weisenburger, Elizabeth A. Holly, Thomas E. Witzig, Liming Liang, Paul I.W. de Bakker, Alex Smith, Jarmo Virtamo, Charles E. Lawrence, Patricia Hartge, Karen Curtin, Anthony Staines, Nikolaus Becker, Nicola J. Camp, Charles C. Chung, Degui Zhi, Brenda M. Birmann, W. Ryan Diver, Roel Vermeulen, Sonja I. Berndt, Tongzhang Zheng, Silvia de Sanjosé, Eleanor Kane, James R. Cerhan, Christopher R. Flowers, Joseph F. Fraumeni, Stephen J. Chanock, Stephen M. Ansell, Angela Brooks-Wilson, Kenneth Offit, Jinyan Huang, Mads Melbye, Edward Giovannucci, Baoshan Ma, Tracy Lightfoot, Brian K. Link, Richard K. Severson, Theodore R. Holford, Yawei Zhang, Anne Tjønneland, Meredith Yeager, Wendy Cozen, Anne J. Novak, Lauren R. Teras, Claire M. Vajdic, Lisa A. Cannon-Albright, Lenka Foretova, Christine F. Skibola, Sophia S. Wang, Hans-Olov Adami, Andrew D. Zelenetz, Jenny Turner, Paolo Vineis, Corinne Haioun, Hervé Tilly, Anne Zeleniuch-Jacquotte, Thomas M. Habermann, Paolo Boffetta, Jacqueline Clavel, Herve Ghesquieres, Stephanie J. Weinstein, Lindsay M. Morton, Susan L. Slager, Simon Crouch, Gilles Salles, Rachel S. Kelly, Karin E. Smedby, Amy Hutchinson, David G. Cox, Elio Riboli, Jacques Riby, Rebecca D. Jackson, Mark Liebow, Thierry Jo Molina, Danylo J. Villano, Marc Maynadie, Yuanqing Ye, Heiner Boeing, Jian Gu, Brian C.-H. Chiu, Simonetta Di Lollo, Mitchell J. Machiela, Alexandra Nieters, Xifeng Wu, Rudolph Kaaks, Machiela, M.J., Lan, Q., Slager, S.L., Vermeulen, R.C.H., Teras, L.R., Camp, N.J., Cerhan, J.R., Spinelli, J.J., Wang, S.S., Nieters, A., Vijai, J., Yeager, M., Wang, Z., Ghesquières, H., McKay, J., Conde, L., de Bakker, P.I.W., Cox, D.G., Burdett, L., Monnereau, A., Flowers, C.R., De Roos, A.J., Brooks-Wilson, A.R., Giles, G.G., Melbye, M., Gu, J., Jackson, R.D., Kane, E., Purdue, M.P., Vajdic, C.M., Albanes, D., Kelly, R.S., Zucca, M., Bertrand, K.A., Zeleniuch-Jacquotte, A., Lawrence, C., Hutchinson, A., Zhi, D., Habermann, T.M., Link, B.K., Novak, A.J., Dogan, A., Asmann, Y.W., Liebow, M., Thompson, C.A., Ansell, S.M., Witzig, T.E., Tilly, H., Haioun, C., Molina, T.J., Hjalgrim, H., Glimelius, B., Adami, H.-O., Roos, G., Bracci, P.M., Riby, J., Smith, M.T., Holly, E.A., Cozen, W., Hartge, P., Morton, L.M., Severson, R.K., Tinker, L.F., North, K.E., Becker, N., Benavente, Y., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., Staines, A., Lightfoot, T., Crouch, S., Smith, A., Roman, E., Ryan Diver, W., Offit, K., Zelenetz, A., Klein, R.J., Villano, D.J., Zheng, T., Zhang, Y., Holford, T.R., Turner, J., Southey, M.C., Clavel, J., Virtamo, J., Weinstein, S., Riboli, E., Vineis, P., Kaaks, R., Boeing, H., Tjønneland, A., Angelucci, E., Di Lollo, S., Rais, M., De Vivo, I., Giovannucci, E., Kraft, P., Huang, J., Ma, B., Ye, Y., Chiu, B.C.H., Liang, L., Park, J.-H., Chung, C.C., Weisenburger, D.D., Fraumeni, J.F., Jr and Salles, G., Glenn, M., Cannon-Albright, L., Curtin, K., Wu, X., Smedby, K.E., de Sanjose, S., Skibola, C.F., Berndt, S.I., Birmann, B.M., Chanock, S.J., Rothman, N., LS IRAS EEPI GRA (Gezh.risico-analyse), Sub Atmospheric physics and chemistry, dIRAS RA-I&I RA, dIRAS RA-2, Service d’Hématologie [Centre Hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Cancer environnement ( EPICENE ), Bordeaux population health ( BPH ), Université de Bordeaux ( UB ) -Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bordeaux ( UB ) -Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Registre des hémopathies malignes de la Gironde, Institut Bergonié - CRLCC Bordeaux, Department of Agronomy, University of Wisconsin-Madison [Madison], Service hématologie Poitiers, CHU, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Université Paris Descartes - Paris 5 ( UPD5 ), Oslo and Akershus University College ( OAUC ), Laboratoire de mécanique Biomécanique Polymère Structures ( LaBPS ), Université de Lorraine ( UL ), The Tisch Cancer Institute, Mount Sinai School of Medicine, International Agency for Cancer Research ( IACR ), International Agency for Cancer Research, Registre des hémopathies malignes de Côte d'Or, Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), University of Chicago Medicine, Institut National de la Santé et de la Recherche Médicale ( INSERM ), French National Registry of Childhood Hematological malignancies (NRCH), NRCH, Division of Epidemiology, Public Health and Primary Care, Imperial College London, Unit of Cancer Epidemiology, AOU S. Giovanni Battista, CPO Piemonte, CeRMS, University of Torino, Department of Epidemiology and Public Health, Department Cancer Epidemiology, German Cancer Research Center, Institute of Human Nutrition Potsdam-Rehbruecke, Diet, Cancer and Health, Danish Cancer Society, Justus Liebig University Giessen, Sino French Research Center for Biomedical Imaging ( HIT-INSA ), Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Harbin Institute of Technology ( HIT ), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé ( CREATIS ), Hospices Civils de Lyon ( HCL ) -Université Jean Monnet [Saint-Étienne] ( UJM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ), Institut de Physique Nucléaire d'Orsay ( IPNO ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de Physique Nucléaire et de Physique des Particules du CNRS ( IN2P3 ) -Centre National de la Recherche Scientifique ( CNRS ), Chinese Academy of Sciences [Beijing] ( CAS ), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cancer environnement (EPICENE ), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, University of Wisconsin-Madison, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Descartes - Paris 5 (UPD5), Akershus University College, Laboratoire de mécanique Biomécanique Polymère Structures (LaBPS), Université de Lorraine (UL), Icahn School of Medicine at Mount Sinai [New York] (MSSM), International Agency for Cancer Research (IACR), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), Institut National de la Santé et de la Recherche Médicale (INSERM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke (DifE), Leibniz Association, Justus-Liebig-Universität Gießen (JLU), Sino French Research Center for Biomedical Imaging (HIT-INSA), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Harbin Institute of Technology (HIT), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Chinese Academy of Sciences [Beijing] (CAS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Harbin Institute of Technology (HIT), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (CRCL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Oslo and Akershus University College (OAUC), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
0301 basic medicine, Serum, Male, Lymphoma, analysis, Chronic lymphocytic leukemia, Follicular lymphoma, Global Health, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, immunology, surgery, 0302 clinical medicine, Endocrinology, immune system diseases, single nucleotide polymorphism, Germany, hemic and lymphatic diseases, London, 80 and over, Odds Ratio, genetics, Prospective Studies, B-cell lymphoma, Association Studies Article, Genetics (clinical), Aged, 80 and over, education.field_of_study, telomere, Genome, Leukemia, Age Factors, General Medicine, Environmental exposure, Genomics, Middle Aged, b-cell lymphoma, small cell lymphoma, Italy, 030220 oncology & carcinogenesis, Medicine, epidemiology, Female, France, Risk of B-cell lymphoma subtypes, Risk, Adult, Canada, China, Lymphoma, B-Cell, Genotype, Adolescent, leukocytes, etiology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Environment, Risk Assessment, methods, Time, 03 medical and health sciences, medicine, Humans, Family, Genetic Predisposition to Disease, education, Molecular Biology, Alleles, Occupational Health, Genetic Association Studies, Aged, B-Cell, International Agencies, Odds ratio, Environmental Exposure, medicine.disease, Telomere, Non-Hodgkin's lymphoma, 030104 developmental biology, Immunology, physiology, Chronic Disease, pathology, Laboratories, metabolism
Abstract

International audience; Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk

Published
2016
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32. Abstract 221: Inherited variants at 3q13.33 and 3p24.1 influences risk of diffuse large B-cell lymphoma

Author

Nathaniel Rothman, James R. Cerhan, James McKay, Mads Melbye, David Cox, Lauren R. Teras, Qing Lan, Vijai Joseph, Mark P. Purdue, Sophia S. Wang, Simon Crouch, Sonja I. Berndt, Claire M. Vajdic, Demetrius Albanes, Stephen J. Chanock, Gilles Salles, Alain Monnereau, Angela Brooks-Wilson, Alexandra Nieters, Yawei Zhang, Xifeng Wu, Michelle Hildebrand, Anne Zeleniuch-Jacquotte, Hervé Ghesquières, Christine F. Skibola, Karin E. Smedby, Rebecca D. Jackson, Susan L. Slager, and Geffen Kleinstern

Subjects
Cancer Research, Oncology, medicine, Cancer research, Biology, medicine.disease, Diffuse large B-cell lymphoma
Abstract

Background: We previously identified 5 SNPs at 4 susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (Cerhan et al, Nat Gen 2014;46:1233-8); however, much of the heritability remains unexplained. To further elucidate genetic susceptibility to DLBCL, we sought to validate 2 loci at 3q13.33 and 3p24.1 that were suggestive in the original report. Methods: We selected two SNPs rs9831894 (3q13.33) and rs6773363 (3p24.1) for de novo replication from studies at the Mayo Clinic, MD Anderson, and Memorial Sloan Kettering. Logistic regression was used to estimate odds ratios (ORs), using a log-additive model, and adjusting for age, gender and significant eigenvectors for each genotyping center separately. For both SNPs, we then conducted a meta-analysis of all replication studies (n=3) and our original GWAS studies (n=4), encompassing in total 5662 cases and 9237 controls for rs9831894, and 5510 cases and 12,817 controls for rs6773363. Meta-analysis was conducted using the fixed-effects inverse variance method based on the β estimates and standard errors from each study. Results: In a meta-analysis of the 4 original GWAS scans (3856 cases and 7666 controls), rs9831894 (MAF=0.40) was associated with DLBCL risk (OR=0.84, P=4.52 x 10-9) and this replicated in a meta-analysis of the 3 studies with de novo genotyping (OR=0.80, P=4.17 x 10-5); the overall meta-analysis showed a strong association with DLBCL risk (OR=0.83, P=3.62 x 10-13). This locus maps near a plausible candidate gene, CD86, a protein coding gene and a member of the immunoglobulin superfamily that encodes a type I membrane protein. Binding of CD86 with cytotoxic T-lymphocyte-associated protein 4 negatively regulates T-cell activation and diminishes the immune response, while binding of CD86 with CD28 antigen is a costimulatory signal for activation of the T-cell. In a meta-analysis of the same 4 GWAS scans, rs6773363 (MAF=0.45) was tentatively associated with DLBCL risk (OR=1.17, P= 3.68 x 10-7) and this replicated in a meta-analysis of the studies with de novo genotyping (OR=1.27, P=3.78 x 10-7); the overall meta-analysis showed a strong association with DLBCL risk (OR=1.20, P=2.31 x 10-12). This locus also maps near a plausible candidate gene, eomesodermin (EOMES), a transcription factor crucial for embryonic development of the central nervous system and also putatively involved in T-cell differentiation in viral infection defense. Conclusion: In this follow-up analysis of our initial GWAS, we have identified two additional loci associated with risk of DLBCL, the most common lymphoma subtype. These loci provide additional evidence for the role of immune function in the etiology of DLBCL. Citation Format: Geffen Kleinstern, Michelle Hildebrand, Vijai Joseph, Sonja I. Berndt, Hervé Ghesquières, James McKay, Sophia S. Wang, Alexandra Nieters, David Cox, Alain Monnereau, Angela R. Brooks-Wilson, Qing Lan, Mads Melbye, Rebecca D. Jackson, Lauren R. Teras, Mark P. Purdue, Claire M. Vajdic, Demetrius Albanes, Anne Zeleniuch-Jacquotte, Simon Crouch, Yawei Zhang, Susan L. Slager, Xifeng Wu, Karin E. Smedby, Gilles Salles, Christine F. Skibola, Nathaniel Rothman, Stephen J. Chanock, James R. Cerhan. Inherited variants at 3q13.33 and 3p24.1 influences risk of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 221.

Published
2018
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33. Identifying risk factors for B-cell lymphoma

Author

Christine F. Skibola and Christopher R. Flowers

Subjects
0301 basic medicine, Male, Lymphoma, B-Cell, Immunology, MEDLINE, Q fever, Biology, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Inside BLOOD Commentary, Risk Factors, hemic and lymphatic diseases, medicine, Humans, Risk factor, B-cell lymphoma, Aged, Macrophages, Cell Biology, Hematology, Dendritic Cells, Middle Aged, medicine.disease, Coxiella burnetii, biology.organism_classification, Prognosis, Lymphoma, Interleukin-10, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, Female, Q Fever, Follow-Up Studies
Abstract

Bacteria can induce human lymphomas, whereas lymphoproliferative disorders have been described in patients with Q fever. We observed a lymphoma in a patient with Q fever that prompted us to investigate the association between the 2 diseases. We screened 1468 consecutive patients of the 2004 to 2014 French National Referral Center for Q fever database. The standardized incidence ratios (SIRs) of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) were calculated comparatively to the 2012 Francim Registry. The presence of Coxiella burnetii was tested using immunofluorescence and fluorescence in situ hybridization using a specific 16S ribosomal RNA probe and genomic DNA probe. Seven patients (0.48%) presented mature B-cell lymphoma consisting of 6 DLBCL and 1 FL. An excess risk of DLBCL and FL was found in Q fever patients compared with the general population (SIR [95% confidence interval], 25.4 [11.4-56.4] and 6.7 [0.9-47.9], respectively). C burnetii was detected in CD68(+) macrophages within both lymphoma and lymphadenitis tissues but localization in CD123(+) plasmacytoid dendritic cells (pDCs) was found only in lymphoma tissues. Q fever patients with persistent focalized infection were found more at risk of lymphoma (hazard ratio, 9.35 [1.10-79.4]). Interleukin-10 (IL10) overproduction (P = .0003) was found in patients developing lymphoma. These results suggest that C burnetii should be added to the list of bacteria that promote human B-cell non-Hodgkin lymphoma, possibly by the infection of pDCs and IL10 overproduction. Screening for early lymphoma diagnosis should be considered in the management of patients with Q fever, especially those with persistent focalized infections.

Published
2016

34. Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia

Author

Nathaniel Rothman, Yolanda Benavente, Paul Brennan, Qing Lan, Pierluigi Cocco, Simon Crouch, Anneclaire J. De Roos, Josh Wright, Christine F. Skibola, Mark P. Purdue, Elisabete Weiderpass, James R. Cerhan, Randy D. Gascoyne, Maria Grazia Ennas, Kari E. North, Zhaoming Wang, Jinyan Huang, Julie M. Cunningham, Alain Monnereau, Peter Kraft, Patricia Hartge, Edward Giovannucci, Karen Curtin, Giovanna Masala, Jacqueline Clavel, Neil E. Kay, Jacques Riby, María Dolores Chirlaque, John J. Spinelli, Delphine Casabonne, Jenny Turner, Lucia Conde, Lesley F. Tinker, Martha Glenn, Sara S. Strom, Donna K. Arnett, Rebecca Montalvan, Ju-Hyun Park, Melissa C. Southey, Ann Maria, Karin E. Smedby, Lindsay M. Morton, Marc Maynadié, Laurie Burdett, Amy Hutchinson, Bengt Glimelius, W. Ryan Diver, Elio Riboli, Sonja I. Berndt, Lisa A. Cannon-Albright, Kimberly A. Bertrand, Aaron D. Norman, Sara J. Achenbach, Celine M. Vachon, Angela Cox, Xifeng Wu, Theodore R. Holford, Neil E. Caporaso, Joseph F. Fraumeni, Roel Vermeulen, Rudolph Kaaks, Mads Melbye, Joseph Vijai, Kari G. Chaffee, Lauren R. Teras, Rebecca D. Jackson, Lenka Foretova, J. Brice Weinberg, Paige M. Bracci, Sophia S. Wang, Demetrius Albanes, Stephen J. Chanock, Wendy Cozen, Mark Liebow, Anne J. Novak, Hans-Olov Adami, George J. Weiner, Angela Brooks-Wilson, Kenneth Offit, Anne Kricker, Claire M. Vajdic, James McKay, Ellen T. Chang, Baoshan Ma, Cristine Allmer, Susan L. Slager, Brian K. Link, Elizabeth A. Holly, Anthony Staines, Liming Liang, Jarmo Virtamo, Timothy G. Call, Nicola J. Camp, Ruth C. Travis, Alexandra Nieters, Degui Zhi, Brenda M. Birmann, Tait D. Shanafelt, Rachel S. Kelly, Graham G. Giles, Nilanjan Chatterjee, John A. Snowden, Yuanqing Ye, Núria Sala, Tongzhang Zheng, Paolo Boffetta, Lynn R. Goldin, Danylo J. Villano, Jose F. Leis, Paolo Vineis, Lucia Miligi, Jian Gu, Justin M. Leach, Silvia de Sanjosé, Richard K. Severson, Yawei Zhang, Henrik Hjalgrim, Roger L. Milne, Charles E. Lawrence, Meredith Yeager, Moara Machado, Nikolaus Becker, Joseph M. Connors, Anne Zeleniuch-Jacquotte, Giovanni Maria Ferri, Stephanie J. Weinstein, LS IRAS EEPI GRA (Gezh.risico-analyse), Sub Atmospheric physics and chemistry, dIRAS RA-I&I RA, dIRAS RA-2, Berndt, S.I., Camp, N.J., Skibola, C.F., Vijai, J., Wang, Z., Gu, J., Nieters, A., Kelly, R.S., Smedby, K.E., Monnereau, A., Cozen, W., Cox, A., Wang, S.S., Lan, Q., Teras, L.R., Machado, M., Yeager, M., Brooks-Wilson, A.R., Hartge, P., Purdue, M.P., Birmann, B.M., Vajdic, C.M., Cocco, P., Zhang, Y., Giles, G.G., Zeleniuch-Jacquotte, A., Lawrence, C., Montalvan, R., Burdett, L., Hutchinson, A., Ye, Y., Call, T.G., Shanafelt, T.D., Novak, A.J., Kay, N.E., Liebow, M., Cunningham, J.M., Allmer, C., Hjalgrim, H., Adami, H.-O., Melbye, M., Glimelius, B., Chang, E.T., Glenn, M., Curtin, K., Cannon-Albright, L.A., Diver, W.R., Link, B.K., Weiner, G.J., Conde, L., Bracci, P.M., Riby, J., Arnett, D.K., Zhi, D., Leach, J.M., Holly, E.A., Jackson, R.D., Tinker, L.F., Benavente, Y., Sala, N., Casabonne, D., Becker, N., Boffetta, P., Brennan, P., Foretova, L., Maynadie, M., McKay, J., Staines, A., Chaffee, K.G., Achenbach, S.J., Vachon, C.M., Goldin, L.R., Strom, S.S., Leis, J.F., Weinberg, J.B., Caporaso, N.E., Norman, A.D., De Roos, A.J., Morton, L.M., Severson, R.K., Riboli, E., Vineis, P., Kaaks, R., Masala, G., Weiderpass, E., Chirlaque, M.-D., Vermeulen, R.C.H., Travis, R.C., Southey, M.C., Milne, R.L., Albanes, D., Virtamo, J., Weinstein, S., Clavel, J., Zheng, T., Holford, T.R., Villano, D.J., Maria, A., Spinelli, J.J., Gascoyne, R.D., Connors, J.M., Bertrand, K.A., Giovannucci, E., Kraft, P., Kricker, A., Turner, J., Ennas, M.G., Ferri, G.M., Miligi, L., Liang, L., Ma, B., Huang, J., Crouch, S., Park, J.-H., Chatterjee, N., North, K.E., Snowden, J.A., Wright, J., Fraumeni, J.F., Offit, K., Wu, X., De Sanjose, S., Cerhan, J.R., Chanock, S.J., Rothman, N., Slager, S.L., National Cancer Institute ( NIH ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Registre des hémopathies malignes de Côte d'Or, Mayo Clinic [Rochester], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), and UNICANCER-UNICANCER

Subjects
0301 basic medicine, Medicin och hälsovetenskap, Chronic lymphocytic leukemia, General Physics and Astronomy, Genome-wide association study, VARIANTS, Medical and Health Sciences, Malalties hereditàries, [ SDV.MHEP.HEM ] Life Sciences [q-bio]/Human health and pathology/Hematology, Chronic, Genetics, RISK, Leukemia, Multidisciplinary, BANK1, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Bcl-2-Like Protein 11, Adaptor Proteins, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Single Nucleotide, Lymphocytic, 3. Good health, PRIORITIZATION, Multidisciplinary Sciences, medicine.anatomical_structure, Science & Technology - Other Topics, TRANSCRIPTION FACTOR EOMESODERMIN, Genetic disorders, EXPRESSION, SUSCEPTIBILITY LOCI, Science, European Continental Ancestry Group, FAS GENE-MUTATIONS, Locus (genetics), Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, CLASSIFICATION, White People, Article, 03 medical and health sciences, Proto-Oncogene Proteins, MD Multidisciplinary, medicine, Genetic predisposition, SNP, Humans, Leucèmia limfocítica crònica, Genetic Predisposition to Disease, Polymorphism, B cell, Serpins, Genetic association, Adaptor Proteins, Signal Transducing, Science & Technology, Signal Transducing, B-Cell, Membrane Proteins, General Chemistry, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 030104 developmental biology, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Apoptosis Regulatory Proteins, T-Box Domain Proteins, FOLLICULAR LYMPHOMA, Genome-Wide Association Study
Abstract

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P, Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPP associated with risk of this disease.

Published
2016
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35. Associations of non-Hodgkin Lymphoma (NHL) risk with autoimmune conditions according to putative NHL loci

Author

Silvia de Sanjosé, Scott Davis, Patricia Hartge, Wendy Cozen, Ora Paltiel, Richard K. Severson, Anne Kricker, Lindsay M. Morton, Yawei Zhang, Pierluigi Cocco, Henrik Hjalgrim, Dennis D. Weisenburger, Anneclaire J. De Roos, Martha S. Linet, Qing Lan, Claire M. Vajdic, Elizabeth A. Holly, James R. Cerhan, Karin E. Smedby, John J. Spinelli, Tracy Lightfoot, Alexandra Nieters, Otoniel Martinez-Maza, Tongzhang Zheng, Elizabeth C. Breen, Christopher R. Flowers, Elizabeth E. Brown, Eve Roman, Marc Maynadié, Graciela S. Alarcón, Stephen J. Chanock, Nikolaus Becker, Nathaniel Rothman, Jennifer Turner, Yolanda Benavente, Christine F. Skibola, Paige M. Bracci, Anthony Staines, Eleanor Kane, Jenna M. Voutsinas, Paolo Boffetta, Martyn T. Smith, Lenka Foretova, Sophia S. Wang, Susan L. Slager, Brenda M. Birmann, Angela Brooks-Wilson, Wang, S.S., Vajdic, C.M., Linet, M.S., Slager, S.L., Voutsinas, J., Nieters, A., De Sanjose, S., Cozen, W., Alarcón, G.S., Martinez-Maza, O., Brown, E.E., Bracci, P.M., Lightfoot, T., Turner, J., Hjalgrim, H., Spinelli, J.J., Zheng, T., Morton, L.M., Birmann, B.M., Flowers, C.R., Paltiel, O., Becker, N., Holly, E.A., Kane, E., Weisenburger, D., Maynadie, M., Cocco, P., Foretova, L., Staines, A., Davis, S., Severson, R., Cerhan, J.R., Breen, E.C., Lan, Q., Brooks-Wilson, A., De Roos, A.J., Smith, M.T., Roman, E., Boffetta, P., Kricker, A., Zhang, Y., Skibola, C., Chanock, S.J., Rothman, N., Benavente, Y., Hartge, P., and Smedby, K.E.

Subjects
Lymphoma, Epidemiology, Original Contributions, tumor necrosis factor, Follicular lymphoma, Non-Hodgkin, interaction, Single-nucleotide polymorphism, Human leukocyte antigen, medicine.disease_cause, Polymorphism, Single Nucleotide, Autoimmune Disease, Medical and Health Sciences, Mathematical Sciences, Autoimmunity, Autoimmune Diseases, Rare Diseases, immune system diseases, HLA Antigens, human leukocyte antigen, hemic and lymphatic diseases, Genotype, medicine, Genetics, Humans, 2.1 Biological and endogenous factors, Polymorphism, Aetiology, Cancer, business.industry, Tumor Necrosis Factor-alpha, Lymphoma, Non-Hodgkin, Inflammatory and immune system, autoimmune conditions, Odds ratio, Single Nucleotide, Hematology, medicine.disease, Autoimmune conditions - risk of non-Hodgkin lymphoma (NHL), Interleukin-10, Case-Control Studies, Immunology, HIV/AIDS, business, Diffuse large B-cell lymphoma, environment
Abstract

Autoimmune conditions and immune system-related genetic variations are associated with risk of non-Hodgkin lymphoma (NHL). In a pooled analysis of 8,692 NHL cases and 9,260 controls from 14 studies (1988-2007) within the International Lymphoma Epidemiology Consortium, we evaluated the interaction between immune system genetic variants and autoimmune conditions in NHL risk. We evaluated the immunity-related single nucleotide polymorphisms rs1800629 (tumor necrosis factor gene (TNF) G308A), rs1800890 (interleukin-10 gene (IL10) T3575A), rs6457327 (human leukocyte antigen gene (HLA) class I), rs10484561 (HLA class II), and rs2647012 (HLA class II)) and categorized autoimmune conditions as primarily mediated by B-cell or T-cell responses. We constructed unconditional logistic regression models to measure associations between autoimmune conditions and NHL with stratification by genotype. Autoimmune conditions mediated by B-cell responses were associated with increased NHL risk, specifically diffuse large B-cell lymphoma (odds ratio (OR) = 3.11, 95% confidence interval (CI): 2.25, 4.30) and marginal zone lymphoma (OR = 5.80, 95% CI: 3.82, 8.80); those mediated by T-cell responses were associated with peripheral T-cell lymphoma (OR = 2.14, 95% CI: 1.35, 3.38). In the presence of the rs1800629 AG/AA genotype, B-cell-mediated autoimmune conditions increased NHL risk (OR = 3.27, 95% CI: 2.07, 5.16; P-interaction = 0.03) in comparison with the GG genotype (OR = 1.82, 95% CI: 1.31, 2.53). This interaction was consistent across major B-cell NHL subtypes, including marginal zone lymphoma (P-interaction = 0.02) and follicular lymphoma (P-interaction = 0.04). © The Author 2015. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.

Published
2015

36. Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition

Author

Christine F. Skibola, Stephen Barnes, Yuanyuan Li, Landon Wilson, Bidisha Paul, Trygve O. Tollefsbol, Casey D. Morrow, Matthew L. Stoll, and Kendra J. Royston

Subjects
0301 basic medicine, Cancer Treatment, Genistein, Gut flora, Pathology and Laboratory Medicine, Feces, Mice, chemistry.chemical_compound, 0302 clinical medicine, Breast Tumors, Medicine and Health Sciences, Eubacterium, 2. Zero hunger, Multidisciplinary, biology, Pharmaceutics, Genomics, Animal Models, Middle Aged, Bacterial Pathogens, 3. Good health, Oncology, Experimental Organism Systems, Medical Microbiology, 030220 oncology & carcinogenesis, Medicine, Female, Pathogens, Research Article, Adult, Clinical Oncology, medicine.medical_specialty, Science, Antineoplastic Agents, Breast Neoplasms, Mouse Models, Microbial Genomics, Research and Analysis Methods, Microbiology, Cancer Chemotherapy, 03 medical and health sciences, Model Organisms, Breast cancer, Drug Therapy, Internal medicine, Breast Cancer, Genetics, medicine, Animals, Anticarcinogenic Agents, Humans, Chemotherapy, Microbiome, Microbial Pathogens, Aged, Nutrition, Clostridium, Bacteria, Catabolism, Gut Bacteria, Organisms, Biology and Life Sciences, Cancers and Neoplasms, Cancer, biology.organism_classification, medicine.disease, Gastrointestinal Microbiome, Diet, Disease Models, Animal, 030104 developmental biology, Endocrinology, chemistry, Clinical Medicine
Abstract

Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients' intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients' post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth.

Published
2017
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37. Abstract 1318: A genome-wide association study of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma demonstrates association with chromosome 6

Author

Nathaniel Rothman, James McKay, Joseph Vijai, Charles C. Chung, Sonja I. Berndt, Claire M. Vajdic, Lynn R. Goldin, Lauren R. Teras, James R. Cerhan, Roel Vermeulen, Henrik Hjalgrim, Lindsay M. Morton, Elizabeth E. Brown, Neil E. Caporaso, Susan L. Slager, Mary L. McMaster, Belynda Hicks, Alex Smith, Geffen Kleinstern, Laurie Burdette, Christine F. Skibola, Shengchao A. Li, Karin Ekstrom-Smedby, Alexandra Nieters, Alain Monnereau, Bin Zhu, Brian K. Link, and Brenda M. Birmann

Subjects
Genetics, Cancer Research, Oncology, medicine, Chromosome, Waldenstrom macroglobulinemia, Genome-wide association study, Biology, medicine.disease, Lymphoplasmacytic Lymphoma
Abstract

Waldenström macroglobulinemia (WM) is a unique subset of lymphoplasmacytic lymphoma (LPL) that is defined by the presence of an LPL infiltrate in the bone marrow together with a monoclonal IgM protein in the serum. A somatic activating mutation, MYD88 L265P, occurs in 85+% of WM and in 25%-50% of patients with the precursor condition, IgM monoclonal gammopathy of undetermined significance (MGUS); however, germline MYD88 mutations have not been observed in WM patients, and the genetic basis for WM predisposition remains undefined. To identify novel WM susceptibility loci we conducted a two-stage genome-wide association study (GWAS) in over 450 WM cases and 4300 controls of European ancestry. Discovery (stage 1) included 217 WM cases (40% familial) and 3798 controls genotyped on the Illumina Omni Express or Illumina Omni2.5 platforms following standard quality control procedures. The genotyped data were imputed using the Haplotype Reference Consortium panel as a reference and analyzed using logistic regression. In stage 1, we identified three loci on chromosomes 6, 14 and 3 significantly associated (P Citation Format: Mary L. McMaster, Sonja I. Berndt, Shengchao A. Li, Susan Slager, Joseph Vijai, Charles C. Chung, Bin Zhu, Laurie Burdette, Brenda Birmann, Elizabeth E. Brown, James R. Cerhan, Karin Ekstrom-Smedby, Henrik Hjalgrim, Geffen Kleinstern, Brian K. Link, James McKay, Alain Monnereau, Lindsay M. Morton, Alexandra Nieters, Nathaniel Rothman, Christine F. Skibola, Alex Smith, Lauren R. Teras, Claire M. Vajdic, Roel Vermeulen, Belynda Hicks, Lynn R. Goldin, Neil E. Caporaso. A genome-wide association study of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma demonstrates association with chromosome 6 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1318. doi:10.1158/1538-7445.AM2017-1318

Published
2017
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38. Serum Proteomic Profiling in Diffuse Large B-Cell Lymphoma

Author

Christine F. Skibola

Subjects
education.field_of_study, Adiponectin, Proteomic Profiling, Immunology, Cancer, Cell Biology, Hematology, Biology, medicine.disease, Biochemistry, Blood proteins, Squamous carcinoma, Extracellular matrix protein 1, medicine, Biomarker (medicine), education, Diffuse large B-cell lymphoma
Abstract

Background: The aim of this study was to conduct an exploratory serum proteomic profiling study of diffuse large B-cell lymphoma (DLBCL) using mass spectrometry (MS) analysis to identify potential biomarkers that may provide further clues to disease mechanisms. Methods: Serum samples from 57 chemotherapy-naive male DLBCL cases and 30 healthy controls matched by age and BMI from a San Francisco Bay Area case-control study were divided into single-use aliquots and stored at -80°C until proteomic analysis. Serum samples were depleted of the 12 most abundant proteins by filtration on immunoaffinity spin columns prior to MS analysis. Proteomic analysis was performed using a GeLC approach. Specifically, equal amounts of protein from serologic specimens were separated by one-dimensional denaturing gel electrophoresis. Each lane was cut into six equal MW fractions followed by in-gel digestion with trypsin. The resultant peptides were analyzed using nano-liquid chromatography MS. Because MS is more qualitative than quantitative, the most significant and biologically relevant proteins of interest were chosen for further confirmation by ELISA in the "sandwich" configuration to specifically and quantitatively measure protein concentrations. ELISA assays were performed on unprocessed serum samples without depletion of the major serum proteins, providing a direct, one-step measurement, thereby avoiding any artifacts due to uncontrolled parameters common in preprocessing. Statistically significant differentially expressed serum peptides between the cases and controls as detected by MS were further analyzed using Systems biology/Pathway analysis. Results: MS data computed as normalized spectral counts of peptides revealed 1,207 protein IDs with >99% confidence, and 44 statistically significant candidates that were differentially expressed between the DLBCL cases and controls. We confirmed 4 [adiponectin (AdipoQ), extracellular matrix protein 1 (ECM1), CD14, and SerpinA3 (ACT)] of the 6 top candidates chosen for further confirmation by ELISA, which were elevated by 68.8, 62.9, 33.6 and 28.8 %, respectively, in DLBCL sera compared to controls. Adiponectin is an adipocyte-derived cytokine that regulates the metabolism of lipids and glucose. There is accumulating evidence that adiponectin also exhibits pro- and anti-tumorigenic activity, depending on the tumor type. Our study confirms previous reports of significantly elevated adiponectin levels in patients with adult non-Hodgkin lymphoma (NHL) and DLBCL, childhood NHL, and Hodgkin lymphoma compared to controls (PMID: 22547160). CD14 is a myeloid differentiation marker found primarily on monocytes and macrophages. Soluble CD14 levels have been positively associated with AIDS-related NHL risk (PMID: 23169327). ECM1 regulates cell migration, invasion and stem-like properties via induction of EMT progression and cancer stem cell formation. High ECM1 levels have been detected in various epithelial cancers, including invasive breast ductal carcinoma, esophageal squamous carcinoma, and gastric and colorectal cancer. ECM1 also has been associated with invasiveness and poor prognosis in thyroid and breast cancer. ACT is a metastasis-associated protein. Elevated ACT levels in serum have been associated with poor overall survival in acute leukemia (PMID: 24179540). The proteins identified in this study were critically analyzed using pathway analysis tools, and were found to be strongly associated with FcR signaling, and response to kinase activation including MAPK, membrane PTK, and neurotrophin TRK. These activities, and the proteins identified appear to involve IL-6 (Jak1/Stat3), ESR1/ CREB1, RXR1/ PPAR1, NF-kB, and HIF-1 signaling pathways at different stages of disease vs. controls. Based on these data, the predicted downstream effectors include regulation of immune processes that involve acute-phase and inflammatory responses, and regulation of lipid metabolism and transport. Conclusions: Through serum proteomic profiling studies, we have identified 3 novel (ECM1, CD14, and ACT) and 1 previously reported biomarker (adiponectin) of DLBCL that may have potential biological relevance in the pathogenesis or progression of the disease. Prospective epidemiology and clinical studies will be needed to determine whether these markers are involved in disease etiology and their possible prognostic value. Disclosures No relevant conflicts of interest to declare.

Published
2015
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39. Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types

Author

Yeul Hong Kim, Sonja I. Berndt, José María Huerta, Morgan Rouprêt, Reury Perng Perng, Yi Young Choi, Lindsay M. Morton, Roberto Tirabosco, H. Bas Bueno-de-Mesquita, Wendy Cozen, Neil E. Caporaso, Stephen J. Chanock, Zhenhong Zhao, Dina Halai, Neyssa Marina, Ann L. Oberg, Stephen M. Ansell, Zhibin Hu, Donghui Li, Anne J. Novak, Jenny Turner, Wen Tan, Julie E. Buring, Stefano Porru, Qincheng He, Tania Carreón, Guoping Wu, Graham G. Giles, Claire M. Vajdic, Rudolf Kaaks, Ulrika Andersson, Susan L. Slager, Jen Yu Hung, Luis Sierrasesúmaga, Roel Vermeulen, Louise A. Brinton, Myron D. Gross, Jennifer Prescott, E. Lund, Chih Yi Chen, Jin Eun Choi, Chaoyu Wang, George J. Weiner, H. Dean Hosgood, Haixin Li, Carrie A. Thompson, Núria Malats, James McKay, Stephanie J. Weinstein, Young Tae Kim, Emily White, Pan-Chyr Yang, Orestis A. Panagiotou, Robert J. Klein, Joseph Vijai, Josep Lloreta, Immaculata De Vivo, Sofia Pavanello, Thomas E. Witzig, Montserrat Garcia-Closas, Roger Henriksson, Bryan A. Bassig, Tait D. Shanafelt, Rachel S. Kelly, Joseph M. Connors, Marco Rais, Wu Chou Su, Alex Smith, John J. Spinelli, Julie M. Gastier-Foster, Anne Kricker, In Kyu Park, Marc J. Gunter, Chancellor Hohensee, Simon Crouch, Jarmo Virtamo, M. G. Ennas, Lucia Conde, Lotte Maxild Mortensen, Lenka Foretova, Eric J. Duell, Anthony Staines, Hongyan Chen, Baosen Zhou, Brian M. Wolpin, Simone Benhamou, Zhaoming Wang, Françoise Clavel-Chapelon, Charles C. Chung, Nan Hu, Domenico Palli, Rebecca Montalvan, Thomas M. Habermann, Debra T. Silverman, Preetha Rajaraman, Christian C. Abnet, Wei-Yen Lim, Yuh Min Chen, Michelle Cotterchio, Lucia Miligi, Claudia Maria Hattinger, Eve Roman, Christopher Kim, Federico Canzian, Alan D. L. Sihoe, Sharon A. Savage, Mark P. Purdue, Maria Teresa Landi, Susan M. Gapstur, M Zucca, Yuanqing Ye, Jian Su, Chong-Jen Yu, Edward Giovannucci, Alain Monnereau, Afshan Siddiq, Ralph L. Erickson, Katherine A. McGlynn, Petra H.M. Peeters, W. Ryan Diver, David Van Den Berg, Gloria M. Petersen, Judith Hoffman-Bolton, Xiao-Ou Shu, Ying Chen, Eric J. Jacobs, Heiner Boeing, Sophia S. Wang, Hans-Olov Adami, Yuqing Li, Jacqueline Clavel, Ellen T. Chang, Tongzhang Zheng, William Pao, Hideo Kunitoh, Ulrike Peters, Jenny Chang-Claude, Alexandra Nieters, Silvia de Sanjosé, Chen Wu, Anders Ahlbom, Jun Suk Kim, Fredrick R. Schumacher, Roberta McKean-Cowdin, Laurence N. Kolonel, Herbert Yu, Li Liu, Vittorio Krogh, Tangchun Wu, Ho Il Yoon, Joseph F. Fraumeni, Olivier Cussenot, Jae Sook Sung, Kari E. North, Andrew D. Zelenetz, Ana Patiño-García, Anne Zeleniuch-Jacquotte, Christopher A. Haiman, Biyun Qian, Giovanni Maria Ferri, Rebecca Rodabough, Xifeng Wu, Maria Feychting, Kuan-Yu Chen, Laure Dossus, Jianjun Liu, Jean Wactawski-Wende, Constance Chen, Robert L. Grubb, Paolo Vineis, Mads Melbye, Chien Chung Lin, Malin Sund, Wei Zheng, Jun Xu, Yi Song Chen, Kay-Tee Khaw, Richard K. Severson, Kun-Chieh Chen, Jian-Min Yuan, Bu Tian Ji, Simonetta Di Lollo, Ping Xu, Howard D. Sesso, Yoo Jin Jung, Margaret R. Karagas, Piero Picci, Gianluca Severi, Margaret A. Tucker, Ti Ding, Gee-Chen Chang, Li Hsin Chien, She-Juan An, Maria Pik Wong, Chien-Jen Chen, Jonine D. Figueroa, Sun-Seog Kweon, Katia Scotlandi, Sara H. Olson, Kendra Schwartz, Chang Hyun Kang, Marta Crous-Bou, Yawei Zhang, Ludmila Prokunina-Olsson, Yolanda Benavente, Christine D. Berg, Kala Visvanathan, Loic Le Marchand, Takashi Kohno, Nilanjan Chatterjee, Tracy Lightfoot, Zhihua Yin, Lee E. Moore, Joanne S. Colt, Laurie Burdett, Tetsuya Mitsudomi, Harvey A. Risch, Alfredo Carrato, Hyo Sung Jeon, Victoria L. Stevens, Richard Gorlick, Danylo J. Villano, Alison P. Klein, Angela Brooks-Wilson, Joshua N. Sampson, Chu Chen, You-Lin Qiao, Kouya Shiraishi, Alan R. Schned, Dominique S. Michaud, Peng Guan, Philip R. Taylor, Gerald L. Andriole, John K.C. Chan, Eva Comperat, Randy D. Gascoyne, Marc Maynadie, Kyong Hwa Park, Amanda Black, Charles Kooperberg, Andrea La Croix, Kenneth Offit, Peter Kraft, David Thomas, Manuela Gago-Dominguez, Manolis Kogevinas, Theodore R. Holford, Pamela L. Horn-Ross, Xingzhou He, Massimo Serra, Satu Männistö, Christoffer Johansen, Meredith Yeager, Robert N. Hoover, Mary Ann Butler, William Wheeler, Jian Gu, Wei Wu, Ying Hsiang Chen, Leslie Bernstein, Yao Jen Li, David J. Hunter, In-Jae Oh, Jay S. Wunder, Meng Zhu, Henrik Hjalgrim, Martyn T. Smith, Alisa M. Goldstein, Linda M. Liao, Chao Agnes Hsiung, Ruth C. Travis, Jiucun Wang, Marie-Christine Boutron-Ruault, Daru Lu, Reina García-Closas, Avima M. Ruder, Martha S. Linet, Wei Tang, Geraldine Cancel-Tassin, Brian K. Link, Rebecca D. Jackson, J. Michael Gaziano, Malcolm C. Pike, Yu-Tang Gao, Lisa Mirabello, Alan A. Arslan, Hong Zheng, Nicolas Wentzensen, Chung Hsing Chen, I. Shou Chang, Meir J. Stampfer, Brenda M. Birmann, Alison Johnson, Wong-Ho Chow, Chin-Fu Hsiao, Neal D. 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Subjects
Male, Cancer Research, Lung Neoplasms, Lymphoma, Genome-wide association study, Polymorphism (computer science), Neoplasms, Medicine, Chronic, Genetics, Osteosarcoma, Oncology And Carcinogenesis, Leukemia, Smoking, Family aggregation, Single Nucleotide, Middle Aged, Familial risk, Diffuse, Kidney Neoplasms, Lymphocytic, Oncology, Adult, Aged, Asian Continental Ancestry Group, Bone Neoplasms, European Continental Ancestry Group, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse, Polymorphism, Single Nucleotide, Testicular Neoplasms, Tissue Array Analysis, Urinary Bladder Neoplasms, Genetic Predisposition to Disease, Genome-Wide Association Study, Genetic correlation, Large B-Cell, Oncology & Carcinogenesis, Polymorphism, business.industry, Extramural, B-Cell, Cancer, Heritability, Genome-wide association studies for thirteen cancer types, medicine.disease, business
Abstract

BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Published
2015
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40. Abstract 4626: Genetic susceptibility to diffuse large B-cell lymphoma in a pooled study of three Eastern Asian populations

Author

Paul Brennan, Sonja I. Berndt, Stephen J. Chanock, Qing Lan, Joseph Vijai, Meredith Yeager, Suleeporn Sangrajrang, Tongzhang Zheng, Jovic Tse, Wei Hu, James R. Cerhan, Nathaniel Rothman, Laurie Burdette, Je-Jung Lee, Pattarapong Pornsopone, Christine F. Skibola, Hyeoung-Joon Kim, Min-Ho Shin, Raymond Liang, Wing-Yan Au, Hee Nam Kim, Heping Zhang, and Bryan A. Bassig

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, Cancer, Single-nucleotide polymorphism, Genome-wide association study, medicine.disease, Lymphoma, hemic and lymphatic diseases, Internal medicine, medicine, Genetic predisposition, Population study, Allele, business, Diffuse large B-cell lymphoma
Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and is the most common NHL subtype diagnosed worldwide. Some epidemiologic data have indicated differences in DLBCL incidence rates and subtype distributions between Eastern Asian and Western countries. The first large-scale genome-wide association study (GWAS) of DLBCL with over 4000 cases conducted among individuals of European ancestry recently identified five independent SNPs that achieved genome-wide significance, and two SNPs that showed a suggestive association with DLBCL risk. In order to evaluate whether Eastern Asians and individuals of European ancestry share similar genetic risk factors for this disease, we attempted to replicate these GWAS findings in a pooled series of 1124 DLBCL cases and 3596 controls from Hong Kong, South Korea, and Thailand. Three of the five genome-wide significant SNPs from the DLBCL GWAS were significantly associated with DLBCL in our study population, including the top finding from the GWAS, EXOC2 rs116446171, which achieved genome-wide significance in our data (per allele OR = 2.04, 95% CI = 1.63-2.56; ptrend = 3.9 × 10-10). Additionally, we observed a significant association with PVT1 rs13255292 (per allele OR = 1.34, 95% CI = 1.19-1.52; ptrend = 2.1 × 10-6), which was the second strongest finding in the GWAS, and with HLA-B rs2523607 (per allele OR = 3.05, 95% CI = 1.32-7.05; ptrend = 0.009). Our study, which provides the first evaluation in Eastern Asians of SNPs definitively associated with DLBCL risk in individuals of European ancestry, indicates that at least some of the genetic factors associated with risk of DLBCL are similar between these populations. Citation Format: Nathaniel Rothman, Bryan A. Bassig, James R. Cerhan, Wing-Yan Au, Hee Nam Kim, Suleeporn Sangrajrang, Wei Hu, Jovic Tse, Sonja Berndt, Tongzhang Zheng, Heping Zhang, Pattarapong Pornsopone, Je-Jung Lee, Hyeoung-Joon Kim, Christine F. Skibola, Joseph Vijai, Laurie Burdette, Meredith Yeager, Paul Brennan, Min-Ho Shin, Raymond Liang, Stephen Chanock, Qing Lan. Genetic susceptibility to diffuse large B-cell lymphoma in a pooled study of three Eastern Asian populations. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4626. doi:10.1158/1538-7445.AM2015-4626

Published
2015
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