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1. Differential long-term bivalent HPV vaccine cross-protection by variants in the Costa Rica HPV vaccine trial

Author: Jaimie Z. Shing, Carolina Porras, Maísa Pinheiro, Rolando Herrero, Allan Hildesheim, Danping Liu, Mitchell H. Gail, Byron Romero, John T. Schiller, Michael Zúñiga, Sambit Mishra, Laurie Burdette, Kristine Jones, John Schussler, Rebeca Ocampo, Jianwen Fang, Zhiwei Liu, Douglas R. Lowy, Sabrina H. Tsang, Ana Cecilia Rodríguez, Mark Schiffman, Cameron B. Haas, Loretto J. Carvajal, Jalen R. Brown, Aimée R. Kreimer, Lisa Mirabello, and Costa Rica HPV Vaccine Trial (CVT) Group
Subjects: Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract The AS04-adjuvanted human papillomavirus (HPV)16/18 vaccine, an L1-based vaccine, provides strong vaccine efficacy (VE) against vaccine-targeted type infections, and partial cross-protection to phylogenetically-related types, which may be affected by variant-level heterogeneity. We compared VE against incident HPV31, 33, 35, and 45 detections between lineages and SNPs in the L1 region among 2846 HPV-vaccinated and 5465 HPV-unvaccinated women through 11-years of follow-up in the Costa Rica HPV Vaccine Trial. VE was lower against HPV31-lineage-B (VE=60.7%;95%CI = 23.4%,82.8%) compared to HPV31-lineage-A (VE=94.3%;95%CI = 83.7%,100.0%) (VE-ratio = 0.64;95%CI = 0.25,0.90). Differential VE was observed at several lineage-associated HPV31-L1-SNPs, including a nonsynonymous substitution at position 6372 on the FG-loop, an important neutralization domain. For HPV35, the only SNP-level difference was at position 5939 on the DE-loop, with significant VE against nucleotide-G (VE=65.0%;95%CI = 28.0,87.8) but not for more the common nucleotide-A (VE=7.4%;95%CI = −34.1,36.7). Because of the known heterogeneity in precancer/cancer risk across cross-protected HPV genotype variants by race and region, our results of differential variant-level AS04-adjuvanted HPV16/18 vaccine efficacy has global health implications.
Published: 2024
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2. Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia

Author: Batel Blechter, Jason Y.Y. Wong, Chao Agnes Hsiung, H.Dean Hosgood, Zhihua Yin, Xiao-Ou Shu, Han Zhang, Jianxin Shi, Lei Song, Minsun Song, Wei Zheng, Zhaoming Wang, Neil Caporaso, Laurie Burdette, Meredith Yeager, Sonja I. Berndt, Maria Teresa Landi, Chien-Jen Chen, Gee-Chen Chang, Chin-Fu Hsiao, Ying-Huang Tsai, Kuan-Yu Chen, Ming-Shyan Huang, Wu-Chou Su, Yuh-Min Chen, Li-Hsin Chien, Chung-Hsing Chen, Tsung-Ying Yang, Chih-Liang Wang, Jen-Yu Hung, Chien-Chung Lin, Reury-Perng Perng, Chih-Yi Chen, Kun-Chieh Chen, Yao-Jen Li, Chong-Jen Yu, Yi-Song Chen, Ying-Hsiang Chen, Fang-Yu Tsai, Wei Jie Seow, Bryan A. Bassig, Wei Hu, Bu-Tian Ji, Wei Wu, Peng Guan, Qincheng He, Yu-Tang Gao, Qiuyin Cai, Wong-Ho Chow, Yong-Bing Xiang, Dongxin Lin, Chen Wu, Yi-Long Wu, Min-Ho Shin, Yun-Chul Hong, Keitaro Matsuo, Kexin Chen, Maria Pik Wong, Daru Lu, Li Jin, Jiu-Cun Wang, Adeline Seow, Tangchun Wu, Hongbing Shen, Joseph F. Fraumeni, Pan-Chyr Yang, I-Shou Chang, Baosen Zhou, Stephen J. Chanock, Nathaniel Rothman, Nilanjan Chatterjee, and Qing Lan
Subjects: Lung adenocarcinoma, Polygenic risk score, Gene-environment interaction, Household coal use, Never-smoking women in Asia, Environmental sciences, GE1-350
Abstract: We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10−26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10−3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.
Published: 2021
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3. 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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4. Genome-wide association study identifies multiple risk loci for renal cell carcinoma

Author: Ghislaine Scelo, Mark P. Purdue, Kevin M. Brown, Mattias Johansson, Zhaoming Wang, Jeanette E. Eckel-Passow, Yuanqing Ye, Jonathan N. Hofmann, Jiyeon Choi, Matthieu Foll, Valerie Gaborieau, Mitchell J. Machiela, Leandro M. Colli, Peng Li, Joshua N. Sampson, Behnoush Abedi-Ardekani, Celine Besse, Helene Blanche, Anne Boland, Laurie Burdette, Amelie Chabrier, Geoffroy Durand, Florence Le Calvez-Kelm, Egor Prokhortchouk, Nivonirina Robinot, Konstantin G. Skryabin, Magdalena B. Wozniak, Meredith Yeager, Gordana Basta-Jovanovic, Zoran Dzamic, Lenka Foretova, Ivana Holcatova, Vladimir Janout, Dana Mates, Anush Mukeriya, Stefan Rascu, David Zaridze, Vladimir Bencko, Cezary Cybulski, Eleonora Fabianova, Viorel Jinga, Jolanta Lissowska, Jan Lubinski, Marie Navratilova, Peter Rudnai, Neonila Szeszenia-Dabrowska, Simone Benhamou, Geraldine Cancel-Tassin, Olivier Cussenot, Laura Baglietto, Heiner Boeing, Kay-Tee Khaw, Elisabete Weiderpass, Borje Ljungberg, Raviprakash T. Sitaram, Fiona Bruinsma, Susan J. Jordan, Gianluca Severi, Ingrid Winship, Kristian Hveem, Lars J. Vatten, Tony Fletcher, Kvetoslava Koppova, Susanna C. Larsson, Alicja Wolk, Rosamonde E. Banks, Peter J. Selby, Douglas F. Easton, Paul Pharoah, Gabriella Andreotti, Laura E. Beane Freeman, Stella Koutros, Demetrius Albanes, Satu Männistö, Stephanie Weinstein, Peter E. Clark, Todd L. Edwards, Loren Lipworth, Susan M. Gapstur, Victoria L. Stevens, Hallie Carol, Matthew L. Freedman, Mark M. Pomerantz, Eunyoung Cho, Peter Kraft, Mark A. Preston, Kathryn M. Wilson, J. Michael Gaziano, Howard D. Sesso, Amanda Black, Neal D. Freedman, Wen-Yi Huang, John G. Anema, Richard J. Kahnoski, Brian R. Lane, Sabrina L. Noyes, David Petillo, Bin Tean Teh, Ulrike Peters, Emily White, Garnet L. Anderson, Lisa Johnson, Juhua Luo, Julie Buring, I-Min Lee, Wong-Ho Chow, Lee E. Moore, Christopher Wood, Timothy Eisen, Marc Henrion, James Larkin, Poulami Barman, Bradley C. Leibovich, Toni K. Choueiri, G. Mark Lathrop, Nathaniel Rothman, Jean-Francois Deleuze, James D. McKay, Alexander S. Parker, Xifeng Wu, Richard S. Houlston, Paul Brennan, and Stephen J. Chanock
Subjects: Science
Abstract: Risk for renal cell carcinoma (RCC) is higher when there are first-degree family members with the disease. Here, Scelo and colleagues perform a genome-wide association meta-analysis and new genome-wide scan to identify seven new loci with significant RCC association.
Published: 2017
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5. The influence of obesity-related factors in the etiology of renal cell carcinoma-A mendelian randomization study.

Author: Mattias Johansson, Robert Carreras-Torres, Ghislaine Scelo, Mark P Purdue, Daniela Mariosa, David C Muller, Nicolas J Timpson, Philip C Haycock, Kevin M Brown, Zhaoming Wang, Yuanqing Ye, Jonathan N Hofmann, Matthieu Foll, Valerie Gaborieau, Mitchell J Machiela, Leandro M Colli, Peng Li, Jean-Guillaume Garnier, Helene Blanche, Anne Boland, Laurie Burdette, Egor Prokhortchouk, Konstantin G Skryabin, Meredith Yeager, Sanja Radojevic-Skodric, Simona Ognjanovic, Lenka Foretova, Ivana Holcatova, Vladimir Janout, Dana Mates, Anush Mukeriya, Stefan Rascu, David Zaridze, Vladimir Bencko, Cezary Cybulski, Eleonora Fabianova, Viorel Jinga, Jolanta Lissowska, Jan Lubinski, Marie Navratilova, Peter Rudnai, Simone Benhamou, Geraldine Cancel-Tassin, Olivier Cussenot, Elisabete Weiderpass, Börje Ljungberg, Raviprakash Tumkur Sitaram, Christel Häggström, Fiona Bruinsma, Susan J Jordan, Gianluca Severi, Ingrid Winship, Kristian Hveem, Lars J Vatten, Tony Fletcher, Susanna C Larsson, Alicja Wolk, Rosamonde E Banks, Peter J Selby, Douglas F Easton, Gabriella Andreotti, Laura E Beane Freeman, Stella Koutros, Satu Männistö, Stephanie Weinstein, Peter E Clark, Todd L Edwards, Loren Lipworth, Susan M Gapstur, Victoria L Stevens, Hallie Carol, Matthew L Freedman, Mark M Pomerantz, Eunyoung Cho, Kathryn M Wilson, J Michael Gaziano, Howard D Sesso, Neal D Freedman, Alexander S Parker, Jeanette E Eckel-Passow, Wen-Yi Huang, Richard J Kahnoski, Brian R Lane, Sabrina L Noyes, David Petillo, Bin Tean Teh, Ulrike Peters, Emily White, Garnet L Anderson, Lisa Johnson, Juhua Luo, Julie Buring, I-Min Lee, Wong-Ho Chow, Lee E Moore, Timothy Eisen, Marc Henrion, James Larkin, Poulami Barman, Bradley C Leibovich, Toni K Choueiri, G Mark Lathrop, Jean-Francois Deleuze, Marc Gunter, James D McKay, Xifeng Wu, Richard S Houlston, Stephen J Chanock, Caroline Relton, J Brent Richards, Richard M Martin, George Davey Smith, and Paul Brennan
Subjects: Medicine
Abstract: BackgroundSeveral obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findingsGenetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.ConclusionsThis study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
Published: 2019
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6. Deep sequencing of HPV16 genomes: A new high-throughput tool for exploring the carcinogenicity and natural history of HPV16 infection

Author: Michael Cullen, Joseph F. Boland, Mark Schiffman, Xijun Zhang, Nicolas Wentzensen, Qi Yang, Zigui Chen, Kai Yu, Jason Mitchell, David Roberson, Sara Bass, Laurie Burdette, Moara Machado, Sarangan Ravichandran, Brian Luke, Mitchell J. Machiela, Mark Andersen, Matt Osentoski, Michael Laptewicz, Sholom Wacholder, Ashlie Feldman, Tina Raine-Bennett, Thomas Lorey, Philip E. Castle, Meredith Yeager, Robert D. Burk, and Lisa Mirabello
Subjects: Infectious and parasitic diseases, RC109-216
Abstract: For unknown reasons, there is huge variability in risk conferred by different HPV types and, remarkably, strong differences even between closely related variant lineages within each type. HPV16 is a uniquely powerful carcinogenic type, causing approximately half of cervical cancer and most other HPV-related cancers. To permit the large-scale study of HPV genome variability and precancer/cancer, starting with HPV16 and cervical cancer, we developed a high-throughput next-generation sequencing (NGS) whole-genome method. We designed a custom HPV16 AmpliSeq™ panel that generated 47 overlapping amplicons covering 99% of the genome sequenced on the Ion Torrent Proton platform. After validating with Sanger, the current “gold standard” of sequencing, in 89 specimens with concordance of 99.9%, we used our NGS method and custom annotation pipeline to sequence 796 HPV16-positive exfoliated cervical cell specimens. The median completion rate per sample was 98.0%.Our method enabled us to discover novel SNPs, large contiguous deletions suggestive of viral integration (OR of 27.3, 95% CI 3.3–222, P=0.002), and the sensitive detection of variant lineage coinfections. This method represents an innovative high-throughput, ultra-deep coverage technique for HPV genomic sequencing, which, in turn, enables the investigation of the role of genetic variation in HPV epidemiology and carcinogenesis. Keywords: HPV16, HPV epidemiology, HPV genomics
Published: 2015
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7. Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations.

Author: Laura S Burke, Paula L Hyland, Ruth M Pfeiffer, Jennifer Prescott, William Wheeler, Lisa Mirabello, Sharon A Savage, Laurie Burdette, Meredith Yeager, Stephen Chanock, Immaculata De Vivo, Margaret A Tucker, Alisa M Goldstein, and Xiaohong R Yang
Subjects: Medicine, Science
Abstract: INTRODUCTION: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. MATERIALS AND METHODS: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. RESULTS: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. DISCUSSION: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.
Published: 2013
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8. Large-scale pathway-based analysis of bladder cancer genome-wide association data from five studies of European background.

Author: Idan Menashe, Jonine D Figueroa, Montserrat Garcia-Closas, Nilanjan Chatterjee, Nuria Malats, Antoni Picornell, Dennis Maeder, Qi Yang, Ludmila Prokunina-Olsson, Zhaoming Wang, Francisco X Real, Kevin B Jacobs, Dalsu Baris, Michael Thun, Demetrius Albanes, Mark P Purdue, Manolis Kogevinas, Amy Hutchinson, Yi-Ping Fu, Wei Tang, Laurie Burdette, Adonina Tardón, Consol Serra, Alfredo Carrato, Reina García-Closas, Josep Lloreta, Alison Johnson, Molly Schwenn, Alan Schned, Gerald Andriole, Amanda Black, Eric J Jacobs, Ryan W Diver, Susan M Gapstur, Stephanie J Weinstein, Jarmo Virtamo, Neil E Caporaso, Maria Teresa Landi, Joseph F Fraumeni, Stephen J Chanock, Debra T Silverman, and Nathaniel Rothman
Subjects: Medicine, Science
Abstract: Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and ∼90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P≤0.01. To minimize false positives, we used the I(2) statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways ('Aromatic amine metabolism' [P(GSEA) = 0.0100, P(ARTP) = 0.0020], 'NAD biosynthesis' [P(GSEA) = 0.0018, P(ARTP) = 0.0086], 'NAD salvage' [P(ARTP) = 0.0068], 'Clathrin derived vesicle budding' [P(ARTP) = 0.0018], 'Lysosome vesicle biogenesis' [P(GSEA) = 0.0023, P(ARTP)
Published: 2012
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9. On the interplay of telomeres, nevi and the risk of melanoma.

Author: Clara Bodelon, Ruth M Pfeiffer, Valentina Bollati, Julien Debbache, Donato Calista, Paola Ghiorzo, Maria Concetta Fargnoli, Giovanna Bianchi-Scarra, Ketty Peris, Mirjam Hoxha, Amy Hutchinson, Laurie Burdette, Laura Burke, Shenying Fang, Margaret A Tucker, Alisa M Goldstein, Jeffrey E Lee, Qingyi Wei, Sharon A Savage, Xiaohong R Yang, Christopher Amos, and Maria Teresa Landi
Subjects: Medicine, Science
Abstract: The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.
Published: 2012
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10. Single nucleotide polymorphisms in the PRDX3 and RPS19 and risk of HPV persistence and cervical precancer/cancer.

Author: Mahboobeh Safaeian, Allan Hildesheim, Paula Gonzalez, Kai Yu, Carolina Porras, Qizhai Li, Ana Cecilia Rodriguez, Mark E Sherman, Mark Schiffman, Sholom Wacholder, Robert Burk, Rolando Herrero, Laurie Burdette, Stephen J Chanock, and Sophia S Wang
Subjects: Medicine, Science
Abstract: Host genetic factors might affect the risk of progression from infection with carcinogenic human papillomavirus (HPV), the etiologic agent for cervical cancer, to persistent HPV infection, and hence to cervical precancer and cancer.We assessed 18,310 tag single nucleotide polymorphisms (SNPs) from 1113 genes in 416 cervical intraepithelial neoplasia 3 (CIN3)/cancer cases, 356 women with persistent carcinogenic HPV infection (median persistence of 25 months) and 425 randomly selected women (non-cases and non-HPV persistent) from the 10,049 women from the Guanacaste, Costa Rica HPV natural history cohort. For gene and SNP associations, we computed age-adjusted odds ratio and p-trend. Three comparisons were made: 1) association with CIN3/cancer (compared CIN3/cancer cases to random controls), 2) association with persistence (compared HPV persistence to random controls), and 3) progression (compared CIN3/cancers with HPV-persistent group). Regions statistically significantly associated with CIN3/cancer included genes for peroxiredoxin 3 PRDX3, and ribosomal protein S19 RPS19. The single most significant SNPs from each gene associated with CIN3/cancer were PRDX3 rs7082598 (P(trend)
Published: 2012
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11. Genetic admixture and population substructure in Guanacaste Costa Rica.

Author: Zhaoming Wang, Allan Hildesheim, Sophia S Wang, Rolando Herrero, Paula Gonzalez, Laurie Burdette, Amy Hutchinson, Gilles Thomas, Stephen J Chanock, and Kai Yu
Subjects: Medicine, Science
Abstract: The population of Costa Rica (CR) represents an admixture of major continental populations. An investigation of the CR population structure would provide an important foundation for mapping genetic variants underlying common diseases and traits. We conducted an analysis of 1,301 women from the Guanacaste region of CR using 27,904 single nucleotide polymorphisms (SNPs) genotyped on a custom Illumina InfiniumII iSelect chip. The program STRUCTURE was used to compare the CR Guanacaste sample with four continental reference samples, including HapMap Europeans (CEU), East Asians (JPT+CHB), West African Yoruba (YRI), as well as Native Americans (NA) from the Illumina iControl database. Our results show that the CR Guanacaste sample comprises a three-way admixture estimated to be 43% European, 38% Native American and 15% West African. An estimated 4% residual Asian ancestry may be within the error range. Results from principal components analysis reveal a correlation between genetic and geographic distance. The magnitude of linkage disequilibrium (LD) measured by the number of tagging SNPs required to cover the same region in the genome in the CR Guanacaste sample appeared to be weaker than that observed in CEU, JPT+CHB and NA reference samples but stronger than that of the HapMap YRI sample. Based on the clustering pattern observed in both STRUCTURE and principal components analysis, two subpopulations were identified that differ by approximately 20% in LD block size averaged over all LD blocks identified by Haploview. We also show in a simulated association study conducted within the two subpopulations, that the failure to account for population stratification (PS) could lead to a noticeable inflation in the false positive rate. However, we further demonstrate that existing PS adjustment approaches can reduce the inflation to an acceptable level for gene discovery.
Published: 2010
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12. Phase I metabolic genes and risk of lung cancer: multiple polymorphisms and mRNA expression.

Author: Melissa Rotunno, Kai Yu, Jay H Lubin, Dario Consonni, Angela C Pesatori, Alisa M Goldstein, Lynn R Goldin, Sholom Wacholder, Robert Welch, Laurie Burdette, Stephen J Chanock, Pier Alberto Bertazzi, Margaret A Tucker, Neil E Caporaso, Nilanjan Chatterjee, Andrew W Bergen, and Maria Teresa Landi
Subjects: Medicine, Science
Abstract: Polymorphisms in genes coding for enzymes that activate tobacco lung carcinogens may generate inter-individual differences in lung cancer risk. Previous studies had limited sample sizes, poor exposure characterization, and a few single nucleotide polymorphisms (SNPs) tested in candidate genes. We analyzed 25 SNPs (some previously untested) in 2101 primary lung cancer cases and 2120 population controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study from six phase I metabolic genes, including cytochrome P450s, microsomal epoxide hydrolase, and myeloperoxidase. We evaluated the main genotype effects and genotype-smoking interactions in lung cancer risk overall and in the major histology subtypes. We tested the combined effect of multiple SNPs on lung cancer risk and on gene expression. Findings were prioritized based on significance thresholds and consistency across different analyses, and accounted for multiple testing and prior knowledge. Two haplotypes in EPHX1 were significantly associated with lung cancer risk in the overall population. In addition, CYP1B1 and CYP2A6 polymorphisms were inversely associated with adenocarcinoma and squamous cell carcinoma risk, respectively. Moreover, the association between CYP1A1 rs2606345 genotype and lung cancer was significantly modified by intensity of cigarette smoking, suggesting an underlying dose-response mechanism. Finally, increasing number of variants at CYP1A1/A2 genes revealed significant protection in never smokers and risk in ever smokers. Results were supported by differential gene expression in non-tumor lung tissue samples with down-regulation of CYP1A1 in never smokers and up-regulation in smokers from CYP1A1/A2 SNPs. The significant haplotype associations emphasize that the effect of multiple SNPs may be important despite null single SNP-associations, and warrants consideration in genome-wide association studies (GWAS). Our findings emphasize the necessity of post-GWAS fine mapping and SNP functional assessment to further elucidate cancer risk associations.
Published: 2009
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13. Supplementary Table 5 from The 19q12 Bladder Cancer GWAS Signal: Association with Cyclin E Function and Aggressive Disease

Author: Ludmila Prokunina-Olsson, Nathaniel Rothman, Debra T. Silverman, Stephen M. Hewitt, Stephen J. Chanock, Joseph Fraumeni, William Wheeler, Laurie Burdette, Amy Hutchinson, Charles C. Chung, Xiang Deng, Zhaoming Wang, H. Barton Grossman, Giuseppe Mastrangelo, Cecilia Arici, Sofia Pavanello, Angela Carta, Stefano Porru, Eva Comperat, Morgan Roupret, Geraldine Cancel-Tassin, Olivier Cussenot, Christopher A. Haiman, Jian-Min Yuan, David Van Den Berg, Malcolm C. Pike, Mariana C. Stern, Manuela Gago-Dominguez, David V. Conti, Victoria K. Cortessis, Rebecca J. Rodabough, Chancellor Hohensee, Charles Kooperberg, Jarmo Virtamo, Stephanie J. Weinstein, Demetrius Albanes, W. Ryan Diver, Eric J. Jacobs, Susan M. Gapstur, Sara Lindstrom, Peter Kraft, David Hunter, Edward Govannucci, Immaculata De Vivo, Constance Chen, Jennifer Prescott, Elio Riboli, Jenny Chang-Claude, Paul Brennan, Anne Tjønneland, Ruth C. Travis, Miren Dorronsoro, Vittorio Krogh, Elisabete Weiderpass, Gianluca Severi, Börje Ljungberg, Dimitrios Trichopoulos, H. Bas Bueno-de-Mesquita, Afshan Siddiq, Paolo Vineis, Neil E. Caporaso, Maria T. Landi, Amanda Black, Robert L. Grubb, Gerald L. Andriole, Mark Purdue, Xifeng Wu, Josep Lloreta, Reina Garcia-Closas, Alfredo Carrato, Consol Serra, Adonina Tardon, Manolis Kogevinas, Nuria Malats, GM Monawar Hosain, Masatoshi Kida, Michael A. Jones, Liliana Guedez, Alan Schned, Adam Mumy, Alison Johnson, McAnthony Tarway, Margaret R. Karagas, Andrea B. Apolo, Molly Schwenn, Kris Ylaya, Ashley Paquin, Dalsu Baris, Brian Muchmore, Montserrat Garcia-Closas, Alexandra Scott-Johnson, Nilanjan Chatterjee, Patricia Porter-Gill, Wei Tang, Jonine D. Figueroa, Petra Lenz, Lee E. Moore, Indu Kohaar, and Yi-Ping Fu
Abstract: Association between CCNE1 variants and bladder cancer
Published: 2023
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14. Supplementary Materials, Figures 1 - 3, Tables 1 - 4, 6 - 8 from The 19q12 Bladder Cancer GWAS Signal: Association with Cyclin E Function and Aggressive Disease

Author: Ludmila Prokunina-Olsson, Nathaniel Rothman, Debra T. Silverman, Stephen M. Hewitt, Stephen J. Chanock, Joseph Fraumeni, William Wheeler, Laurie Burdette, Amy Hutchinson, Charles C. Chung, Xiang Deng, Zhaoming Wang, H. Barton Grossman, Giuseppe Mastrangelo, Cecilia Arici, Sofia Pavanello, Angela Carta, Stefano Porru, Eva Comperat, Morgan Roupret, Geraldine Cancel-Tassin, Olivier Cussenot, Christopher A. Haiman, Jian-Min Yuan, David Van Den Berg, Malcolm C. Pike, Mariana C. Stern, Manuela Gago-Dominguez, David V. Conti, Victoria K. Cortessis, Rebecca J. Rodabough, Chancellor Hohensee, Charles Kooperberg, Jarmo Virtamo, Stephanie J. Weinstein, Demetrius Albanes, W. Ryan Diver, Eric J. Jacobs, Susan M. Gapstur, Sara Lindstrom, Peter Kraft, David Hunter, Edward Govannucci, Immaculata De Vivo, Constance Chen, Jennifer Prescott, Elio Riboli, Jenny Chang-Claude, Paul Brennan, Anne Tjønneland, Ruth C. Travis, Miren Dorronsoro, Vittorio Krogh, Elisabete Weiderpass, Gianluca Severi, Börje Ljungberg, Dimitrios Trichopoulos, H. Bas Bueno-de-Mesquita, Afshan Siddiq, Paolo Vineis, Neil E. Caporaso, Maria T. Landi, Amanda Black, Robert L. Grubb, Gerald L. Andriole, Mark Purdue, Xifeng Wu, Josep Lloreta, Reina Garcia-Closas, Alfredo Carrato, Consol Serra, Adonina Tardon, Manolis Kogevinas, Nuria Malats, GM Monawar Hosain, Masatoshi Kida, Michael A. Jones, Liliana Guedez, Alan Schned, Adam Mumy, Alison Johnson, McAnthony Tarway, Margaret R. Karagas, Andrea B. Apolo, Molly Schwenn, Kris Ylaya, Ashley Paquin, Dalsu Baris, Brian Muchmore, Montserrat Garcia-Closas, Alexandra Scott-Johnson, Nilanjan Chatterjee, Patricia Porter-Gill, Wei Tang, Jonine D. Figueroa, Petra Lenz, Lee E. Moore, Indu Kohaar, and Yi-Ping Fu
Abstract: Supplementary Figure 1: Electrophoretic mobility shift assays (EMSA) for CCNE1 SNPs rs8102137 and rs7257330. Supplementary Figure 2: Alignment of cyclin E protein isoforms - WT1, WT2 and ES and ET. Supplementary Figure 3: Functional analysis of cyclin E isoforms.Supplementary Table 1: Description of sub-studies included in NCI-GWAS1 and GWAS2 of bladder cancer. Supplementary Table 2: Characteristics of bladder tissue samples used for mRNA expression analysis. Supplementary Table 3: PCR primers, genotyping and gene expression assays, EMSA probes and antibodies. Supplementary Table 4: Bladder cancer stage and grade information for patients in the combined GWAS1+2 set. Supplementary Table 6: Association with bladder cancer risk with mutual adjustment for CCNE1 variants. Supplementary Table 7: Association with bladder cancer risk for CCNE1 variants previously associated with other cancers and for two non-synonymous coding variants. Supplementary Table 8: Association between cyclin E protein expression (IHC scores), bladder cancer patient characteristics and CCNE1 variants.
Published: 2023
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15. Integrated Analysis of Coexpression and Exome Sequencing to Prioritize Susceptibility Genes for Familial Cutaneous Melanoma

Author: Sally Yepes, Margaret A. Tucker, Hela Koka, Yanzi Xiao, Tongwu Zhang, Kristine Jones, Aurelie Vogt, Laurie Burdette, Wen Luo, Bin Zhu, Amy Hutchinson, Meredith Yeager, Belynda Hicks, Kevin M. Brown, Neal D. Freedman, Stephen J. Chanock, Alisa M. Goldstein, and Xiaohong R. Yang
Subjects: Skin Neoplasms, Exome Sequencing, Humans, Exome, Genetic Predisposition to Disease, Cell Biology, Dermatology, Molecular Biology, Biochemistry, Melanoma
Abstract: The application of whole-exome sequencing has led to the identification of high- and moderate-risk variants that contribute to cutaneous melanoma susceptibility. However, confirming disease-causing variants remains challenging. We applied a gene coexpression network analysis to prioritize the candidate genes identified from whole-exome sequencing of 34 melanoma-prone families, with at least three affected members sequenced per family (N = 119 cases). A coexpression network was constructed from genotype-tissue expression project, skin melanoma from the cancer genome atlas, and primary melanocyte cultures. We performed module-specific enrichment and focused on modules associated with pigmentation processes because they are the best-studied and most well-known risk factors for melanoma susceptibility. We found that pigmentation-associated modules across the four expression datasets examined were enriched for well-known melanoma susceptibility genes plus genes associated with pigmentation. We also used network properties to prioritize genes within pigmentation modules as candidate susceptibility genes. Integrating information from coexpression network analysis and variant prioritization, we identified 36 genes (such as DCT, TPCN2, TRPM1, ATP10A, and EPHA5) as potential melanoma risk genes in the families. Our approach also allowed us to link families with private gene mutations on the basis of gene coexpression patterns and thereby may provide an innovative perspective in gene identification in high-risk families.
Published: 2021

16. Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia

Author: Chen Wu, Yi Song Chen, Yu-Tang Gao, Chao A. Hsiung, Qincheng He, Wu Chou Su, Tangchun Wu, Joseph F. Fraumeni, Chien Chung Lin, Yi-Long Wu, Chih-Liang Wang, Kun-Chieh Chen, Li Hsin Chien, Ying-Huang Tsai, Keitaro Matsuo, Yuh Min Chen, Gee-Chen Chang, Hongbing Shen, Peng Guan, Ming Shyan Huang, Lei Song, Sonja I. Berndt, Reury Perng Perng, Zhaoming Wang, Maria Teresa Landi, Bu Tian Ji, Batel Blechter, Jiucun Wang, Meredith Yeager, Stephen J. Chanock, Jason Y.Y. Wong, Tsung-Ying Yang, Yong-Bing Xiang, Zhihua Yin, Daru Lu, Minsun Song, Wei Wu, Ying Hsiang Chen, Xiao-Ou Shu, Fang Yu Tsai, Bryan A. Bassig, Kexin Chen, Baosen Zhou, Wei Hu, Nilanjan Chatterjee, Han Zhang, Pan-Chyr Yang, Wei Jie Seow, Jen Yu Hung, Chin-Fu Hsiao, Yao Jen Li, Li Jin, Chung Hsing Chen, I. Shou Chang, Min-Ho Shin, Qiuyin Cai, Wong Ho Chow, Laurie Burdette, Chih Yi Chen, Chong-Jen Yu, Wei Zheng, Dongxin Lin, Yun-Chul Hong, Kuan-Yu Chen, Jianxin Shi, Nathaniel Rothman, Maria Pik Wong, Qing Lan, Chien-Jen Chen, Neil E. Caporaso, Adeline Seow, and H. Dean Hosgood
Subjects: Lung adenocarcinoma, China, Asia, Lung Neoplasms, 010504 meteorology & atmospheric sciences, Taiwan, Adenocarcinoma of Lung, Genome-wide association study, 010501 environmental sciences, Logistic regression, 01 natural sciences, Article, Polygenic risk score, Risk Factors, medicine, Genetic predisposition, Humans, Household coal use, Lung cancer, Never-smoking women in Asia, lcsh:Environmental sciences, 0105 earth and related environmental sciences, General Environmental Science, lcsh:GE1-350, business.industry, Smoking, Cancer, Odds ratio, respiratory system, medicine.disease, Confidence interval, Gene-environment interaction, respiratory tract diseases, Coal, Air Pollution, Indoor, Case-Control Studies, Adenocarcinoma, Female, business, Genome-Wide Association Study, Demography
Abstract: We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10−26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10−3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.
Published: 2021

17. Using whole-exome sequencing and protein interaction networks to prioritize candidate genes for germline cutaneous melanoma susceptibility

Author: Sally Yepes, Bin Zhu, Alisa M. Goldstein, Aurelie Vogt, Yanzi Xiao, Amy Hutchinson, Wen Luo, Neal D. Freedman, Meredith Yeager, Laurie Burdette, Hela Koka, Belynda Hicks, Margaret A. Tucker, Xiaohong R. Yang, Kristine Jones, and Stephen J. Chanock
Subjects: Male, Candidate gene, Skin Neoplasms, lcsh:Medicine, Context (language use), Computational biology, Biology, Germline, Article, Genetic Heterogeneity, Exome Sequencing, Genetics, Humans, Exome, Gene Regulatory Networks, Genetic Predisposition to Disease, Protein Interaction Maps, NGLY1, lcsh:Science, Gene, Melanoma, Exome sequencing, Cancer, Multidisciplinary, Genetic heterogeneity, lcsh:R, High-Throughput Nucleotide Sequencing, Germ Cells, Cutaneous melanoma, lcsh:Q, Female, Systems biology
Abstract: Although next-generation sequencing has demonstrated great potential for novel gene discovery, confirming disease-causing genes after initial discovery remains challenging. Here, we applied a network analysis approach to prioritize candidate genes identified from whole-exome sequencing analysis of 98 cutaneous melanoma patients from 27 families. Using a network propagation method, we ranked candidate genes by their similarity to known disease genes in protein–protein interaction networks and identified gene clusters with functional connectivity. Using this approach, we identified several new candidate susceptibility genes that warrant future investigations such as NGLY1, IL1RN, FABP2, PRKDC, and PROSER2. The propagated network analysis also allowed us to link families that did not have common underlying genes but that carried variants in genes that interact on protein–protein interaction networks. In conclusion, our study provided an analysis perspective for gene prioritization in the context of genetic heterogeneity across families and prioritized top potential candidate susceptibility genes in our dataset.
Published: 2020

18. Rare Germline Copy Number Variations and Disease Susceptibility in Familial Melanoma

Author: Xijun Zhang, Margaret A. Tucker, Stephen J. Chanock, Lei Song, Laura Burke, Hunter Bennett, Laurie Burdette, Casey L. Dagnall, Daoud Meerzaman, Yanzi Xiao, Belynda Hicks, Bin Zhu, Chih Hao Hsu, Chunhua Yan, Meredith Yeager, Alisa M. Goldstein, Paula L. Hyland, Xiaohong R. Yang, Qing-Rong Chen, Neal D. Freedman, Jianxin Shi, and Weiyin Zhou
Subjects: Male, 0301 basic medicine, congenital, hereditary, and neonatal diseases and abnormalities, Skin Neoplasms, DNA Copy Number Variations, endocrine system diseases, Single-nucleotide polymorphism, Genome-wide association study, Dermatology, Biology, Real-Time Polymerase Chain Reaction, Risk Assessment, Biochemistry, Article, Germline, 03 medical and health sciences, Germline mutation, CDKN2A, mental disorders, Gene duplication, Humans, Genetic Predisposition to Disease, Copy-number variation, Melanoma, neoplasms, Molecular Biology, Germ-Line Mutation, Genetics, Sequence Analysis, RNA, Incidence, Cell Biology, Pedigree, 030104 developmental biology, Female, Genome-Wide Association Study, Comparative genomic hybridization
Abstract: Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and single nucleotide polymorphism arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g., PARP1, CDKN2A) or cosegregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.
Published: 2016
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19. Deep sequencing of HPV16 genomes: A new high-throughput tool for exploring the carcinogenicity and natural history of HPV16 infection

Author: Xijun Zhang, Robert D. Burk, Sholom Wacholder, Jason Mitchell, Lisa Mirabello, Mark Schiffman, Michael Cullen, Thomas Lorey, Matt Osentoski, Joseph Boland, Mark Andersen, Mitchell J. Machiela, Ashlie Feldman, Michael Laptewicz, Qi Yang, Nicolas Wentzensen, Sarangan Ravichandran, Sara Bass, Brian T. Luke, Meredith Yeager, Moara Machado, Philip E. Castle, Laurie Burdette, Zigui Chen, Tina Raine-Bennett, Kai Yu, and David Roberson
Subjects: HPV16, Cervical cancer, Genetics, Lineage (genetic), virus diseases, Single-nucleotide polymorphism, Ion semiconductor sequencing, HPV genomics, Amplicon, Biology, medicine.disease, HPV epidemiology, Genome, Article, female genital diseases and pregnancy complications, Deep sequencing, lcsh:Infectious and parasitic diseases, Infectious Diseases, Virology, Genetic variation, medicine, lcsh:RC109-216
Abstract: For unknown reasons, there is huge variability in risk conferred by different HPV types and, remarkably, strong differences even between closely related variant lineages within each type. HPV16 is a uniquely powerful carcinogenic type, causing approximately half of cervical cancer and most other HPV-related cancers. To permit the large-scale study of HPV genome variability and precancer/cancer, starting with HPV16 and cervical cancer, we developed a high-throughput next-generation sequencing (NGS) whole-genome method. We designed a custom HPV16 AmpliSeq™ panel that generated 47 overlapping amplicons covering 99% of the genome sequenced on the Ion Torrent Proton platform. After validating with Sanger, the current “gold standard” of sequencing, in 89 specimens with concordance of 99.9%, we used our NGS method and custom annotation pipeline to sequence 796 HPV16-positive exfoliated cervical cell specimens. The median completion rate per sample was 98.0%.Our method enabled us to discover novel SNPs, large contiguous deletions suggestive of viral integration (OR of 27.3, 95% CI 3.3–222, P=0.002), and the sensitive detection of variant lineage coinfections. This method represents an innovative high-throughput, ultra-deep coverage technique for HPV genomic sequencing, which, in turn, enables the investigation of the role of genetic variation in HPV epidemiology and carcinogenesis. Keywords: HPV16, HPV epidemiology, HPV genomics
Published: 2015
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20. Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

Author: Kathryn M. Wilson, Sharon A. Savage, I-Min Lee, Stella Koutros, Gabriella Andreotti, Rosamonde E. Banks, Simone Benhamou, David Petillo, Laurie Burdette, Douglas F. Easton, Susanna C. Larsson, Peter Kraft, Marc Henrion, Lenka Foretova, Peng Li, H. Bas Bueno-de-Mesquita, Amanda Black, Konstantin G. Skryabin, Börje Ljungberg, Toni K. Choueiri, Loren Lipworth, Stephen J. Chanock, Robert Carreras-Torres, Sabrina L. Noyes, Olivier Cussenot, Marie Navratilova, Matthew L. Freedman, Mark Pomerantz, Wong-Ho Chow, David Zaridze, Eunyoung Cho, Lee E. Moore, James McKay, Lars J. Vatten, Ghislaine Scelo, Christopher G. Wood, Anush Mukeriya, Mirjana Mijuskovic, Jonathan N. Hofmann, Kevin M. Brown, Ulrike Peters, Valerie Gaborieau, Mark P. Purdue, Fiona Bruinsma, Richard J. Kahnoski, Paul Brennan, Susan J. Jordan, V. Janout, Cezary Cybulski, Timothy Eisen, Paul D.P. Pharoah, Howard S. Sesso, Hallie Carol, Neonila Szeszenia-Dabrowska, Garnet L. Anderson, Gianluca Severi, Céline Besse, Egor Prokhortchouk, Eric J. Duell, Satu Männistö, Geraldine Cancel-Tassin, Mitchell J. Machiela, Meredith Yeager, Eleonora Fabianova, Laura E. Beane Freeman, Mark A. Preston, Kvetoslava Koppova, John Anema, Jean-François Deleuze, G. Mark Lathrop, Victoria L. Stevens, Emily White, Zhaoming Wang, Stephanie J. Weinstein, Juhua Luo, Julie E. Buring, Viorel Jinga, Joshua N. Sampson, Peter Rudnai, Raviprakash T. Sitaram, Brian R. Lane, Stefan Rascu, Lisa Johnson, Jan Lubinski, Demetrius Albanes, Kristian Hveem, Leandro M. Colli, Dana Mates, Peter Selby, Miodrag Ognjanovic, Todd E. Edwards, Nathaniel Rothman, Richard S. Houlston, Matthieu Foll, Xifeng Wu, Peter E. Clark, Jolanta Lissowska, Vladimir Bencko, Ivana Holcatova, Anne Boland, James Larkin, Bin Tean Teh, J. Michael Gaziano, Hélène Blanché, Alicja Wolk, Neal D. Freedman, Federico Canzian, Mattias Johansson, Susan M. Gapstur, Yuanqing Ye, Tony Fletcher, Wen-Yi Huang, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Eisen, Tim [0000-0001-9663-4873], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Risk, Genetic variants, Urology, Genome-wide association study, macromolecular substances, urologic and male genital diseases, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, 0302 clinical medicine, Telomere Homeostasis, Renal cell carcinoma, Risk Factors, Mendelian randomization, Carcinoma, Leukocytes, Odds Ratio, Medicine, Humans, Genetic Predisposition to Disease, Carcinoma, Renal Cell, Genetics, Telomere length, business.industry, Case-control study, Odds ratio, Mendelian Randomization Analysis, Telomere, medicine.disease, female genital diseases and pregnancy complications, Kidney Neoplasms, 030104 developmental biology, Phenotype, 030220 oncology & carcinogenesis, Case-Control Studies, Cancer research, business, Genome-Wide Association Study
Abstract: BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p
Published: 2018
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21. Corrigendum re 'Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma' [Eur Urol 2017;72:747-54]

Author: Jolanta Lissowska, Douglas F. Easton, Ivana Holcatova, Matthieu Foll, Mark Pomerantz, Susan M. Gapstur, Peter E. Clark, Mitchell J. Machiela, Amanda Black, G. Mark Lathrop, Miodrag Ognjanovic, Marie Navratilova, Bin Tean Teh, Yuanqing Ye, Tony Fletcher, Matthew L. Freedman, Zhaoming Wang, Alicja Wolk, Wen-Yi Huang, Timothy Eisen, Dana Mates, Mark A. Preston, Eric J. Duell, I-Min Lee, Anush Mukeriya, Fiona Bruinsma, James McKay, Jan Lubinski, Kathryn M. Wilson, Sharon A. Savage, Neal D. Freedman, Julie E. Buring, Raviprakash T. Sitaram, Hallie Carol, Rosamonde E. Banks, Victoria L. Stevens, Garnet L. Anderson, Joshua N. Sampson, Simone Benhamou, Céline Besse, Stefan Rascu, Mark P. Purdue, Konstantin G. Skryabin, Börje Ljungberg, Kristian Hveem, Federico Canzian, Marc Henrion, Richard S. Houlston, Xifeng Wu, Wong-Ho Chow, Neonila Szeszenia-Dabrowska, Jonathan N. Hofmann, Anne Boland, Peter Rudnai, Eunyoung Cho, Egor Prokhortchouk, Stella Koutros, Lee E. Moore, Cezary Cybulski, Mirjana Mijuskovic, Valerie Gaborieau, Paul D.P. Pharoah, Susan J. Jordan, Vladimir Janout, Susanna C. Larsson, Viorel Jinga, Stephen J. Chanock, Loren Lipworth, Kevin M. Brown, Olivier Cussenot, Sabrina L. Noyes, Brian R. Lane, Laurie Burdette, Ulrike Peters, Satu Männistö, Meredith Yeager, Mattias Johansson, James Larkin, Stephanie J. Weinstein, Juhua Luo, Demetrius Albanes, Robert Carreras-Torres, J. Michael Gaziano, H. B. Bueno-De-Mesquita, Christopher G. Wood, Lisa Johnson, David Petillo, Howard S. Sesso, Hélène Blanché, Vladimir Bencko, Peng Li, Ghislaine Scelo, Geraldine Cancel-Tassin, Lars J. Vatten, Jean-François Deleuze, Peter Selby, John Anema, Emily White, Lenka Foretova, Kvetoslava Koppova, David Zaridze, Gianluca Severi, Gabriella Andreotti, Paul Brennan, Leandro M. Colli, Todd E. Edwards, Eleonora Fabianova, Laura E. Beane Freeman, Richard J. Kahnoski, Nathaniel Rothman, Peter Kraft, and Toni K. Choueiri
Subjects: Oncology, medicine.medical_specialty, business.industry, Urology, Genetic variants, MEDLINE, medicine.disease, Article, Telomere, 03 medical and health sciences, 0302 clinical medicine, Increased risk, Renal cell carcinoma, 030220 oncology & carcinogenesis, Internal medicine, medicine, 030212 general & internal medicine, business
Abstract: It has come to our attention that authors Lenka Foretova, Ivana Holcatova, Vladimir Janout, Dana Mates, Anush Mukeriya, Stefan Rascu, David Zaridze, Vladimir Bencko, and Cezary Cybulski were not assigned to the correct affiliations. Their correct affiliations are as in the list above. Conflicts of interest: The authors have nothing to disclose.
Published: 2018

22. 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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23. Interactions between household air pollution and GWAS-identified lung cancer susceptibility markers in the Female Lung Cancer Consortium in Asia (FLCCA)

Author: Jen Yu Hung, Laurie Burdette, Chih Yi Chen, Jiucun Wang, Yu-Tang Gao, Keitaro Matsuo, Pan-Chyr Yang, Yi-Long Wu, Yuh Min Chen, Chao A. Hsiung, Chong-Jen Yu, Sonja I. Berndt, Reury Perng Perng, Kuan-Yu Chen, Maria Pik Wong, Baosen Zhou, Chien-Jen Chen, Tangchun Wu, Dara Lu, Stephen J. Chanock, Wei Jie Seow, Joseph F. Fraumeni, Zhaoming Wang, Wei Wu, Ying Hsiang Chen, Neil E. Caporaso, Maria Teresa Landi, Chien Chung Lin, Zhihua Yin, Minsun Song, Nathaniel Rothman, Xiao-Ou Shu, Nilanjan Chatterjee, Fang Yu Tsai, Yao Jen Li, Qing Lan, Li Jin, Chung Hsing Chen, I. Shou Chang, Dongxin Lin, Yun-Chul Hong, Hongbing Shen, Ming Shyan Huang, H. Dean Hosgood, Kexin Chen, Adeline Seow, Tsung-Ying Yang, Christopher Kim, Qincheng He, Qiuyin Cai, Chen Wu, Yi Song Chen, Gee-Chen Chang, Yong-Bing Xiang, Wei Zheng, Peng Guan, Chih-Liang Wang, Ying-Huang Tsai, Meredith Yeager, Li Hsin Chien, Min-Ho Shin, Wu Chou Su, Kun-Chieh Chen, Wong Ho Chow, Bryan A. Bassig, and Chin-Fu Hsiao
Subjects: Adult, Genetic Markers, Risk, Oncology, medicine.medical_specialty, Lung Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Adenocarcinoma, Biology, Polymorphism, Single Nucleotide, Article, Internal medicine, Genetic variation, TP63, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Lung cancer, Genetics (clinical), Carcinogen, Aged, Air Pollutants, Middle Aged, medicine.disease, Lung cancer susceptibility, Air Pollution, Indoor, Case-Control Studies, Female, Gene-Environment Interaction, Genome-Wide Association Study
Abstract: We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene–HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30 % increased risk of lung cancer (OR 1.3, 95 % CI 1.0–1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.
Published: 2015
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24. Rare germline variants in known melanoma susceptibility genes in familial melanoma

Author: Jiali Han, Bin Zhu, Yixuan Wen, Margaret A. Tucker, Yanzi Xiao, Stephen J. Chanock, Laurie Burdette, Stella Koutros, Immaculata De Vivo, Laura Beane-Freeman, Hunter Bennett, Melissa Rotunno, Wen Luo, Belynda Hicks, Meredith Yeager, Gabriella Andreotti, Kristine Jones, Xiaohong R. Yang, Mark P. Purdue, Aurelie Vogt, Alisa M. Goldstein, Neal D. Freedman, and Joshua N. Sampson
Subjects: 0301 basic medicine, Nonsynonymous substitution, Adult, Male, Risk, Skin Neoplasms, Genotype, Population, Biology, medicine.disease_cause, Germline, Group VI Phospholipases A2, 03 medical and health sciences, Germline mutation, Exome Sequencing, Genetics, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, TYRP1, education, Molecular Biology, Melanoma, Genetics (clinical), Germ-Line Mutation, OCA2, Mutation, education.field_of_study, General Medicine, Articles, Middle Aged, Pedigree, 030104 developmental biology, Female
Abstract: Known high-risk cutaneous malignant melanoma (CMM) genes account for melanoma risk in
Published: 2017

25. The 19q12 Bladder Cancer GWAS Signal: Association with Cyclin E Function and Aggressive Disease

Author: Kris Ylaya, Michael A. Jones, Andrea B. Apolo, Masatoshi Kida, Paul Brennan, Paolo Vineis, Sara Lindström, Edward Govannucci, Dimitrios Trichopoulos, Afshan Siddiq, Brian Muchmore, Stephen M. Hewitt, Reina Garcia-Closas, Alfredo Carrato, Robert L. Grubb, H. Barton Grossman, Petra Lenz, Alexandra Scott-Johnson, Molly Schwenn, Rebecca J. Rodabough, Montserrat Garcia-Closas, Consol Serra, Anne Tjønneland, Chancellor Hohensee, Miren Dorronsoro, Mark P. Purdue, Alison Johnson, Cecilia Arici, Constance Chen, Christopher A. Haiman, Zhaoming Wang, Jennifer Prescott, Lee E. Moore, Joseph F. Fraumeni, David Van Den Berg, G. M. Monawar Hosain, Elisabete Weiderpass, Dalsu Baris, Margaret R. Karagas, Gerald L. Andriole, Ruth C. Travis, Xiang Deng, Jian-Min Yuan, Vittorio Krogh, Geraldine Cancel-Tassin, Eric J. Jacobs, Adam Mumy, Börje Ljungberg, Josep Lloreta, Debra T. Silverman, Indu Kohaar, Demetrius Albanes, Stephanie J. Weinstein, Charles Kooperberg, W. Ryan Diver, Malcolm C. Pike, Alan R. Schned, Patricia Porter-Gill, Peter Kraft, Angela Carta, Elio Riboli, Amy Hutchinson, Olivier Cussenot, Victoria K. Cortessis, Maria Teresa Landi, Susan M. Gapstur, Laurie Burdette, Sofia Pavanello, Jenny Chang-Claude, McAnthony Tarway, Xifeng Wu, Yi-Ping Fu, Gianluca Severi, Ashley Paquin, Ludmila Prokunina-Olsson, Amanda Black, Manuela Gago-Dominguez, Eva Comperat, Adonina Tardón, Giuseppe Mastrangelo, Manolis Kogevinas, Mariana C. Stern, Neil E. Caporaso, Nilanjan Chatterjee, William Wheeler, David J. Hunter, Liliana Guedez, Wei Tang, David V. Conti, Nathaniel Rothman, Immaculata De Vivo, Jonine D. Figueroa, Morgan Rouprêt, H. Bas Bueno-de-Mesquita, Stephen J. Chanock, Stefano Porru, Núria Malats, Jarmo Virtamo, and Charles C. Chung
Subjects: EXPRESSION, Cancer Research, Cyclin E, VARIANT, Urinary Bladder, Gene Expression, Case-Control Studies, Chromosomes, Human, Pair 19, Gene Frequency, Genome-Wide Association Study, Haplotypes, HeLa Cells, Humans, Oncogene Proteins, Polymorphism, Single Nucleotide, Urinary Bladder Neoplasms, Oncology, Single-nucleotide polymorphism, Genome-wide association study, Biology, Bioinformatics, OVARIAN-CANCER, Article, Chromosomes, medicine, GENOME-WIDE ASSOCIATION, Polymorphism, CONFERS SUSCEPTIBILITY, RISK, Bladder cancer, Urinary bladder, Pair 19, MUTATIONS, GENETIC-VARIATION, AMPLIFICATION, Single Nucleotide, Cell cycle, medicine.disease, CCNE1 Gene, medicine.anatomical_structure, Cancer research, COMPLEXES, Ovarian cancer, Human
Abstract: A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2 ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09–1.27, P = 4.67 × 10−5] versus OR = 1.01 (95% CI, 0.93–1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808–18. ©2014 AACR.
Published: 2014
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26. Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations

Author: Laurie Burdette, Xiao-Hang Zhao, Guo-Lan Xing, Yin Li, Chaoyu Wang, Yu-Tang Gao, Jin Wang, William Wheeler, Ying Huang, Shengli Zhou, Haijun Yang, Teng Ma, Peter Kraft, She-Gan Gao, Chang-Wei Feng, Xiaoping Miao, Li-Sha Chen, Shu-Wei Ren, Hongbing Shen, Dongxin Lin, Zhaoming Wang, Yifeng Zhou, Woon-Puay Koh, Ilyar Sheyhidin, Zhao Xueke, Yi-Min Mao, Wei Hua Jia, Li Bei, Ji-Lin Li, Wen-Bin Yue, Wancai Yang, Xiu-Qing Peng, Maxwell P. Lee, Ya-Li Liu, Xiao Liu, Yang Ke, Liangdan Sun, Ying-Fa Zhou, Charles C. Chung, Nan Hu, Bin Liu, Xiao-Shan Feng, Margaret A. Tucker, Ti Ding, Yu Liu, Amy Hutchinson, Alisa M. Goldstein, Xiu-Min Li, En-Min Li, Kan Zhai, Yan Li, Zhi-Qing Yuan, Jing Liu, Jian-Wei Ku, Yuan Yuan, Yan-Rui Zhang, Zhihua Liu, Guang-Yan Lei, Qi-De Bao, Qimin Zhan, Wei Zheng, Wu Wei, Sa Tang, Er-Tao Guo, Qirenwang Qige, Linda M. Liao, Yu-Hua Yang, Jin-Hu Fan, Shuqing Chen, Wen-Jun Yang, Neal D. Freedman, Xi Chen, Kevin B. Jacobs, Jianhua Fu, Philip R. Taylor, Ze-Zhong Tang, Stephen J. Chanock, Kai Yu, Meredith Yeager, Zhou Fuyou, Ran Wang, Yan-Long Hu, Xiao-Ou Shu, Jeff Yuenger, Wen Tan, Feng Li, Ling Yuan, Guangfu Jin, Zhi-Chao Hou, Ji-Li Cui, Jie He, Changdong Lu, Jing-Jing Han, Zhibin Hu, Xuejun Zhang, Chunling Liu, Min Han, Yi Xin Zeng, Hong-Zhang Hao, Chen Wu, Jian-Min Yuan, Chuanhai Guo, Bao-Chi Liu, Li Sun, Xin-Min Li, Christian C. Abnet, Long-Qi Chen, Liu Qin Yang, Yan Qiao, Wei Zhang, Peng Zhang, Mitchell H. Gail, Hong-Li Lin, Lixuan Wei, Zhou Wang, Tangchun Wu, Hui Meng, Joseph F. Fraumeni, Dongyun Zhang, Guo Yuan, Carol Giffen, Zong-Min Fan, Lu-Wen Wang, Dianke Yu, Sanford M. Dawsey, Bao-Gen Ma, Xue-Min Li, Jun-Yan Hong, Jiang Chang, Xue-Ping Fan, Ai-Li Li, Yong-Bing Xiang, Mei Zhang, Fang-Heng Zhu, Qing-Peng Kong, Li-Dong Wang, Li Wang, Dong Xie, Xianbo Zuo, Xin Song, Jing-Li Ren, You-Lin Qiao, Liang Wang, Weixing Zhao, Zhonghu He, Han Xuena, and Ai-Qun Wu
Subjects: Oncology, Male, Risk, medicine.medical_specialty, Esophageal Neoplasms, Genotype, Locus (genetics), Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Asian People, Internal medicine, Genetics, medicine, SNP, Humans, Genetic Predisposition to Disease, Alleles, 030304 developmental biology, Genetic association, 0303 health sciences, Case-control study, Odds ratio, Middle Aged, 3. Good health, Genetic Loci, 030220 oncology & carcinogenesis, Case-Control Studies, Carcinoma, Squamous Cell, Female, Esophageal Squamous Cell Carcinoma, Genome-Wide Association Study
Abstract: We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 × 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 × 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 × 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.
Published: 2014

27. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33

Author: Hidemi Ito, Stephen K. Van Den Eeden, Abdisamad M. Ibrahim, Ching C. Lau, Preetha Rajaraman, Gloria M. Petersen, Judith Hoffman-Bolton, Colin P.N. Dinney, Chang Hyun Kang, Melinda C. Aldrich, Mark P. Purdue, Xiao-Ou Shu, William J. Blot, Sanjay Shete, Alpa V. Patel, Charles Kooperberg, Paolo Vineis, David Van Den Berg, Chao A. Hsiung, Anthony J. Swerdlow, Qing Lan, Wu Chou Su, Afshan Siddiq, Ulrike Peters, Katia Scotlandi, Sara H. Olson, Kendra Schwartz, Kelly L. Bolton, Chancellor Hohensee, Josep Lloreta, Kevin B. Jacobs, Debra T. Silverman, Rudolf Kaaks, Wei Zheng, Steven Gallinger, Junwen Wang, Angela Carta, Massimo Serra, Petra H.M. Peeters, Victoria L. Stevens, Yasushi Yatabe, Geraldine Cancel-Tassin, Joshua N. Sampson, Young Tae Kim, Graham A. Colditz, Pan-Chyr Yang, Baosen Zhou, Fredrick R. Schumacher, Nicolas Wentzensen, Evelyn Tay, Claudia Maria Hattinger, Chen Wu, Pilar Amiano, Mattias Johansson, Maxwell P. Lee, Christian P. Kratz, Michael B. Cook, Mingfeng Zhang, Kay-Tee Khaw, Jian-Min Yuan, Anne Zeleniuch-Jacquotte, Jinping Jia, Roberto Tirabosco, Jing Ma, Neil E. Caporaso, Christopher A. Haiman, Bu Tian Ji, Adrienne M. Flanagan, Neyssa Marina, Eric J. Jacobs, Sophia S. Wang, Chong-Jen Yu, Edward Giovannucci, Margaret Wrensch, Robert L. Grubb, Bin Zhu, Daniel O. Stram, Manolis Kogevinas, Margaret R. Karagas, Mazda Jenab, Alison M. Mondul, Jun Xu, Preethi S. Raj, Anders Ahlbom, Christine D. Berg, Shelley Niwa, Kala Visvanathan, Loic Le Marchand, Jorge R. Toro, Robert N. Hoover, Heather Spencer Feigelson, Michelle Brotzman, Laurence N. Kolonel, Krista A. Zanetti, Chengfeng Wang, Mary Ann Butler, Ann Truelove, Irene L. Andrulis, Hongbing Shen, H. Dean Hosgood, Ming Shyan Huang, Gee-Chen Chang, Jianjun Liu, John K. Wiencke, Stephanie J. Weinstein, Beatrice Melin, Kouya Shiraishi, Zhihua Yin, Lee E. Moore, Börje Ljungberg, Jolanta Lissowska, Elizabeth M. Gillanders, M. T. Landi, Cari M. Kitahara, Maria Feychting, Kuan-Yu Chen, Matthias Simon, Brian M. Wolpin, Hemang Parikh, Hannah P. Yang, Graham G. Giles, Alison Johnson, Demetrius Albanes, Carlos González, Brian E. Henderson, Xifeng Wu, Harvey A. Risch, Amy Hutchinson, Christopher Hautman, Constance Chen, Zhibin Hu, Donghui Li, Elio Riboli, Julie E. Buring, Curtis C. Harris, Xu Che, Núria Malats, Roger Henriksson, Rosario Tumino, Joanne S. Colt, Alfredo Carrato, Paolo Boffetta, Maria Pik Wong, Hideo Tanaka, Federico Canzian, Alan D. L. Sihoe, Chien-Jen Chen, Kenneth Muir, Chen Ying, Qincheng He, Melissa C. Southey, Marc Sanson, Victoria K. Cortessis, Sharon A. Savage, Wei Hu, Yao Tettey, Daniela S. Gerhard, Sofia Pavanello, Guangwen Cao, H. Barton Grossman, Michael Goggins, Hideo Kunitoh, Peter D. Inskip, Seth P. Lerner, Peter Kraft, David Thomas, Peng Guan, Chung Hsing Chen, I. Shou Chang, Christoffer Johansen, Roberta McKean-Cowdin, Lee J. Helman, Yuh Min Chen, Ana Patiño-García, Pär Stattin, Xiaoping Miao, Tangchun Wu, Jay S. Wunder, Ann W. Hsing, Yu-Tang Gao, Brooke L. Fridley, Tania Carreón, Charles C. Chung, Nan Hu, Yoo Jin Jung, Richard B. Biritwum, Eric J. Duell, Philip R. Taylor, Satu Männistö, Kai Yu, Meredith Yeager, Xia Pu, Vittorio Krogh, Anand P. Chokkalingam, Susan M. Gapstur, W. Ryan Diver, Yuanqing Ye, Keitaro Matsuo, Cecilia Arici, You-Lin Qiao, Alan R. Schned, Dominique S. Michaud, Joanne W. Elena, Christopher Kim, Dongxin Lin, Yun-Chul Hong, Daru Lu, Reina García-Closas, Jonine D. Figueroa, Linda M. Liao, Yi-Long Wu, Heiner Boeing, Mark Lathrop, Göran Hallmans, Elizabeth A. Holly, Carol Giffen, Andrew A. Adjei, Consol Serra, Anne Tjønneland, Joseph F. Fraumeni, Alisa M. Goldstein, Ruth C. Travis, Rebecca Troisi, Dalsu Baris, Nalan Gokgoz, Olivier Cussenot, Xiang Deng, Yeul Hong Kim, Malin Sund, Sonja I. Berndt, E. David Crawford, Edward D. Yeboah, Sook Whan Sung, Françoise Clavel-Chapelon, Woon-Puay Koh, Nilgun Kurucu, Richard B. Hayes, Ashish M. Kamat, Beata Peplonska, Laurie Burdette, Ze Zhang Tang, Alan A. Arslan, Malcolm C. Pike, Sabina Sierri, J. Michael Gaziano, Lorna H. McNeil, Katherine A. McGlynn, Ulla Vogel, Logan G. Spector, H. Bas Bueno-de-Mesquita, Stephen J. Chanock, Jae Yong Park, Jennifer Prescott, Fernando Lecanda, Margaret A. Tucker, Ti Ding, Christian C. Abnet, Jenny Chang-Claude, Dimitrios Trichopoulos, Wei-Yen Lim, Wen Tan, Nick Orr, Jin Hee Kim, Stefano Porru, Chand Khanna, Robert R. McWilliams, Zhaoming Wang, Jeong Seon Ryu, David V. Conti, Alison P. Klein, Adonina Tardón, Robert J. Klein, Rebecca J. Rodabough, Mark H. Greene, Aruna Kamineni, Jie Lin, Rachael Z. Stolzenberg-Solomon, Patricia Hartge, Susan E. Hankinson, Young-Chul Kim, In Sam Kim, Luis Sierrasesúmaga, Roel Vermeulen, Paige M. Bracci, Mariana C. Stern, Louise A. Brinton, Myron D. Gross, Yong-Bing Xiang, Chih Yi Chen, G. A. Gerald Andriole, Paul S. Meltzer, Ying-Huang Tsai, Faith G. Davis, Ulrika Andersson, Paul Brennan, Sara Lindström, Chaoyu Wang, Giuseppe Mastrangelo, Laufey T. Amundadottir, Immaculata De Vivo, Bryan A. Bassig, Elisabete Weiderpass, Takashi Kohno, Nilanjan Chatterjee, Margaret R. Spitz, Pier Alberto Bertazzi, William Wheeler, David J. Hunter, Wei Tang, Qiuyin Cai, Naomi E. Allen, Molly Schwenn, Emily White, Min Shen, Adeline Seow, Laura E. Beane Freeman, James E. Mensah, Howard D. Sesso, Anna Luisa Di Stefano, Amanda Black, Manuela Gago-Dominguez, Christine B. Ambrosone, Avima M. Ruder, Martha S. Linet, Meir J. Stampfer, Robert C. Kurtz, Donald A. Barkauskas, Lisa W. Chu, Montserrat Garcia-Closas, Jason W. Hoskins, Melissa A. Austin, Kyoung Mu Lee, Jianxin Shi, Charles S. Fuchs, Nathaniel Rothman, Richard Gorlick, Piero Picci, Gianluca Severi, Ann G. Schwartz, Jian Gu, Christopher I. Amos, Marie-Christine Boutron-Ruault, Salvatore Panico, Alicja Wolk, Sara S. Strom, Lisa Mirabello, Jin-Hu Fan, Chin-Fu Hsiao, Neal D. Freedman, Geoffrey S. Tobias, Julie M. 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Kang, Ch, Jung, Yj, Kitahara, Cm, Klein, Ap, Klein, R, Kogevinas, M, Koh, Wp, Kohno, T, Kolonel, Ln, Kooperberg, C, Kratz, Cp, Krogh, V, Kunitoh, H, Kurtz, Rc, Kurucu, N, Lan, Q, Lathrop, M, Lau, Cc, Lecanda, F, Lee, Km, Lee, Mp, Le Marchand, L, Lerner, Sp, Li, D, Liao, Lm, Lim, Wy, Lin, D, Lin, J, Lindstrom, S, Linet, M, Lissowska, J, Liu, J, Ljungberg, B, Lloreta, J, Lu, D, Ma, J, Malats, N, Mannisto, S, Marina, N, Mastrangelo, G, Matsuo, K, Mcglynn, Ka, McKean Cowdin, R, Mcneill, Lh, Mcwilliams, Rr, Melin, B, Meltzer, P, Mensah, Je, Miao, X, Michaud, D, Mondul, Am, Moore, Le, Muir, K, Niwa, S, Olson, Sh, Orr, N, Panico, Salvatore, Park, Jy, Patel, Av, Patino Garcia, A, Pavanello, S, Peeters, Ph, Peplonska, B, Peters, U, Petersen, Gm, Picci, P, Pike, Mc, Porru, S, Prescott, J, Pu, X, Purdue, Mp, Qiao, Yl, Rajaraman, P, Riboli, E, Risch, Ha, Rodabough, Rj, Rothman, N, Ruder, Am, Ryu, J, Sanson, M, Schned, A, Schumacher, Fr, Schwartz, Ag, Schwartz, Kl, Schwenn, M, Scotlandi, K, Seow, A, Serra, C, Serra, M, Sesso, Hd, Severi, G, Shen, H, Shen, M, Shete, S, Shiraishi, K, Shu, Xo, Siddiq, A, Sierrasesumaga, L, Sierri, S, Loon Sihoe, Ad, Silverman, Dt, Simon, M, Southey, Mc, Spector, L, Spitz, M, Stampfer, M, Stattin, P, Stern, Mc, Stevens, Vl, Stolzenberg Solomon, Rz, Stram, Do, Strom, S, Su, Wc, Sund, M, Sung, Sw, Swerdlow, A, Tan, W, Tanaka, H, Tang, W, Tang, Zz, Tardon, A, Tay, E, Taylor, Pr, Tettey, Y, Thomas, Dm, Tirabosco, R, Tjonneland, A, Tobias, G, Toro, Jr, Travis, Rc, Trichopoulos, D, Troisi, R, Truelove, A, Tsai, Yh, Tucker, Ma, Tumino, R, Van Den Berg, D, Van Den Eeden, Sk, Vermeulen, R, Vineis, P, Visvanathan, K, Vogel, U, Wang, C, Wang, J, Wang, S, Weiderpass, E, Weinstein, Sj, Wentzensen, N, Wheeler, W, White, E, Wiencke, Jk, Wolk, A, Wolpin, Bm, Wong, Mp, Wrensch, M, Wu, C, Wu, T, Wu, X, Wu, Yl, Wunder, J, Xiang, Yb, Xu, J, Yang, Hp, Yang, Pc, Yatabe, Y, Ye, Y, Yeboah, Ed, Yin, Z, Ying, C, Yu, Cj, Yu, K, Yuan, Jm, Zanetti, Ka, Zeleniuch Jacquotte, A, Zheng, W, Zhou, B, Mirabello, L, Savage, Sa, Kraft, P, Chanock, Sj, Yeager, M, Landi, Mt, Shi, J, Chatterjee, N, Amundadottir, Lt, Wang, Z., Zhu, B., Zhang, M., Parikh, H., Jia, J., Chung, C.C., Sampson, J.N., Hoskins, J.W., Hutchinson, A., Burdette, L., Ibrahim, A., Hautman, C., Raj, P.S., Abnet, C.C., Adjei, A.A., Ahlbom, A., Albanes, D., Allen, N.E., Ambrosone, C.B., Aldrich, M., Amiano, P., Amos, C., Andersson, U., Gerald Andriole, G.A., Jr., Andrulis, I.L., Arici, C., Arslan, A.A., Austin, M.A., Baris, D., Barkauskas, D.A., Bassig, B.A., Freeman, L.E.B., Berg, C.D., Berndt, S.I., Bertazzi, P.A., Biritwum, R.B., Black, A., Blot, W., Boeing, H., Boffetta, P., Bolton, K., Boutron-Ruault, M.-C., Bracci, P.M., Brennan, P., Brinton, L.A., Brotzman, M., Bueno-de-Mesquita, H.B., Buring, J.E., Butler, M.A., Cai, Q., Cancel-Tassin, G., Canzian, F., Cao, G., Caporaso, N.E., Carrato, A., Carreon, T., Carta, A., Chang, G.-C., Chang, I.-S., Chang-Claude, J., Che, X., Chen, C.-J., Chen, C.-Y., 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Subjects: Male, SINGLE-NUCLEOTIDE POLYMORPHISM, Genome-wide association study, Epigenesis, Genetic, Gene Frequency, Molecular Biology, Genetics, Genetics (clinical), Neoplasms, Odds Ratio, Genome-wide association studies (GWAS), Telomerase, DNA METHYLATION Author Information, Association Studies Articles, General Medicine, PANCREATIC-CANCER, PROSTATE-CANCER, Neoplasm Proteins, POSTMENOPAUSAL BREAST-CANCER, TERT PROMOTER MUTATIONS, Gene Expression Regulation, Neoplastic, 2 SUSCEPTIBILITY LOCI, DNA methylation, Chromosomes, Human, Pair 5, Female, Risk, Locus (genetics), Single-nucleotide polymorphism, TERT and CLPTM1L gene, Biology, Polymorphism, Single Nucleotide, LUNG-CANCER, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Allele, Gene, Allele frequency, Alleles, Genetic association, chromosome 5p15.33, Computational Biology, Membrane Proteins, DNA Methylation, Genetic Loci, TELOMERE LENGTH, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
Published: 2014
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28. Association of Genetic Variants in CDK6 and XRCC1 with the Risk of Dysplastic Nevi in Melanoma-Prone Families

Author: Maria Teresa Landi, Laura S. Burke, Xueying Liang, Laurie Burdette, William Wheeler, Diana Zelenika, Meredith Yeager, Alisa M. Goldstein, Myriam Brossard, Giovanna Bianchi-Scarrà, Donato Calista, Wen-Qing Li, Ketty Peris, Valérie Chaudru, Stephen J. Chanock, Margaret A. Tucker, Xiaohong R. Yang, Florence Demenais, Maria Concetta Fargnoli, Ruth M. Pfeiffer, Dennis Maeder, and Paola Ghiorzo
Subjects: Adult, Male, Candidate gene, Skin Neoplasms, Single-nucleotide polymorphism, Dermatology, Biology, Biochemistry, Article, Dysplastic nevus syndrome, CDKN2A, Risk Factors, Genetic variation, medicine, SNP, Humans, Genetic Predisposition to Disease, Melanoma, Molecular Biology, Genetics, Family Health, Genetic Variation, Cyclin-Dependent Kinase 6, Cell Biology, Middle Aged, medicine.disease, DNA-Binding Proteins, X-ray Repair Cross Complementing Protein 1, Female, Settore MED/35 - MALATTIE CUTANEE E VENEREE, Melanocyte proliferation, Dysplastic Nevus Syndrome
Abstract: Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each single-nucleotide polymorphism (SNP) separately, adjusted for age, sex, CMM, and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific P-values. Two genes, CDK6 (cyclin-dependent kinase 6) and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation–positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and -negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent data sets (random-effect meta-analysis: P
Published: 2014
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29. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer

Author: Laurie Burdette, Rick A. Kittles, Hidewaki Nakagawa, Janet L. Stanford, Wojciech Kluźniak, Karen Park, Sofia Maia, Lisa A. Cannon-Albright, Douglas F. Easton, Dennis J. Hazelett, Hermann Brenner, Paula Paulo, Peter Klarskov, Zhaoming Wang, Koveela Govindasami, Loic Le Marchand, David V. Conti, Phyllis J. Goodman, Chavdar Slavov, Manuel R. Teixeira, Sara Lindström, Maren Weischer, Suzanne Kolb, Lisa B. Signorello, Jianfeng Xu, W. Ryan Diver, Barbara Nemesure, Fredrick R. Schumacher, Michael B. Cook, Qiyuan Li, William J. Blot, Jyotsna Batra, Malgorzata Tymrakiewicz, Anand P. Chokkalingam, Esther M. John, Christopher A. Haiman, Merideth Yeager, David E. Neal, John D. Carpten, Daniel Leongamornlert, Cezary Cybulski, Kathryn L. Penney, Sara Benlloch, Peter Iversen, Judith A. Clements, Shannon K. McDonnell, Matthew L. Freedman, Adam B. Murphy, Mahbubl Ahmed, Kenneth Muir, Sonja I. Berndt, Aida Karina Dieffenbach, Cristina Leske, William B. Isaacs, Chee Goh, Edward D. Yeboah, Jong Y. Park, Ruth C. Travis, Atsushi Takahashi, Nora Pashayan, Timothy J. Key, Evelyn Tay, Lorelei A. Mucci, Edward Giovannucci, Stephen N. Thibodeau, Fredrik Wiklund, Amanda B. Spurdle, Teuvo L.J. Tammela, Peter Kraft, Johanna Schleutker, Melissa C. Southey, Elio Riboli, Afshan Siddiq, Sara S. Strom, Hardev Pandha, Curtis A. Pettaway, Sue A. Ingles, Demetrius Albanes, Brian E. Henderson, Rosalind A. Eeles, Meir J. Stampfer, Markus Aly, Suh-Yuh Wu, Constance Chen, Sune F. Nielsen, Federico Canzian, Christa Stegmaier, Hui-Yi Lin, Amy K. Hutchinson, John S. Witte, Andrzej M. Kierzek, Elizabeth M. Gillanders, Vanio Mitev, Dominika Wokołorczyk, Ali Amin Al Olama, Richard B. Biritwum, Andrew A. Adjei, Ann Truelove, Daniel J. Schaid, Mitchell J. Machiela, Graham Casey, Børge G. Nordestgaard, Wei Zheng, Tokhir Dadaev, Thomas A. Sellers, Lucy Xia, Antonio Hurtado Coll, Tiina Wahlfors, Paul D.P. Pharoah, Jenny L Donovan, Victoria L. Stevens, Kristin A. Rand, Kai Yu, Alex Stram, Anssi Auvinen, Lisa Chu, Adam S. Kibel, Yao Tettey, Gerhard A. Coetzee, Martin Andreas Røder, Gianluca Severi, Daniel O. Stram, Anselm Hennis, Charles C. Chung, Jing Ma, Stephen J. Chanock, Katri A. Leinonen, Stephanie J. Weinstein, Jonathan Tyrer, Freddie C. Hamdy, Shelley Niwa, Kathleen Herkommer, Beatrice S. Knudsen, Laurence N. Kolonel, David J. Hunter, Christine Neslund-Dudas, Loreall Pooler, Robert N. Hoover, Antje E. Rinckleb, Jarmo Virtamo, Henrik Grönberg, Peggy Wan, Eric A. Klein, Michelle Guy, Manuel Luedeke, Radka Kaneva, Xin Sheng, Zsofia Kote-Jarai, Daniella Seminara, Tapio Visakorpi, Christiane Maier, Ann W. Hsing, Susan M. Gapstur, Sara Jugurnauth-Little, Ying Han, Ed Saunders, Agnieszka Michael, Alan W. Partin, Graham G. Giles, S. Lilly Zheng, Michiaki Kubo, Benjamin A. Rybicki, Kay-Tee Khaw, and Sarah K. Holt
Subjects: Male, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Disease, Biology, ta3111, Polymorphism, Single Nucleotide, Risk Assessment, Article, Prostate cancer, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic association, ta113, ta112, ta1184, ta1182, Cancer, Prostatic Neoplasms, medicine.disease, ta3122, Genetic Loci, Meta-analysis, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
Published: 2014

30. The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study

Author: Elisabete Weiderpass, J. Brent Richards, Peter Selby, Emily White, Peng Li, Ghislaine Scelo, David C. Muller, Garnet L. Anderson, Nicholas J. Timpson, David Zaridze, Mattias Johansson, Poulami Barman, Laura E. Beane Freeman, Alexander S. Parker, Simone Benhamou, Mark P. Purdue, Ingrid Winship, Victoria L. Stevens, Wong-Ho Chow, Valerie Gaborieau, Neal D. Freedman, Jean-François Deleuze, Juhua Luo, Philip C Haycock, Kevin M. Brown, Todd L. Edwards, Jeanette E. Eckel-Passow, Tony Fletcher, Ulrike Peters, Anush Mukeriya, Christel Häggström, Fiona Bruinsma, Timothy Eisen, Richard J. Kahnoski, George Davey Smith, I-Min Lee, Laurie Burdette, Lisa Johnson, Hallie Carol, Alicja Wolk, Jolanta Lissowska, Zhaoming Wang, Stephen J. Chanock, Yuanqing Ye, Sabrina L. Noyes, Jan Lubinski, Marie Navratilova, Matthew L. Freedman, Xifeng Wu, Ivana Holcatova, Stella Koutros, Vladimir Janout, Richard S. Houlston, James D. McKay, Toni K. Choueiri, Anne Boland, Susanna C. Larsson, Rosamonde E. Banks, Gabriella Andreotti, Sanja Radojevic-Skodric, Egor Prokhortchouk, Eunyoung Cho, Stefan Rascu, Paul Brennan, Hélène Blanché, David Petillo, James Larkin, Konstantin G. Skryabin, Börje Ljungberg, Marc J. Gunter, Viorel Jinga, Howard D. Sesso, Matthieu Foll, Brian R. Lane, Peter Rudnai, Jean-Guillaume Garnier, J. Michael Gaziano, Geraldine Cancel-Tassin, Caroline L Relton, Julie E. Buring, Meredith Yeager, Raviprakash T. Sitaram, Kristian Hveem, Loren Lipworth, Olivier Cussenot, Bin Tean Teh, Robert Carreras-Torres, Peter E. Clark, Vladimir Bencko, Simona Ognjanovic, Mark Pomerantz, Stephanie J. Weinstein, Mitchell J. Machiela, G. Mark Lathrop, Dana Mates, Lenka Foretova, Gianluca Severi, Bradley C. Leibovich, Leandro M. Colli, Daniela Mariosa, Marc Henrion, Satu Männistö, Susan J. Jordan, Kathryn M. Wilson, Richard M. Martin, Eleonora Fabianova, Jonathan N. Hofmann, Lars J. Vatten, Susan M. Gapstur, Cezary Cybulski, Wen-Yi Huang, Douglas F. Easton, Lee E. Moore, Cancer Research UK, Carreras-Torres, Robert [0000-0002-2925-734X], Timpson, Nicolas J [0000-0002-7141-9189], Haycock, Philip C [0000-0001-5001-3350], Brown, Kevin M [0000-0002-8558-6711], Machiela, Mitchell J [0000-0001-6538-9705], Li, Peng [0000-0002-0682-9819], Radojevic-Skodric, Sanja [0000-0002-5395-8285], Holcatova, Ivana [0000-0002-1366-0337], Mates, Dana [0000-0002-6219-9807], Mukeriya, Anush [0000-0002-6847-9295], Fabianova, Eleonora [0000-0002-5519-8427], Jinga, Viorel [0000-0001-7632-5328], Cancel-Tassin, Geraldine [0000-0002-9583-6382], Cussenot, Olivier [0000-0002-9912-0533], Weiderpass, Elisabete [0000-0003-2237-0128], Bruinsma, Fiona [0000-0002-9356-2015], Jordan, Susan J [0000-0002-4566-1414], Severi, Gianluca [0000-0001-7157-419X], Winship, Ingrid [0000-0001-8535-6003], Fletcher, Tony [0000-0003-3385-200X], Larsson, Susanna C [0000-0003-0118-0341], Wolk, Alicja [0000-0001-7387-6845], Banks, Rosamonde E [0000-0002-0042-8715], Beane Freeman, Laura E [0000-0003-1294-4124], Weinstein, Stephanie [0000-0002-3834-1535], Edwards, Todd L [0000-0003-4318-6119], Gapstur, Susan M [0000-0002-1934-2110], Stevens, Victoria L [0000-0003-0259-4407], Carol, Hallie [0000-0001-8890-9785], Pomerantz, Mark M [0000-0003-4914-1157], Freedman, Neal D [0000-0003-0074-1098], Huang, Wen-Yi [0000-0002-4440-3368], Petillo, David [0000-0001-7234-4644], Anderson, Garnet L [0000-0001-5087-7837], Moore, Lee E [0000-0002-5957-8283], Henrion, Marc [0000-0003-1242-839X], Barman, Poulami [0000-0002-4604-9868], Choueiri, Toni K [0000-0002-9201-3217], McKay, James D [0000-0002-1787-3874], Richards, J Brent [0000-0002-3746-9086], Martin, Richard M [0000-0002-7992-7719], Davey Smith, George [0000-0002-1407-8314], Brennan, Paul [0000-0002-0518-8714], and Apollo - University of Cambridge Repository
Subjects: Blood Glucose, Male, Physiology, Epidemiology, Blood Pressure, Genome-wide association study, 030204 cardiovascular system & hematology, urologic and male genital diseases, Bioinformatics, Biochemistry, Vascular Medicine, Body Mass Index, Endocrinology, Mathematical and Statistical Techniques, 0302 clinical medicine, Risk Factors, Renal cell carcinoma, Medicine and Health Sciences, Insulin, Medicine, 030212 general & internal medicine, 2. Zero hunger, Cancer Risk Factors, Statistics, Public Health, Global Health, Social Medicine and Epidemiology, Mendelian Randomization Analysis, Genomics, 11 Medical And Health Sciences, General Medicine, Lipids, Kidney Neoplasms, 3. Good health, Oncology, Physiological Parameters, Physical Sciences, Female, ICEP, Research Article, Genetic Markers, medicine.medical_specialty, Research and Analysis Methods, Instrumental Variable Analysis, Carcinomas, 03 medical and health sciences, General & Internal Medicine, Mendelian randomization, Genome-Wide Association Studies, Genetics, Carcinoma, Humans, VDP::Medisinske Fag: 700, Obesity, Statistical Methods, Carcinoma, Renal Cell, Diabetic Endocrinology, Cancer och onkologi, business.industry, Body Weight, Renal Cell Carcinoma, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Cancer, Human Genetics, Genome Analysis, medicine.disease, Hormones, VDP::Medical disciplines: 700, Genitourinary Tract Tumors, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, Diabetes Mellitus, Type 2, Medical Risk Factors, Cancer and Oncology, Etiology, business, Mathematics, Genome-Wide Association Study
Abstract: Background Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. Methods and findings Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. Conclusions This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk., Using mendelian randomization approaches, Paul Brennan and colleagues reveal an association between 12 obesity-related factors, including insulin and the development of renal cell carcinoma., Author summary Why was this study done? Traditional observational studies wherein putative risk factors are measured directly have found several obesity-related factors associated with increased risk of renal cell carcinoma (RCC). Traditional observational studies are subject to confounding and reverse causation and have not been able to disentangle which obesity-related risk factors directly influence RCC risk. This study used an alternative methodology commonly referred to as mendelian randomization (MR). MR circumvents many of the inherent limitations of traditional observational study by use of genetic proxies of putative risk factors when evaluating their associations with disease risk, as they are not subject to reverse causation and are less likely to be confounded by other risk factors. What did the researchers do and find? First, we used large-scale genome-wide association studies (GWAS) to identify genetic variants associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose. Second, these genetic variants were used as proxies for the above-mentioned risk factors and evaluated in relation RCC risk using GWAS data from 10,000 RCC patients and 20,000 control participants. Based on these genetic data, we found that multiple measures of obesity, as well as diastolic blood pressure (DBP) and fasting insulin, are associated with RCC risk. In contrast, we found little evidence for an association with RCC risk for systolic blood pressure (SBP), circulating lipids, overall diabetes, or fasting glucose. What do these findings mean? This study provided robust and confirmatory evidence of an important role of obesity as an important risk factor of RCC. Further confirmatory evidence was found for elevated DBP as a risk factor of RCC, but it is not clear why DBP rather than SBP is important in RCC. The study, to our knowledge, provided novel evidence of an important role of circulating insulin in RCC etiology. This study provided some novel insights into the pathways involved in mediating the risk increase in RCC that is caused by obesity, most notably through insulin and DBP, but further research is needed to fully elucidate the important relationship between obesity and RCC.
Published: 2019
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31. Germline variation inNCF4, an innate immunity gene, is associated with an increased risk of colorectal cancer

Author: Wen-Yi Huang, Mark J. Gunter, Sonja I. Berndt, Julie E. Goodman, Meredith Yeager, Krista A. Zanetti, Aaron J. Schetter, Ana I. Robles, Bríd M. Ryan, Laurie Burdette, Curtis C. Harris, and Richard B. Hayes
Subjects: Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, Case-control study, Cancer, Single-nucleotide polymorphism, Odds ratio, Colorectal adenoma, Biology, medicine.disease, Germline mutation, Internal medicine, Cancer screening, Immunology, medicine
Abstract: Chronic inflammation has been implicated in the etiology of colorectal adenoma and cancer; however, few key inflammatory genes mediating this relationship have been identified. In this study, we investigated the association of germline variation in innate immunity genes in relation to the risk of colorectal neoplasia. Our study was based on the analysis of samples collected from the prostate, lung, colorectal and ovarian (PLCO) Cancer Screening Trial. We investigated the association between 196 tag single nucleotide polymorphisms (SNPs) in 20 key innate immunity genes with risk of advanced colorectal adenoma and cancer in 719 adenoma cases, 481 cancer cases and 719 controls. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). After Bonferroni correction, the AG/GG genotype of rs5995355, which is upstream of NCF4, was associated with an increased risk of colorectal cancer (OR = 2.43, 95% CI = 1.73-3.39; p < 0.0001). NCF4 is part of the NAPDH complex, a key factor in biochemical pathways and the innate immune response. While not definitive, our analyses suggest that the variant allele does not affect expression of NCF4, but rather modulates activity of the NADPH complex. Additional studies on the functional consequences of rs5995355 in NCF4 may help to clarify the mechanistic link between inflammation and colorectal cancer.
Published: 2013
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32. Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer

Author: Edward Giovannucci, Rachael S. Stolzenberg-Solomon, Daniela Basso, Markus W. Büchler, Donghui Li, Manal M. Hassan, Niccola Funel, Mark D. Thornquist, Steven Gallinger, Andrea Z. LaCroix, Nathalia Giese, Julie E. Buring, Eric J. Jacobs, Michelle Brotzman, Philip R. Taylor, Aruna Kamineni, Neil E. Caporaso, Gabriella Andreotti, Cosmeri Rizzato, Satu Männistö, Timothy J. Key, Howard D. Sesso, Paige M. Bracci, Eric A. Klein, Renata Talar-Wojnarowska, Petra H.M. Peeters, Charles Kooperberg, Patricia Hartge, Pavel Soucek, Anne Zeleniuch-Jacquotte, Anne Tjønneland, Vittorio Krogh, Herbert Yu, Jean Wactawski-Wende, Roger L. Milne, Laufey T. Amundadottir, Francisco X. Real, Sonja I. Berndt, Andrea Mambrini, Melissa A. Austin, Kathy J. Helzlsouer, Miquel Porta, Rudolf Kaaks, Wei Zheng, Richard Barfield, Robert C. Kurtz, Alan A. Arslan, Ulrike Peters, Matthew H. Kulke, Federico Canzian, Maria Teresa Landi, Charles S. Fuchs, H. Bas Bueno-de-Mesquita, Nathaniel Rothman, Stephen J. Chanock, Kouros Owzar, Debra T. Silverman, Kai Yu, Harvey A. Risch, Daniele Campa, Marie-Christine Boutron-Ruault, Juozas Kupcinskas, Ann L. Oberg, Manolis Kogevinas, Laurie Burdette, Laurence N. Kolonel, Michelle Cotterchio, Robert N. Hoover, Núria Malats, Malin Sund, Megan J. Gorman, Raffaele Pezzilli, Peter Bugert, Nicolas Wentzensen, Myron D. Gross, Geoffrey S. Tobias, Pavel Vodicka, Dimitrios Trichopoulos, Charles C. Chung, Stefano Landi, Nan Hu, Gary E. Goodman, Emily White, Christopher A. Haiman, J. Michael Gaziano, Phyllis J. Goodman, Kala Visvanathan, Loic Le Marchand, George Theodoropoulos, Christian C. Abnet, Yusuke Nakamura, Alison P. Klein, Gabriele Capurso, Eric J. Duell, Zhaoming Wang, Federico Innocenti, Gloria M. Petersen, Xiao-Ou Shu, Chen Wu, Kay-Tee Khaw, Mazda Jenab, Graham G. Giles, Laura Beane-Freeman, Brian E. Henderson, Elio Riboli, Michael Goggins, Eithne Costello, David J. Hunter, Alpa V. Patel, Sara H. Olson, Aldo Scarpa, Brian M. Wolpin, Demetrius Albanes, Peter Kraft, Joanne W. Elena, Elizabeth A. Holly, and Ada Piepoli
Subjects: Male, Linkage disequilibrium, multistage genome-wide association study, pancreatic cancer, Genotype, European Continental Ancestry Group, Genome-wide association study, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, White People, Pancreatic cancer, Genetics, medicine, Humans, Aged, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Middle Aged, Pancreatic Neoplasms, Genetic Loci, Polymorphism, Càncer de pàncrees, Pancreas cancer, Case-control study, Single Nucleotide, Genomics, Odds ratio, medicine.disease, Molecular biology, Confidence interval, 3. Good health, Genòmica
Abstract: We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 x 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 x 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 x 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 x 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 x 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 x 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.
Published: 2016

33. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author: Anne Tjønneland, Jason W. Hoskins, Kala Visvanathan, Yogesh K. Vashist, Dimitrios Trichopoulos, Matthew H. Kulke, Ruth C. Travis, Charles S. Fuchs, Herbert Yu, Kai Yu, Phyllis J. Goodman, Michael Goggins, Jean Wactawski-Wende, Laurie Burdette, Joanne W. Elena, Andrea Mambrini, Petra H.M. Peeters, H. Bas Bueno-de-Mesquita, Maria Teresa Landi, Ulrike Peters, Mingfeng Zhang, Laurence N. Kolonel, Hermann Brenner, Elżbieta Iskierka-Jażdżewska, Robert C. Kurtz, Stephen J. Chanock, Marie-Christine Boutron-Ruault, Ann L. Oberg, Elio Riboli, Maarten F. Bijlsma, Eric J. Jacobs, Manolis Kogevinas, Evelina Mocci, Steven Gallinger, Jinping Jia, Mark P. Purdue, Raffaele Pezzilli, Harvey A. Risch, Demetrius Albanes, Irene Collins, Maria Gazouli, Michelle Cotterchio, Oliver Strobel, Erica J. Childs, Charles C. Chung, Geoffrey S. Tobias, J. Ramón Quirós, Núria Malats, Robert N. Hoover, Pavel Vodicka, Brian M. Wolpin, Ugo Boggi, Patricia Hartge, Gloria M. Petersen, Peter Kraft, Christopher Hautman, Gary E. Goodman, Manal Hassan, Donghui Li, Howard D. Sesso, Malin Sund, Julie E. Buring, Loic Le Marchand, Wei Zheng, Xiao-Ou Shu, Ewa Małecka-Panas, Pavel Soucek, Salvatore Panico, Nicolas Wentzensen, Graham G. Giles, Alpa V. Patel, Daniele Campa, Myron D. Gross, Ghislaine Scelo, J. Michael Gaziano, Juozas Kupcinskas, Debra T. Silverman, Laufey T. Amundadottir, Rachael S. Stolzenberg-Solomon, Neil E. Caporaso, Mazda Jenab, Sara H. Olson, Stefano Landi, Giulia Martina Cavestro, Aruna Kamineni, Laura Beane-Freeman, Roger L. Milne, Rachel E. Neale, Aldo Scarpa, Kathy J. Helzlsouer, Miquel Porta, Emily White, Eric J. Duell, Paige M. Bracci, Nan Hu, Federico Canzian, Eric A. Klein, Gabriele Capurso, Anne Zeleniuch-Jacquotte, Eithne Costello, David J. Hunter, Rudolf Kaaks, Sonja I. Berndt, Kay-Tee Khaw, Nathaniel Rothman, Christian C. Abnet, Francesca Tavano, Christopher A. Haiman, Zhaoming Wang, Ofure Obazee, Alan A. Arslan, Edward Giovannucci, Alison P. Klein, Daniela Basso, Charles Kooperberg, Philip R. Taylor, Satu Männistö, Timothy J. Key, Mark D. Thornquist, Gabriella Andreotti, Lauren K. Brais, Gisella Figlioli, Vittorio Krogh, University Medical Center Utrecht, Imperial College Trust, Cancer Research UK, Medical Research Council UK (MRC), National Institute for Health Research (NIHR), Cancer Research UK (Reino Unido), Medical Research Council (Reino Unido), National Institute for Health Research (Reino Unido), Zhang, Mingfeng, Wang, Zhaoming, Obazee, Ofure, Jia, Jinping, Childs, Erica J, Hoskins, Jason, Figlioli, Gisella, Mocci, Evelina, Collins, Irene, Chung, Charles C, Hautman, Christopher, Arslan, Alan A, Beane Freeman, Laura, Bracci, Paige M, Buring, Julie, Duell, Eric J, Gallinger, Steven, Giles, Graham G, Goodman, Gary E, Goodman, Phyllis J, Kamineni, Aruna, Kolonel, Laurence N, Kulke, Matthew H, Malats, Núria, Olson, Sara H, Sesso, Howard D, Visvanathan, Kala, White, Emily, Zheng, Wei, Abnet, Christian C, Albanes, Demetriu, Andreotti, Gabriella, Brais, Lauren, Bueno de Mesquita, H. Ba, Basso, Daniela, Berndt, Sonja I, Boutron Ruault, Marie Christine, Bijlsma, Maarten F, Brenner, Hermann, Burdette, Laurie, Campa, Daniele, Caporaso, Neil E, Capurso, Gabriele, Cavestro, Giulia Martina, Cotterchio, Michelle, Costello, Eithne, Elena, Joanne, Boggi, Ugo, Gaziano, J. Michael, Gazouli, Maria, Giovannucci, Edward L, Goggins, Michael, Gross, Myron, Haiman, Christopher A, Hassan, Manal, Helzlsouer, Kathy J, Hu, Nan, Hunter, David J, Iskierka Jazdzewska, Elzbieta, Jenab, Mazda, Kaaks, Rudolf, Key, Timothy J, Khaw, Kay Tee, Klein, Eric A, Kogevinas, Manoli, Krogh, Vittorio, Kupcinskas, Juoza, Kurtz, Robert C, Landi, Maria T, Landi, Stefano, Le Marchand, Loic, Mambrini, Andrea, Mannisto, Satu, Milne, Roger L, Neale, Rachel E, Oberg, Ann L, Panico, Salvatore, Patel, Alpa V, Peeters, Petra H. M, Peters, Ulrike, Pezzilli, Raffaele, Porta, Miquel, Purdue, Mark, Quiros, J. Ramón, Riboli, Elio, Rothman, Nathaniel, Scarpa, Aldo, Scelo, Ghislaine, Shu, Xiao Ou, Silverman, Debra T, Soucek, Pavel, Strobel, Oliver, Sund, Malin, Małecka Panas, Ewa, Taylor, Philip R, Tavano, Francesca, Travis, Ruth C, Thornquist, Mark, Tjønneland, Anne, Tobias, Geoffrey S, Trichopoulos, Dimitrio, Vashist, Yogesh, Vodicka, Pavel, Wactawski Wende, Jean, Wentzensen, Nicola, Yu, Herbert, Yu, Kai, Zeleniuch Jacquotte, Anne, Kooperberg, Charle, Risch, Harvey A, Jacobs, Eric J, Li, Donghui, Fuchs, Charle, Hoover, Robert, Hartge, Patricia, Chanock, Stephen J, Petersen, Gloria M, Stolzenberg Solomon, Rachael S, Wolpin, Brian M, Kraft, Peter, Klein, Alison P, Canzian, Federico, Amundadottir, Laufey T., Khaw, Kay-Tee [0000-0002-8802-2903], Apollo - University of Cambridge Repository, CCA -Cancer Center Amsterdam, Center of Experimental and Molecular Medicine, Radiotherapy, Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, Ej, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, Cc, Hautman, C, Arslan, Aa, Beane Freeman, L, Bracci, Pm, Buring, J, Duell, Ej, Gallinger, S, Giles, Gg, Goodman, Ge, Goodman, Pj, Kamineni, A, Kolonel, Ln, Kulke, Mh, Malats, N, Olson, Sh, Sesso, Hd, Visvanathan, K, White, E, Zheng, W, Abnet, Cc, Albanes, D, Andreotti, G, Brais, L, Bueno de Mesquita, Hb, Basso, D, Berndt, Si, Boutron Ruault, Mc, Bijlsma, Mf, Brenner, H, Burdette, L, Campa, D, Caporaso, Ne, Capurso, G, Cavestro, GIULIA MARTINA, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, Jm, Gazouli, M, Giovannucci, El, Goggins, M, Gross, M, Haiman, Ca, Hassan, M, Helzlsouer, Kj, Hu, N, Hunter, Dj, Iskierka Jazdzewska, E, Jenab, M, Kaaks, R, Key, Tj, Khaw, Kt, Klein, Ea, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, Rc, Landi, Mt, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, Rl, Neale, Re, Oberg, Al, Panico, S, Patel, Av, Peeters, Ph, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Quiros, Jr, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, Xo, Silverman, Dt, Soucek, P, Strobel, O, Sund, M, Małecka Panas, E, Taylor, Pr, Tavano, F, Travis, Rc, Thornquist, M, Tjønneland, A, Tobias, G, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch Jacquotte, A, Kooperberg, C, Risch, Ha, Jacobs, Ej, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, Sj, Petersen, Gm, Stolzenberg Solomon, R, Wolpin, Bm, Kraft, P, Klein, Ap, Canzian, F, and Amundadottir, L. T.
Subjects: 0301 basic medicine, Candidate gene, Pancreatic disease, GENETIC SUSCEPTIBILITY, pancreatic cancer, Datasets as Topic, Genome-wide association study, imputation, TRET, 0302 clinical medicine, Fine-mapping, GWAS, Imputation, NR5A2, Pancreatic cancer, Oncology, Genotype, Genetics, 3. Good health, fine-mapping, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 8, 616.37-006.6 [udc], BLADDER-CANCER, Single-nucleotide polymorphism, GENOTYPE IMPUTATION, BREAST, Polymorphism, Single Nucleotide, 03 medical and health sciences, Journal Article, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, Pàncrees -- Càncer, Cancer och onkologi, LONG-RANGE INTERACTION, business.industry, medicine.disease, Pancreatic neoplasms, genetics, Polymorphism, single nucleotide, RISK LOCI, Fold change, COMMON VARIANT, Cromosomes, Pancreatic Neoplasms, 030104 developmental biology, Cancer and Oncology, business, Imputation (genetics), LRH-1, Priority Research Paper, Genome-Wide Association Study
Abstract: Altres ajuts: The authors acknowledge the contribution of the staff of the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help throughout the project. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Additional acknowledgements for individual participating studies are listed in the Supplemental Materials. Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88×10 −15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22×10 −9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70×10 −8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L - TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7×10 −8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5×10 −4 -2.0×10 −3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
Published: 2016

34. Genetic variants in DNA repair genes and the risk of cutaneous malignant melanoma in melanoma-prone families with/without CDKN2A mutations

Author: Xiaohong R. Yang, William Wheeler, Stephen J. Chanock, Meredith Yeager, Margaret A. Tucker, Xueying Sharon Liang, Ruth M. Pfeiffer, Dennis Maeder, Alisa M. Goldstein, and Laurie Burdette
Subjects: Cancer Research, Skin Neoplasms, DNA Repair, DNA repair, DNA damage, Single-nucleotide polymorphism, DNA-Activated Protein Kinase, DNA-Directed DNA Polymerase, Biology, Polymorphism, Single Nucleotide, Article, Risk Factors, CDKN2A, Polymorphism (computer science), medicine, Humans, SNP, Genetic Predisposition to Disease, Melanoma, neoplasms, Gene, Cyclin-Dependent Kinase Inhibitor p16, Genetic Association Studies, Genetics, integumentary system, Nuclear Proteins, medicine.disease, DNA Repair Enzymes, Exodeoxyribonucleases, Oncology, Cancer research
Abstract: Cutaneous malignant melanoma (CMM) is an etiologically heterogeneous disease with genetic, environmental (sun exposure) and host (pigmentation/nevi) factors and their interactions contributing to risk. Genetic variants in DNA repair genes may be particularly important since their altered function in response to sun exposure-related DNA damage maybe related to risk for CMM. However, systematic evaluations of genetic variants in DNA repair genes are limited, particularly in high-risk families. We comprehensively analyzed DNA repair gene polymorphisms and CMM risk in melanoma-prone families with/without CDKN2A mutations. A total of 586 individuals (183 CMM) from 53 families (23 CDKN2A (+), 30 CDKN2A (-)) were genotyped for 2964 tagSNPs in 131 DNA repair genes. Conditional logistic regression, conditioning on families, was used to estimate trend p-values, odds ratios and 95% confidence intervals for the association between CMM and each SNP separately, adjusted for age and sex. p-Values for SNPs in the same gene were combined to yield gene specific p-values. Two genes, POLN and PRKDC, were significantly associated with melanoma after Bonferroni correction for multiple testing (p = 0.0003 and 0.00035, respectively). DCLRE1B showed suggestive association (p = 0.0006). 28 ∼ 56% of genotyped SNPs in these genes had single SNP p < 0.05. The most significant SNPs in POLN and PRKDC had similar effects in CDKN2A (+) and CDKN2A (-) families. Our finding suggests that polymorphisms in DNA repair genes, POLN and PRKDC, were associated with increased melanoma risk in melanoma families with and without CDKN2A mutations.
Published: 2011
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35. Selected human leukocyte antigen class II polymorphisms and risk of adult glioma

Author: Jay S. Loeffler, Laurie Burdette, Robert Dubrow, Robert G. Selker, Peter McL. Black, William R. Shapiro, Howard A. Fine, Alina V. Brenner, Bryan A. Bassig, and Peter D. Inskip
Subjects: Adult, Male, musculoskeletal diseases, Inverse Association, Immunology, Human leukocyte antigen, Biology, Logistic regression, Article, immune system diseases, HLA-DQ Antigens, Glioma, medicine, HLA-DQ beta-Chains, Humans, Immunology and Allergy, Genetic Predisposition to Disease, Allele, HLA-DR Antigen, Aged, Polymorphism, Genetic, HLA-DQ Antigen, Brain Neoplasms, Case-control study, nutritional and metabolic diseases, HLA-DR Antigens, Middle Aged, medicine.disease, Neurology, Case-Control Studies, Female, Neurology (clinical), HLA-DRB1 Chains
Abstract: Few studies have examined the relationship between human leukocyte antigen (HLA) polymorphisms and adult glioma, particularly at class II loci. We evaluated the association between selected HLA class II polymorphisms and adult glioma in a large, hospital-based case-control study, using unconditional logistic regression. DQB1*06 (OR = 1.67, 95% CI = 1.17–2.39) and DRB1*13 (OR = 1.69, 95% CI = 1.08–2.64) alleles were associated with an increased risk of glioma, while the DQB1*05 allele showed an inverse association (OR = 0.63, 95% CI = 0.43–0.93). These results, which were of borderline significance once controlled for the false discovery rate, suggest a potential role for the DQB1*06 , DQB1*05 , and DRB1*13 alleles in glioma susceptibility.
Published: 2011
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36. Abstract 2970: Multiple new susceptibility loci identified in genome-wide association study of Ewing sarcoma

Author: Andreas E. Kulozik, Gaëlle Pierron, Nadège Corradini, Udo Kontny, Stelly Ballet, Gregory T. Armstrong, Lindsay M. Morton, Stéphanie Reynaud, Piero Picci, Nathalie Gaspar, Javed Khan, Nathaniel Rothman, Valérie Laurence, Jean Michon, Sandrine Grossetête-Lalami, Anna González-Neira, Markus Metzler, Weiyin Zhou, Mitchell J. Machiela, Leslie L. Robison, Margaret A. Tucker, Robert N. Hoover, Wolfgang Hartmann, Eric Karlins, David G. Cox, Thomas Kirchner, Kristine Jones, Laurie Burdette, Casey L. Dagnall, Olivier Delattre, Kathleen Wyatt, Uta Dirksen, Thomas G. P. Grunewald, Olivier Mirabeau, Rebeca Alba Rubio, Heinrich Kovar, Michelle Manning, Meredith Yeager, Konstantin Strauch, Eve Lapouble, Stephen J. Chanock, Wendy M. Leisenring, Javier Alonso, Sakina Zaidi, Didier Surdez, Ana Patiño-García, Lisa Mirabello, Smita Bhatia, Neal D. Freedman, and Franck Tirode
Subjects: Cancer Research, Oncology, Ballet, media_common.quotation_subject, medicine, Susceptibility locus, Pediatric Tumor, Genome-wide association study, Art, Sarcoma, medicine.disease, Humanities, media_common
Abstract: Ewing sarcoma (EWS) is a rare pediatric tumor predominantly occurring in children of European ancestry and is characterized by the pathognomonic EWSR1-FLI1 fusion oncogene. To identify germline susceptibility loci associated with EWS risk, we performed a genome-wide association study (GWAS) meta-analysis of 749 EWS cases and 1,378 unaffected individuals of European ancestry from sample collections within the Institut Curie, National Cancer Institute and the Childhood Cancer Survivor Study. Our study replicated previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1 as well as identified novel loci at 6p25.1, 8q24.23, 20p11.22 and 20p11.23 (P-values Citation Format: Mitchell J. Machiela, Thomas G. Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetete-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Nathalie Gaspar, Udo Kontny, Anna González-Neira, Piero Picci, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Neal D. Freedman, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdette, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G. Cox, Robert N. Hoover, Javed Khan, Gregory T. Armstrong, Wendy M. Leisenring, Smita Bhatia, Leslie L. Robison, Uta Dirksen, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Andreas E. Kulozik, Lindsay M. Morton, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Stephen J. Chanock, Olivier Delattre. Multiple new susceptibility loci identified in genome-wide association study of Ewing sarcoma [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 2970.
Published: 2018
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37. Novel Breast Cancer Risk Alleles and Interaction with Ionizing Radiation among U.S. Radiologic Technologists

Author: Stephen J. Chanock, Marvin Rosenstein, Dale L. Preston, Bruce H. Alexander, Meredith Yeager, Gilles Thomas, Robert M. Weinstock, Steven L. Simon, Michele M. Doody, Marilyn Stovall, Preetha Rajaraman, Parveen Bhatti, Martha S. Linet, David J. Hunter, Laurie Burdette, Alice J. Sigurdson, Robert N. Hoover, and Amy Hutchinson
Subjects: Oncology, medicine.medical_specialty, Allied Health Personnel, Biophysics, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, Breast cancer, Radiation, Ionizing, Internal medicine, Genotype, medicine, Humans, Genetic Predisposition to Disease, Radiology, Nuclear Medicine and imaging, Technology, Radiologic, Alleles, Carcinogen, Genetic association, Chromosomes, Human, Pair 14, Gynecology, Radiation, Public health, Cancer, medicine.disease, United States, DNA-Binding Proteins, Genetic marker, Case-Control Studies, Cohort, Workforce, Chromosomes, Human, Pair 5, Female, Genome-Wide Association Study
Abstract: As genome-wide association studies of breast cancer are replicating findings and refinement studies are narrowing the signal location, additional efforts are necessary to elucidate the underlying functional relationships. One approach is to evaluate variation in risk by genotype based on known breast carcinogens, such as ionizing radiation. Given the public health concerns associated with recent increases in medical radiation exposure, this approach may also identify potentially susceptible subpopulations. We examined interaction between 27 newly identified breast cancer risk alleles (identified within the NCI Cancer Genetic Markers of Susceptibility and the Breast Cancer Association Consortium genome-wide association studies) and occupational and medical diagnostic radiation exposure among 859 cases and 1083 controls nested within the United States Radiologic Technologists cohort. We did not find significant variation in the radiation-related breast cancer risk for the variant in RAD51L1 (rs10483813) on 14q24.1 as we had hypothesized. In exploratory analyses, we found that the radiation-associated breast cancer risk varied significantly by linked markers in 5p12 (rs930395, rs10941679, rs2067980 and rs4415084) in the mitochondrial ribosomal protein S30 (MRPS30) gene (P(interaction) = 0.04). Chance, however, may explain these findings, and as such, these results need to be confirmed in other populations with low to moderate levels of radiation exposure. Even though a complete understanding of the way(s) in which these variants may increase breast cancer risk remains elusive, this approach may yield clues for further investigation.
Published: 2010
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38. Dietary quercetin, quercetin-gene interaction, metabolic gene expression in lung tissue and lung cancer risk

Author: Angela Cecilia Pesatori, Amy F. Subar, Melissa Rotunno, Neil E. Caporaso, Dario Consonni, Maria Teresa Landi, Laurie Burdette, Alisa M. Goldstein, Sholom Wacholder, Pier Alberto Bertazzi, Margaret A. Tucker, Tram Kim Lam, Jay H. Lubin, and Stephen J. Chanock
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, Lung Neoplasms, Biology, medicine.disease_cause, Polymorphism, Single Nucleotide, GSTP1, Cytochrome P-450 Enzyme System, Gene interaction, Risk Factors, Internal medicine, Vegetables, medicine, Humans, heterocyclic compounds, Lung cancer, Lung, Carcinogen, Aged, Glutathione Transferase, Molecular Epidemiology, Case-control study, Cancer, General Medicine, Odds ratio, Middle Aged, medicine.disease, Case-Control Studies, Fruit, Immunology, Female, Quercetin, Carcinogenesis
Abstract: Epidemiological and mechanistic evidence on the association of quercetin-rich food intake with lung cancer risk and carcinogenesis are inconclusive. We investigated the role of dietary quercetin and the interaction between quercetin and P450 and glutathione S-transferase (GST) polymorphisms on lung cancer risk in 1822 incident lung cancer cases and 1991 frequency-matched controls from the Environment And Genetics in Lung cancer Etiology study. In non-tumor lung tissue from 38 adenocarcinoma patients, we assessed the correlation between quercetin intake and messenger RNA expression of the same P450 and GST metabolic genes. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) for sex-specific quintiles of intake were calculated using unconditional logistic regression adjusting for putative risk factors. Frequent intake of quercetin-rich foods was inversely associated with lung cancer risk (OR = 0.49; 95% CI: 0.37–0.67; P-trend < 0.001) and did not differ by P450 or GST genotypes, gender or histological subtypes. The association was stronger in subjects who smoked >20 cigarettes per day (OR = 0.35; 95% CI: 0.19–0.66; P-trend = 0.003). Based on a two-sample t-test, we compared gene expression and high versus low consumption of quercetin-rich foods and observed an overall upregulation of GSTM1, GSTM2, GSTT2, and GSTP1 as well as a downregulation of specific P450 genes (P-values < 0.05, adjusted for age and smoking status). In conclusion, we observed an inverse association of quercetin-rich food with lung cancer risk and identified a possible mechanism of quercetin-related changes in the expression of genes involved in the metabolism of tobacco carcinogens in humans. Our findings suggest an interplay between quercetin intake, tobacco smoking, and lung cancer risk. Further research on this relationship is warranted.
Published: 2009
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39. A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma

Author: James McKay, Neil E. Caporaso, Jarmo Virtamo, Lars J. Vatten, Heike Bickeböller, Egil Arnesen, Christine Bouchard, Sharon A. Savage, Dario Consonni, Rayjean J. Hung, Yufei Wang, Simone Benhamou, Ryan Diver, Angela Cecilia Pesatori, John R. McLaughlin, Demetrius Albanes, Hans E. Krokan, Melissa Rotunno, Andrew W. Bergen, Stephen J. Chanock, Kari Stefansson, Qizhai Li, Elizabeth W. Pugh, Meredith Yeager, H.-Erich Wichmann, Kai Yu, Michael J. Thun, Alisa M. Goldstein, Patrick Sulem, Laurie Burdette, Albert Rosenberger, Thorunn Rafnar, Sholom Wacholder, Mari Nelis, Tõnu Vooder, Kevin B. Jacobs, Gudmar Thorleifsson, Christopher I. Amos, Richard S. Houlston, Angela Risch, Joseph F. Fraumeni, Valerie Gaborieau, Timothy Eisen, Wiebke Sauter, Ming-Sound Tsao, Paul Brennan, Lynn R. Goldin, Zhaoming Wang, Cathy C. Laurie, Gary E. Goodman, Kimberly F. Doheny, Margaret A. Tucker, Kristian Välk, Jenny Chang-Claude, Frank Skorpen, John K. Field, Chu Chen, Margaret R. Spitz, Ying Wang, Lisa Mirabello, Martin M. Oken, Maria Teresa Landi, Nilanjan Chatterjee, Pier Alberto Bertazzi, William Wheeler, Andres Metsapalu, and Mark Lathrop
Subjects: Oncology, medicine.medical_specialty, Lung Neoplasms, Genotype, Population, Genome-wide association study, Adenocarcinoma, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Meta-Analysis as Topic, Risk Factors, Report, Internal medicine, Odds Ratio, Genetics, medicine, Humans, Genetics(clinical), Genetic Predisposition to Disease, education, Lung cancer, Genetics (clinical), 030304 developmental biology, 0303 health sciences, education.field_of_study, Case-control study, Chromosome, Genetic Variation, Cancer, Odds ratio, medicine.disease, Lung cancer susceptibility, Human genetics, 3. Good health, Case-Control Studies, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, Erratum, Genome-Wide Association Study
Abstract: Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.13–1.33, p = 3.02 × 10−7), but not with other histologic types (OR = 1.01, p = 0.84 and OR = 1.00, p = 0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR = 1.24, 95% CI = 1.17–1.31, p = 3.74 × 10−14 for AD; OR = 0.99, p = 0.69 and OR = 0.97, p = 0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.
Published: 2009
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40. Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population

Author: Christopher I. Amos, Lynn Rosenberg, Edward A. Ruiz-Narváez, David C. Christiani, William J. Blot, Jennette D. Sison, Qiuyin Cai, Zhaoming Wang, Alyssa G. Rieber, Curtis C. Harris, Elise D. Bowman, Laurie Burdette, Yongyue Wei, Neil E. Caporaso, Shengchao Li, Brian E. Henderson, Margaret Wrensch, Christopher A. Haiman, Anil Vachani, Krista A. Zanetti, Laurence N. Kolonel, Margaret A. Tucker, Margaret R. Spitz, John K. Wiencke, Loic Le Marchand, Weiyin Zhou, Lynne R. Wilkens, Trevor M. Penning, Angela S. Wenzlaff, Helen M. Hansen, Alexander S. Whitehead, Bríd M. Ryan, Wei Zheng, Elizabeth M. Gillanders, Melinda C. Aldrich, Lorna H. McNeill, Julie R. Palmer, Li Su, Xifeng Wu, Charles C. Chung, Stephen J. Chanock, and Ann G. Schwartz
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, Cancer Research, Candidate gene, Lung Neoplasms, Population, Quantitative Trait Loci, Genome-wide association study, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Lung cancer, education, Genetic association, Genetics, education.field_of_study, Chromosomes, Human, Pair 15, business.industry, medicine.disease, Lung cancer susceptibility, Black or African American, 030104 developmental biology, Oncology, Case-Control Studies, Population Surveillance, Chromosomes, Human, Pair 5, business, Genome-Wide Association Study
Abstract: Objectives Genome-wide association studies (GWAS) of lung cancer have identified regions of common genetic variation with lung cancer risk in Europeans who smoke and never-smoking Asian women. This study aimed to conduct a GWAS in African Americans, who have higher rates of lung cancer despite smoking fewer cigarettes per day when compared with Caucasians. This population provides a different genetic architecture based on underlying African ancestry allowing the identification of new regions and exploration of known regions for finer mapping. Materials and methods We genotyped 1,024,001 SNPs in 1737 cases and 3602 controls in stage 1, followed by a replication phase of 20 SNPs ( p −5 ) in an independent set of 866 cases and 796 controls in stage 2. Results and conclusion In the combined analysis, we confirmed two loci to be associated with lung cancer that achieved the threshold of genome-wide significance: 15q25.1 marked by rs2036527 ( p =1.3×10 −9 ; OR=1.32; 95% CI=1.20–1.44) near CHRNA5 , and 5p15.33 marked by rs2853677 ( p =2.8×10 −9 ; OR=1.28; 95% CI=1.18–1.39) near TERT . The association with rs2853677 is driven by the adenocarcinoma subtype of lung cancer ( p =1.3×10 −8 ; OR=1.37; 95% CI=1.23–1.54). No SNPs reached genome-wide significance for either of the main effect models examining smoking − cigarettes per day and current or former smoker. Our study was powered to identify strong risk loci for lung cancer in African Americans; we confirmed results previously reported in African Americans and other populations for two loci near plausible candidate genes, CHRNA5 and TERT , on 15q25.1 and 5p15.33 respectively, are associated with lung cancer. Additional work is required to map and understand the biological underpinnings of the strong association of these loci with lung cancer risk in African Americans.
Published: 2015

41. Identification of new susceptibility loci for gastric non-cardia adenocarcinoma: pooled results from two Chinese genome-wide association studies

Author: Woon-Puay Koh, Hua Su, Ti Ding, Caiwang Yan, Christian C. Abnet, Xiao-Ou Shu, Rong Zhong, Ningbing Dai, Zhaoming Wang, Chen Wu, Zhibin Hu, Philip R. Taylor, Jian-Min Yuan, Charles C. Chung, Nan Hu, Jiaping Chen, Ming Yang, Lu Xie, Yu-Tang Gao, Yue Jiang, Alisa M. Goldstein, Wei Zheng, Stephen J. Chanock, Meilin Wang, Guangfu Jin, Chaoyu Wang, Chuanli Ren, Xiaoping Miao, Juncheng Dai, Hongbing Shen, Lemin Wang, Carol Giffen, Sanford M. Dawsey, Neal D. Freedman, Laurie Burdette, Zhendong Zhang, Dongxin Lin, Linda M. Liao, Wenting Pan, Jinfei Chen, Yong-Bing Xiang, Xun Zhu, You-Lin Qiao, Yongyong Shi, Hongxia Ma, and Jiangbo Du
Subjects: 0301 basic medicine, China, RNA, Untranslated, Genotype, Locus (genetics), Genome-wide association study, Biology, Adenocarcinoma, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Asian People, Stomach Neoplasms, Genetic predisposition, SNP, Humans, EPIDEMIOLOGY, Genetic Predisposition to Disease, GENETIC POLYMORPHISMS, Genotyping, Genetic association, Genetics, Stomach, Gastroenterology, Minor allele frequency, 030104 developmental biology, GASTRIC CANCER, Chromosomes, Human, Pair 1, Genetic Loci, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 5, Genome-Wide Association Study
Abstract: © 2017, BMJ Publishing Group. All rights reserved. Objective: Although several genome-wide association studies (GWAS) of non-cardia gastric cancer have been published, more novel association signals could be exploited by combining individual studies together, which will further elucidate the genetic susceptibility of non-cardia gastric cancer. Design: We conducted a meta-analysis of two published Chinese GWAS studies (2031 non-cardia gastric cancer cases and 4970 cancer-free controls) and followed by genotyping of additional 3564 cases and 4637 controls in two stages. Results: The overall meta-analysis revealed two new association signals. The first was a novel locus at 5q14.3 and marked by rs7712641 (per-allele OR=0.84, 95% CI 0.80 to 0.88; p=1.21×10-11). This single-nucleotide polymorphism (SNP) marker maps to the intron of the long non-coding RNA, lnc-POLR3G-4 (XLOC-004464), which we observed has lower expression in non-cardia gastric tumour compared with matched normal tissue (Pwilcoxon signed-rank=7.20×10-4). We also identified a new signal at the 1q22 locus, rs80142782 (per-allele OR=0.62; 95% CI 0.56 to 0.69; p=1.71×10-19), which was independent of the previously reported SNP at the same locus, rs4072037 (per-allele OR=0.74; 95% CI 0.69 to 0.79; p=6.28×10-17). Analysis of the new SNP conditioned on the known SNP showed that the new SNP remained genome-wide significant (Pconditional=3.47×10-8). Interestingly, rs80142782 has a minor allele frequency of 0.05 in East Asians but is monomorphic in both European and African populations. Conclusion: These findings add new evidence for inherited genetic susceptibility to non-cardia gastric cancer and provide further clues to its aetiology in the Han Chinese population.
Published: 2015
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42. Integration of multiethnic fine-mapping and genomic annotation to prioritize candidate functional SNPs at prostate cancer susceptibility regions

Author: Suh Yuh Wu, Meir J. Stampfer, Fredrick R. Schumacher, Rick A. Kittles, Ying Han, Jing Ma, Edward Giovannucci, Constance Chen, Robert N. Hoover, Anand P. Chokkalingam, Demetrius Albanes, Gerhard A. Coetzee, Dennis J. Hazelett, Janet L. Stanford, Rosalind A. Eeles, Fredrik Wiklund, Henry W. Long, John S. Witte, John D. Carpten, Jarmo Virtamo, Zhaoming Wang, Laurie Burdette, Sue A. Ingles, Peter Kraft, Ruth C. Travis, Christine Neslund-Dudas, Charles C. Chung, William J. Blot, Ann W. Hsing, Evelyn Tay, Susan M. Gapstur, Richard B. Biritwum, Kristin A. Rand, Jianfeng Xu, Graham Casey, Atsushi Takahashi, Lisa B. Signorello, Suzanne Kolb, S. Lilly Zheng, Sonja I. Berndt, Phyllis J. Goodman, Daniel O. Stram, W. Ryan Diver, Anselm Hennis, S. Lindstrom, Stephen J. Chanock, Michiaki Kubo, Sara S. Strom, Federico Canzian, Brian E. Henderson, Lisa Chu, Amy Hutchinson, M. Yeager, Elio Riboli, Kai Yu, Afshan Siddiq, Stephanie J. Weinstein, David V. Conti, David J. Hunter, Zsofia Kote-Jarai, Fugen Li, Ali Amin Al Olama, Andrew A. Adjei, Michael B. Cook, Curtis A. Pettaway, Wei Zheng, Edward D. Yeboah, Christopher A. Haiman, Victoria L. Stevens, William B. Isaacs, Hidewaki Nakagawa, Barbara Nemesure, Loic Le Marchand, Matthew L. Freedman, Adam B. Murphy, M. Cristina Leske, Timothy J. Key, Ann Truelove, Mark Pomerantz, Shelley Niwa, Mitchell J. Machiela, Yao Tettey, Benjamin A. Rybicki, Henrik Grönberg, Eric A. Klein, Qiyuan Li, Esther M. John, Douglas F. Easton, and National Institutes of Health
Subjects: Male, Linkage disequilibrium, Genome-wide association study, Medical and Health Sciences, ANALYSES REVEAL, Linkage Disequilibrium, Genotype, MULTIPLE, SEQUENCE VARIANTS, 2.1 Biological and endogenous factors, WIDE ASSOCIATION, Aetiology, Genetics (clinical), Cancer, GENE-EXPRESSION, African Continental Ancestry Group, Genetics, Genetics & Heredity, Prostate Cancer, Association Studies Articles, Chromosome Mapping, Single Nucleotide, Hispanic or Latino, General Medicine, 11 Medical And Health Sciences, Biological Sciences, Hispanic Americans, Life Sciences & Biomedicine, Biotechnology, Urologic Diseases, Asian Continental Ancestry Group, Biochemistry & Molecular Biology, European Continental Ancestry Group, Quantitative Trait Loci, TRANSETHNIC METAANALYSIS, Black People, Single-nucleotide polymorphism, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, White People, Asian People, Humans, Genetic Predisposition to Disease, Polymorphism, Molecular Biology, Genotyping, CAUSAL VARIANTS, Science & Technology, IDENTIFICATION, Human Genome, Prostatic Neoplasms, Molecular Sequence Annotation, 06 Biological Sciences, COMMON VARIANT, Expression quantitative trait loci, RISK-ASSOCIATED LOCI, Imputation (genetics), Genome-Wide Association Study
Abstract: Interpretation of biological mechanisms underlying genetic risk associations for prostate cancer is complicated by the relatively large number of risk variants (n = 100) and the thousands of surrogate SNPs in linkage disequilibrium. Here, we combined three distinct approaches: multiethnic fine-mapping, putative functional annotation (based upon epigenetic data and genomeencoded features), and expression quantitative trait loci (eQTL) analyses, in an attempt to reduce this complexity. We examined 67 risk regions using genotyping and imputation-based fine-mapping in populations of European (cases/controls: 8600/6946), African (cases/controls: 5327/5136), Japanese (cases/controls: 2563/4391) and Latino (cases/controls: 1034/1046) ancestry. Markers at 55 regions passed a region-specific significance threshold (P-value cutoff range: 3.9 × 10−4 –5.6 × 10−3 ) and in 30 regions 5604 | Human Molecular Genetics, 2015, Vol. 24, No. 19 we identified markers that were more significantly associated with risk than the previously reported variants in the multiethnic sample. Novel secondary signals (P < 5.0 × 10−6 ) were also detected in two regions (rs13062436/3q21 and rs17181170/3p12). Among 666 variants in the 55 regions with P-values within one order of magnitude of the most-associated marker, 193 variants (29%) in 48 regions overlapped with epigenetic or other putative functional marks. In 11 of the 55 regions, cis-eQTLs were detected with nearby genes. For 12 of the 55 regions (22%), the most significant region-specific, prostate-cancer associated variant represented the strongest candidate functional variant based on our annotations; the number of regions increased to 20 (36%) and 27 (49%) when examining the 2 and 3 most significantly associated variants in each region, respectively. These results have prioritized subsets of candidate variants for downstream functional evaluation.
Published: 2015

43. Genome-wide association study of gastric adenocarcinoma in Asia: a comparison of associations between cardia and non-cardia tumours

Author: Jeong Hwan Yook, Wei Zheng, Linda M. Liao, Peng Zhang, Yi Min Mao, Dongxin Lin, Chen Wu, Christian C. Abnet, Yu-Tang Gao, Hee Sung Kim, Zhaoming Wang, Chaoyu Wang, Woon-Puay Koh, Kyuyoung Song, Jian-Min Yuan, Laurie Burdette, Stephen J. Chanock, Lixuan Wei, You-Lin Qiao, Myunghee Hong, Zhao Xueke, Ti Ding, Sanford M. Dawsey, Wen Tan, Philip R. Taylor, Yaling Han, Meredith Yeager, Xin Song, Alisa M. Goldstein, Xiao-Ou Shu, Byung Sik Kim, Charles C. Chung, Nan Hu, Neal D. Freedman, Min-Jie Wu, Jiwon Baek, Carol Giffen, Jia Huang, Jiang Chang, Yong-Bing Xiang, and Li-Dong Wang
Subjects: 0301 basic medicine, Oncology, Male, medicine.medical_specialty, China, Genome-wide association study, Single-nucleotide polymorphism, AMP-Activated Protein Kinases, Adenocarcinoma, digestive system, Gastroenterology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Asian People, Stomach Neoplasms, Internal medicine, Pancreatic cancer, Republic of Korea, otorhinolaryngologic diseases, medicine, SNP, Humans, Genetic Predisposition to Disease, Allele, neoplasms, Genetic association, business.industry, Stomach, Mucin-1, Case-control study, Intracellular Signaling Peptides and Proteins, Cardia, medicine.disease, digestive system diseases, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Case-Control Studies, Female, business, Genome-Wide Association Study
Abstract: Objective Genome-wide association studies (GWAS) of gastric cancer have reported differences in single-nucleotide polymorphism (SNP) associations for tumour subtypes, particularly when divided by location into the gastric cardia versus the non-cardia. Design Here we present results for a GWAS using 2350 East Asian gastric cancer cases divided as 1189 gastric cardia and 1027 gastric non-cardia cases and 2708 controls. We also included up to 3042 cardia cases, 4359 non-cardia cases and 7548 controls for replication from two Chinese studies and one Korean study. From the GWAS, we selected 12 top SNPs for each gastric cancer subtype, 4 top SNPs for total gastric cancer and 1 SNP in MUC1 for replication testing. Results We observed genome-wide significant associations for rs10074991 in PRKAA1 at 5p13.1 for cardia (p=7.36×10 −12 ) and non-cardia cancers (p=2.42×10 −23 ) with per allele OR (95% CI) for the combined endpoint of 0.80 (0.77 to 0.83). At 6p21.1, rs2294693 near UNC5CL was significantly associated with gastric non-cardia cancer risk (p=2.50×10 −8 ), with OR (95% CI) of 1.18 (1.12 to 1.26), but there was only a nominal association for cardia cancer (p=1.47×10 −2 ). We also confirmed a previously reported association for rs4072037 in MUC1 with p=6.59×10 −8 for total gastric cancer and similar estimates for cardia and non-cardia cancers. Three SNPs in PSCA previously reported to be associated with gastric non-cardia cancer showed no apparent association for cardia cancer. Conclusions Our results suggest that associations for SNPs with gastric cancer show some different results by tumour location in the stomach.
Published: 2015

44. 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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45. Abstract 4249: Evidence of APOBEC3 editing in the HPV16 genome

Author: Sara Bass, Lisa Mirabello, Meredith Yeager, Robert D. Burk, Philip E. Castle, Mark Schiffman, Tina Raine-Bennett, Yanzi Xiao, David Roberson, Nicolas Wentzensen, Bin Zhu, Thomas Lorey, Mia Steinberg, Laurie Burdette, Zigui Chen, Qi Yang, Michael Cullen, Kai Yu, and Joseph Boland
Subjects: Cancer Research, Oncology, Computational biology, Biology, Genome
Abstract: Human papillomavirus (HPV) is a very common sexually transmitted infection, however only a small proportion of women progress to cervical precancer or cancer. HPV16 is the most carcinogenic type, causing more than half of the cervical cancer globally. The HPV16 genome is 7,906base-pairs coding for 8 genes (E6, E7, E1, E2, E4, E5, L2, L1) and one upstream regulatory region (URR). Within HPV16 there are 4 main lineages (A, B, C, D) that are strongly associated with disease risk. Human APOBEC3A (hA3A) cytidine deaminases have been shown to have antiviral effects. The APOBEC mutational process results in a C to T base change at specific motifs (5’ [C/T]•C>T•W 3’). Previous studies established that there was evidence of APOBEC3 editing on a small number of HPV16 samples. It’s unknown how these mutations are related to infection clearance or the long-term accumulation of genomic mutations that contribute to HPV-associated cancers. We conducted detailed analyses to comprehensively evaluate APOBEC3 editing on HPV16 genomes using HPV16 whole-genome sequencing data from 3,215 HPV16-infected women in the NCI-HPV Persistence and Progression (PaP) cohort. Cases were defined as women with cervical precancer (CIN3, N = 1,093) or cancer (N = 109) and controls were women with no histologic evidence of precancer or cancer (T•W 3’) out of 96 potential motifs of 3 base-pairs. Using logistic regression, we compared the number of APOBEC3-associated variants in cases and controls, among HPV16 variant lineages, and among genome regions of the virus. We discovered that there is evidence of APOBEC3 editing throughout the HPV16 genome. Specifically, we observed that women with precancer or cancer had less APOBEC3-associated variants compared to the controls (OR = 0.84, p-value = 0.06). We further showed that women with an HPV16 A lineage infection have more APOBEC3-associated variants compared to those with a non-A lineage infection (OR = 1.35, p-value = 0.02). After controlling for the number of APOBEC3 vulnerable loci, we observed that the L1 (OR = 0.23, p-value = 0.04) and E7 (OR = 0.29, p-value = 0.07) genes have less APOBEC3 footprints overall, and particularly in the cases compared to the controls in these regions, compared to the viral non-coding upstream regulatory region (URR). Overall, we found that APOBEC3 is not affecting the HPV16 genome in a uniform way, and instead, it appears to be targeting specific regions which could suggest antiviral activity. Importantly, we determined that APOBEC3-associated variants are less prevalent in cases which could be related to disease progression in these individuals. Further evaluation is underway. Citation Format: Yanzi Xiao, Bin Zhu, Meredith Yeager, Michael Cullen, Joseph Boland, Nicolas Wentzensen, Tina Raine-Bennett, Zigui Chen, Kai Yu, Qi Yang, Mia Steinberg, David Roberson, Sara Bass, Laurie Burdette, Thomas Lorey, Philip Castle, Robert Burk, Mark Schiffman, Lisa Mirabello. Evidence of APOBEC3 editing in the HPV16 genome [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 4249. doi:10.1158/1538-7445.AM2017-4249
Published: 2017
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46. Genetic susceptibility to diffuse large B-cell lymphoma in a pooled study of three Eastern Asian populations

Author: Wei Hu, Jovic Tse, Joseph Vijai, Bryan A. Bassig, Tongzhang Zheng, Laurie Burdette, Nathaniel Rothman, Paul Brennan, Je-Jung Lee, Raymond Liang, Qing Lan, Christine F. Skibola, Meredith Yeager, Wing Y. Au, Min-Ho Shin, Pattarapong Pornsopone, Hyeoung Joon Kim, James R. Cerhan, Sonja I. Berndt, Hee Nam Kim, Heping Zhang, Stephen J. Chanock, and Suleeporn Sangrajrang
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Vesicular Transport Proteins, Single-nucleotide polymorphism, Genome-wide association study, Polymorphism, Single Nucleotide, immune system diseases, hemic and lymphatic diseases, Internal medicine, Genotype, Genetic predisposition, medicine, Humans, Genetic Predisposition to Disease, Allele, Aged, Genetics, business.industry, Asia, Eastern, Case-control study, Hematology, General Medicine, Middle Aged, medicine.disease, Population study, Female, Lymphoma, Large B-Cell, Diffuse, business, Diffuse large B-cell lymphoma, Genome-Wide Association Study
Abstract: Objectives Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) and is the most common NHL subtype diagnosed worldwide. 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. Methods 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. Results 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). Conclusions 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.
Published: 2014

47. Genome-wide association study identifies multiple loci associated with bladder cancer risk

Author: Núria Malats, Paul Brenan, Chancellor Hohensee, M. Rouprêt, Manolis Kogevinas, Nilanjan Chatterjee, Ruth C. Travis, Gerald L. Andriole, Rebecca Rodabough, Jarmo Virtamo, Amanda Black, H. Barton Grossman, Angela Carta, Robert L. Grubb, William Wheeler, David J. Hunter, Jennifer Prescott, Manuela Gago-Dominguez, Jian Gu, Wei Tang, Dalsu Baris, Afshan Siddiq, Karla R. Armenti, Nathaniel Rothman, Mark P. Purdue, Eva Compérat, Demetrius Albanes, Christopher A. Haiman, Zhaoming Wang, Dimitrios Trichopoulos, Françoise Clavel-Chapelon, Debra T. Silverman, Colin P.N. Dinney, David Van Den Berg, H. Bas Bueno-de-Mesquita, Xia Pu, W. Ryan Diver, Peter Kraft, Reina García-Closas, Stephanie J. Weinstein, Stephen J. Chanock, Edward Giovannucci, Neil E. Caporaso, Vittorio Krogh, Jonine D. Figueroa, Joseph F. Fraumeni, Molly Schwenn, Olivier Cussenot, Ashish M. Kamat, Charles C. Chung, Elio Riboli, Victoria K. Cortessis, Immaculata De Vivo, Stefano Porru, Consol Serra, Laurie Burdette, Xiang Deng, Miren Dorronsoro, Anne Tjønneland, Sara Lindström, Seth P. Lerner, Cecilia Arici, Alison Johnson, Josep Lloreta, Amy Hutchinson, Jie Lin, Margaret R. Karagas, Malcolm C. Pike, Elisabete Weiderpass, Maria Teresa Landi, Susan M. Gapstur, Yuanqing Ye, Montserrat Garcia-Closas, Börje Ljungberg, G. M. Hosain, G. Cancel-Tassin, Paolo Vineis, Adonina Tardón, Giuseppe Mastrangelo, Eric J. Jacobs, Mariana C. Stern, Jian-Min Yuan, Xifeng Wu, Constance Chen, Jenny Chang-Claude, Ludmila Prokunina-Olsson, David V. Conti, Sofia Pavanello, Alfredo Carrato, Charles Kooperberg, Simone Benhamou, and Alan R. Schned
Subjects: Risk, medicine.medical_specialty, Linkage disequilibrium, Genotype, Genomics, Genome-wide association study, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Meta-Analysis as Topic, Genetics, medicine, Humans, Genetic Predisposition to Disease, Association Studies Article, Molecular Biology, Genetics (clinical), Genetic association, Bladder cancer, Case-control study, General Medicine, medicine.disease, 3. Good health, Urinary Bladder Neoplasms, Genetic Loci, Case-Control Studies, Medical genetics, Genome-Wide Association Study
Abstract: Candidate gene and genome-wide association studies (GWAS) have identified 11 independent susceptibility loci associated with bladder cancer risk. To discover additional risk variants, we conducted a new GWAS of 2422 bladder cancer cases and 5751 controls, followed by a meta-analysis with two independently published bladder cancer GWAS, resulting in a combined analysis of 6911 cases and 11 814 controls of European descent. TaqMan genotyping of 13 promising single nucleotide polymorphisms with P < 1 × 10(-5) was pursued in a follow-up set of 801 cases and 1307 controls. Two new loci achieved genome-wide statistical significance: rs10936599 on 3q26.2 (P = 4.53 × 10(-9)) and rs907611 on 11p15.5 (P = 4.11 × 10(-8)). Two notable loci were also identified that approached genome-wide statistical significance: rs6104690 on 20p12.2 (P = 7.13 × 10(-7)) and rs4510656 on 6p22.3 (P = 6.98 × 10(-7)); these require further studies for confirmation. In conclusion, our study has identified new susceptibility alleles for bladder cancer risk that require fine-mapping and laboratory investigation, which could further understanding into the biological underpinnings of bladder carcinogenesis.
Published: 2014

48. Genome-wide interaction study of smoking and bladder cancer risk

Author: Manolis Kogevinas, Paul Brenan, Sofia Pavanello, Zhaoming Wang, Françoise Clavel-Chapelon, Ruth C. Travis, Debra T. Silverman, Mark P. Purdue, Immaculata De Vivo, Mariana C. Stern, Constance Chen, Joseph F. Fraumeni, Anne Tjønneland, Olivier Cussenot, Charles Kooperberg, Alan Schned, Manuela Gago-Dominguez, David Van Den Berg, Eric J. Jacobs, Chancellor Hohensee, Margaret R. Karagas, Jian-Min Yuan, Simone Benhamou, Nilanjan Chatterjee, Jenny Chang-Claude, Ludmila Prokunina-Olsson, Christopher A. Haiman, Dimitrios Trichopoulos, Jennifer Prescott, William Wheeler, David J. Hunter, Vittorio Krogh, Jonine D. Figueroa, Alison Johnson, Cecilia Arici, Dalsu Baris, David V. Conti, Geraldine Cancel-Tassin, Paolo Vineis, Edward Giovannucci, Eva Comperat, Laurie Burdette, Peter Kraft, Afshan Siddiq, Neil E. Caporaso, Montserrat Garcia-Closas, Núria Malats, Elio Riboli, Victoria K. Cortessis, G. M. Monawar Hosain, Angela Carta, Karla R. Armenti, Morgan Rouprêt, Elisabete Weiderpass, H. Bas Bueno-de-Mesquita, Stephen J. Chanock, Stefano Porru, Summer S. Han, Nathaniel Rothman, Börje Ljungberg, Molly Schwenn, Malcolm C. Pike, Rebecca J. Rodabough, Sara Lindström, Giuseppe Mastrangelo, Amy Hutchinson, Maria Teresa Landi, and Miren Dorronsoro
Subjects: Oncology, Adult, medicine.medical_specialty, Cancer Research, Genome-wide association study, Single-nucleotide polymorphism, Original Manuscript, Bioinformatics, Polymorphism, Single Nucleotide, Meta-Analysis as Topic, Risk Factors, Internal medicine, medicine, Biomarkers, Tumor, SNP, Bladder cancer, Gene-environment interaction, Humans, Genetic Predisposition to Disease, Gene–environment interaction, business.industry, Genome, Human, fungi, Smoking, Case-control study, Cancer, General Medicine, Odds ratio, medicine.disease, Prognosis, Urinary Bladder Neoplasms, Case-Control Studies, Gene-Environment Interaction, business
Abstract: Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10(-) (5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 × 10(-) (7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 × 10(-) (7)). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.
Published: 2014

49. Pesticide exposure and inherited variants in vitamin d pathway genes in relation to prostate cancer

Author: Jane A. Hoppin, Meredith Yeager, Lee E. Moore, Laurie Burdette, Aaron Blair, Laura E. Beane Freeman, Kathryn Hughes Barry, Summer S. Han, Dale P. Sandler, Sara Karami, Gabriella Andreotti, Stella Koutros, Jay H. Lubin, Michael C. R. Alavanja, and Jeffrey Yuenger
Subjects: Oncology, Male, medicine.medical_specialty, Genotype, Epidemiology, Single-nucleotide polymorphism, Apoptosis, Cell Growth Processes, Biology, medicine.disease_cause, Calcitriol receptor, Polymorphism, Single Nucleotide, Article, Cohort Studies, Prostate cancer, Risk Factors, Internal medicine, Surveys and Questionnaires, medicine, Vitamin D and neurology, Humans, Pesticides, Vitamin D, Aged, Aged, 80 and over, Case-control study, Prostatic Neoplasms, Odds ratio, Middle Aged, medicine.disease, United States, Endocrinology, Case-Control Studies, Carcinogenesis
Abstract: Background: Vitamin D and its metabolites are believed to impede carcinogenesis by stimulating cell differentiation, inhibiting cell proliferation, and inducing apoptosis. Certain pesticides have been shown to deregulate vitamin D's anticarcinogenic properties. We hypothesize that certain pesticides may be linked to prostate cancer via an interaction with vitamin D genetic variants. Methods: We evaluated interactions between 41 pesticides and 152 single-nucleotide polymorphisms (SNP) in nine vitamin D pathway genes among 776 prostate cancer cases and 1,444 male controls in a nested case–control study of Caucasian pesticide applicators within the Agricultural Health Study. We assessed Pinteraction values using likelihood ratio tests from unconditional logistic regression and a false discovery rate (FDR) to account for multiple comparisons. Results: Five significant interactions (P < 0.01) displayed a monotonic increase in prostate cancer risk with individual pesticide use in one genotype and no association in the other. These interactions involved parathion and terbufos use and three vitamin D genes (VDR, RXRB, and GC). The exposure–response pattern among participants with increasing parathion use with the homozygous CC genotype for GC rs7041 compared with unexposed participants was noteworthy [low vs. no exposure: OR, 2.58, 95% confidence interval (CI), 1.07–6.25; high vs. no exposure: OR, 3.09, 95% CI, 1.10–8.68; Pinteraction = 3.8 × 10−3]. Conclusions: In this study, genetic variations in vitamin D pathway genes, particularly GC rs7041, an SNP previously linked to lower circulating vitamin D levels, modified pesticide associations with prostate cancer risk. Impact: Because our study is the first to examine this relationship, additional studies are needed to rule out chance findings. Cancer Epidemiol Biomarkers Prev; 22(9); 1557–66. ©2013 AACR.
Published: 2013

50. Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations

Author: Sharon A. Savage, Xiaohong R. Yang, William Wheeler, Stephen J. Chanock, Paula L. Hyland, Laura S. Burke, Margaret A. Tucker, Ruth M. Pfeiffer, Alisa M. Goldstein, Lisa Mirabello, Laurie Burdette, Jennifer Prescott, Meredith Yeager, and Immaculata De Vivo
Subjects: Oncology, Male, Melanomas, Skin Neoplasms, Epidemiology, lcsh:Medicine, CDKN2A, Genotype, lcsh:Science, Melanoma, Multidisciplinary, Pigmentation, Chromosome Biology, Cancer Risk Factors, Genomics, Middle Aged, Telomere, Phenotype, Telomeres, Genetic Epidemiology, Sunlight, Medicine, Female, Epigenetics, Cancer Epidemiology, Research Article, Adult, medicine.medical_specialty, Single-nucleotide polymorphism, Malignant Skin Neoplasms, Dermatology, Biology, Polymorphism, Single Nucleotide, Germline mutation, Internal medicine, medicine, Genetics, Cancer Genetics, Humans, Genetic Predisposition to Disease, Allele, neoplasms, Cyclin-Dependent Kinase Inhibitor p16, Germ-Line Mutation, lcsh:R, Cancers and Neoplasms, medicine.disease, Cutaneous melanoma, Immunology, Mutation, Genetics of Disease, lcsh:Q
Abstract: INTRODUCTION: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. MATERIALS AND METHODS: We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. RESULTS: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02-7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. DISCUSSION: Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk.
Published: 2013

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