438 results on '"Maria Teresa Landi"'
Search Results
102. Supplementary Data from MicroRNA Expression Differentiates Histology and Predicts Survival of Lung Cancer
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Ena Wang, Lisa M. McShane, Neil E. Caporaso, Angela C. Pesatori, Pier Alberto Bertazzi, Margaret A. Tucker, Francesco M. Marincola, Ilona Linnoila, Alisa M. Goldstein, Maurizia Rubagotti, Andrew W. Bergen, Hui Liu, Jill Koshiol, Melissa Rotunno, Yingdong Zhao, and Maria Teresa Landi
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Supplementary Data from MicroRNA Expression Differentiates Histology and Predicts Survival of Lung Cancer
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- 2023
103. Data from A Novel Pathway-Based Approach Improves Lung Cancer Risk Prediction Using Germline Genetic Variations
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Christopher I. Amos, Daniela Seminara, Maria Teresa Landi, John R. McLaughlin, Rayjean J. Hung, Hae Ri Shin, Jinyoung Byun, Younghun Han, and David C. Qian
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Background: Although genome-wide association studies (GWAS) have identified many genetic variants that are strongly associated with lung cancer, these variants have low penetrance and serve as poor predictors of lung cancer in individuals. We sought to increase the predictive value of germline variants by considering their cumulative effects in the context of biologic pathways.Methods: For individuals in the Environment and Genetics in Lung Cancer Etiology study (1,815 cases/1,971 controls), we computed pathway-level susceptibility effects as the sum of relevant SNP variant alleles weighted by their log-additive effects from a separate lung cancer GWAS meta-analysis (7,766 cases/37,482 controls). Logistic regression models based on age, sex, smoking, genetic variants, and principal components of pathway effects and pathway–smoking interactions were trained and optimized in cross-validation and further tested on an independent dataset (556 cases/830 controls). We assessed prediction performance using area under the receiver operating characteristic curve (AUC).Results: Compared with typical binomial prediction models that have epidemiologic predictors (AUC = 0.607) in addition to top GWAS variants (AUC = 0.617), our pathway-based smoking-interactive multinomial model significantly improved prediction performance in external validation (AUC = 0.656, P < 0.0001).Conclusions: Our biologically informed approach demonstrated a larger increase in AUC over nongenetic counterpart models relative to previous approaches that incorporate variants.Impact: This model is the first of its kind to evaluate lung cancer prediction using subtype-stratified genetic effects organized into pathways and interacted with smoking. We propose pathway–exposure interactions as a potentially powerful new contributor to risk inference. Cancer Epidemiol Biomarkers Prev; 25(8); 1208–15. ©2016 AACR.
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- 2023
104. Supplemental Table 6 from Nut Consumption and Lung Cancer Risk: Results from Two Large Observational Studies
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Tram Kim Lam, Maria Teresa Landi, Neal D. Freedman, Angela C. Pesatori, Pier Alberto Bertazzi, Amy F. Subar, Linda M. Liao, Gabriel Y. Lai, and Jennifer T. Lee
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Hazard ratios (95% Confidence Intervals) for the lag analyses by 5 years and 10 years for lung cancer and nut consumption in AARP, by histologic subtypes
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- 2023
105. Supplementary Table 1 from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations
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Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer
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Variants selected for replication
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- 2023
106. Supplemental Table 4 from Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk
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Loïc Le Marchand, Christopher Amos, Daniel O. Stram, Sharon Murphy, Rayjean Hung, John McLaughlin, James McKay, Richard Houlston, Paul Brennan, David C. Christiani, Yongyue Wei, Angela Risch, Irene Brüske, Maria Teresa Landi, Neil Caporaso, Albert Rosenberger, Heike Bickeböller, Lynne R. Wilkens, Younghun Han, Sunghim L. Park, and Yesha M. Patel
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Results of the six overlapping globally significant associations (p < 5E-8) with lung cancer risk in TRICL and with CYP2A6 activtiy in MEC stratified by cell type.
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- 2023
107. Supplementary Material: Funding, Acknowledgements, Consortia, and Bioinformatics Tools Funding sources from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations
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Rayjean J. Hung, Brian E. Henderson, Christopher A. Haiman, David J. Hunter, Douglas F. Easton, Thomas A. Sellers, Christopher I. Amos, Stephen B. Gruber, Ulrike Peters, Jian Gong, Stephen J. Chanock, Daniela Seminara, Qiyuan Li, Matthew L. Freedman, Wim Timens, David Nickle, Ma'en Obeidat, Yohan Bossé, Atsushi Takahashi, Kouya Shiraishi, Xiao-Ou Shu, Zhibin Hu, Hongbing Shen, Yongyue Wei, David C. Christiani, Jonathan P. Tyrer, Y. Ann Chen, Patrick Sulem, Kari Stefansson, Simon N. Stacey, Julius Gudmundsson, Thorunn Rafnar, Michael O. Woods, Stephen N. Thibodeau, Stephanie L. Schmit, Noralene M. Lindor, Li Li, Loïc Le Marchand, Mark Jenkins, Robert W. Haile, Steven Gallinger, Christopher K. Edlund, David V. Conti, Graham Casey, Daniel D. Buchanan, Wei Zheng, Xiaohong R. Yang, Alice S. Whittemore, Zhaoming Wang, Andre G. Uitterlinden, Clare Turnbull, Ruth C. Travis, Rulla Tamimi, Melissa C. Southey, Rita K. Schmutzler, Daniel F. Schmidt, Maria Jose Sanchez, Nazneen Rahman, Ross L. Prentice, Julian Peto, Petra H. Peeters, Heli Nevanlinna, Taru A. Muranen, Bertram Müller-Myhsok, Alfons Meindl, Enes Makalic, Eiliv Lund, Jianjun Liu, Peter Lichtner, Muhammad G. Kibriya, Rudolf Kaaks, Mattias Johansson, Astrid Irwanto, John L. Hopper, Albert Hofman, Rebecca Hein, Aditi Hazra, Per Hall, Nichola Johnson, Mia M. Gaudet, Montserrat Garcia-Closas, Olivia Fletcher, Dieter Flesch-Janys, Jonine D. Figueroa, A. Heather Eliassen, Isabel dos-Santos-Silva, Kamila Czene, Federico Canzian, Carl Blomquist, Laura Baglietto, Kristiina Aittomäki, Habibul Ahsan, Muriel A. Adank, Emily White, Martha L. Slattery, Robert E. Schoen, Polly A. Newcomb, Jonathan K. Kocarnik, Thomas J. Hudson, Jenny Chang-Claude, Andrew T. Chan, Hermann Brenner, Stephane Bezieau, Brett M. Reid, Harvey A. Risch, Jennifer B. Permuth, Ellen L. Goode, Walter C. Willett, Fredrik Wiklund, Victoria L. Stevens, Meir J. Stampfer, Kenneth Muir, Jing Ma, Zsofia Kote-Jarai, Henrik Grönberg, Edward L. Giovannucci, Sonja I. Berndt, Ali Amin Al Olama, Angela Risch, Neil Caporaso, Maria Teresa Landi, Richard S. Houlston, Heike Bickeböller, Paul Brennan, Sara Lindström, Joellen M. Schildkraut, Fredrick R. Schumacher, Nilanjan Chatterjee, Rosalind A. Eeles, Paul D. Pharoah, Peter Kraft, and Gordon Fehringer
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Funding sources, acknowledgements, consortia involved in study and bioinformatics tools used
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- 2023
108. Supplementary Table 1 from Intakes of Red Meat, Processed Meat, and Meat Mutagens Increase Lung Cancer Risk
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Maria Teresa Landi, Amy F. Subar, Rashmi Sinha, Neil E. Caporaso, Pier Alberto Bertazzi, Vincenzo Bagnardi, Giorgia Randi, Dario Consonni, Amanda J. Cross, and Tram Kim Lam
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Supplementary Table 1 from Intakes of Red Meat, Processed Meat, and Meat Mutagens Increase Lung Cancer Risk
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- 2023
109. Supplementary Methods from Genetic Determinants for Promoter Hypermethylation in the Lungs of Smokers: A Candidate Gene-Based Study
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Steven A. Belinsky, Frank D. Gilliland, Yohannes Tesfaigzi, Jill M. Siegfried, Christopher I. Amos, Neil E. Caporaso, David Van Den Berg, Richard E. Crowell, Shannon E. Bruse, Maria A. Picchi, Michael Thun, Maria Teresa Landi, Younghun Han, Randall P. Willink, Christopher K. Edlund, Yushi Liu, Christine A. Stidley, and Shuguang Leng
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PDf file - 81K
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- 2023
110. Supplementary Table 2 from Intakes of Red Meat, Processed Meat, and Meat Mutagens Increase Lung Cancer Risk
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Maria Teresa Landi, Amy F. Subar, Rashmi Sinha, Neil E. Caporaso, Pier Alberto Bertazzi, Vincenzo Bagnardi, Giorgia Randi, Dario Consonni, Amanda J. Cross, and Tram Kim Lam
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Supplementary Table 2 from Intakes of Red Meat, Processed Meat, and Meat Mutagens Increase Lung Cancer Risk
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- 2023
111. Supplementary Tables 1-3, Figure 1 from Genetic Determinants for Promoter Hypermethylation in the Lungs of Smokers: A Candidate Gene-Based Study
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Steven A. Belinsky, Frank D. Gilliland, Yohannes Tesfaigzi, Jill M. Siegfried, Christopher I. Amos, Neil E. Caporaso, David Van Den Berg, Richard E. Crowell, Shannon E. Bruse, Maria A. Picchi, Michael Thun, Maria Teresa Landi, Younghun Han, Randall P. Willink, Christopher K. Edlund, Yushi Liu, Christine A. Stidley, and Shuguang Leng
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PDF file - 642K
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- 2023
112. Data from Intakes of Red Meat, Processed Meat, and Meat Mutagens Increase Lung Cancer Risk
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Maria Teresa Landi, Amy F. Subar, Rashmi Sinha, Neil E. Caporaso, Pier Alberto Bertazzi, Vincenzo Bagnardi, Giorgia Randi, Dario Consonni, Amanda J. Cross, and Tram Kim Lam
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Red and processed meat intake may increase lung cancer risk. However, the epidemiologic evidence is inconsistent and few studies have evaluated the role of meat mutagens formed during high cooking temperatures. We investigated the association of red meat, processed meat, and meat mutagen intake with lung cancer risk in Environment And Genetics in Lung cancer Etiology, a population-based case-control study. Primary lung cancer cases (n = 2,101) were recruited from 13 hospitals within the Lombardy region of Italy examining ∼80% of the cases from the area. Noncancer population controls (n = 2,120), matched to cases on gender, residence, and age, were randomly selected from the same catchment area. Diet was assessed in 1,903 cases and 2,073 controls and used in conjunction with a meat mutagen database to estimate intake of heterocyclic amines (HCA) and benzo(a)pyrene (BaP). Multivariable odds ratios (OR) and 95% confidence intervals (95% CI) for sex-specific tertiles of intake were calculated using unconditional logistic regression. Red and processed meat were positively associated with lung cancer risk (highest-versus-lowest tertile: OR, 1.8; 95% CI, 1.5–2.2; P trend < 0.001 and OR, 1.7; 95% CI, 1.4–2.1; P trend < 0.001, respectively); the risks were strongest among never smokers (OR, 2.4; 95% CI, 1.4–4.0; P trend = 0.001 and OR, 2.5; 95% CI, 1.5–4.2; P trend = 0.001, respectively). HCAs and BaP were significantly associated with increased risk of lung cancer. When separated by histology, significant positive associations for both meat groups were restricted to adenocarcinoma and squamous cell carcinoma but not small cell carcinoma of the lung. In summary, red meat, processed meat, and meat mutagens were independently associated with increased risk of lung cancer. [Cancer Res 2009;69(3):932–9]
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- 2023
113. Data from Genetic Determinants for Promoter Hypermethylation in the Lungs of Smokers: A Candidate Gene-Based Study
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Steven A. Belinsky, Frank D. Gilliland, Yohannes Tesfaigzi, Jill M. Siegfried, Christopher I. Amos, Neil E. Caporaso, David Van Den Berg, Richard E. Crowell, Shannon E. Bruse, Maria A. Picchi, Michael Thun, Maria Teresa Landi, Younghun Han, Randall P. Willink, Christopher K. Edlund, Yushi Liu, Christine A. Stidley, and Shuguang Leng
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The detection of tumor suppressor gene promoter methylation in sputum-derived exfoliated cells predicts early lung cancer. Here, we identified genetic determinants for this epigenetic process and examined their biologic effects on gene regulation. A two-stage approach involving discovery and replication was used to assess the association between promoter hypermethylation of a 12-gene panel and common variation in 40 genes involved in carcinogen metabolism, regulation of methylation, and DNA damage response in members of the Lovelace Smokers Cohort (N = 1,434). Molecular validation of three identified variants was conducted using primary bronchial epithelial cells. Association of study-wide significance (P < 8.2 × 10−5) was identified for rs1641511, rs3730859, and rs1883264 in TP53, LIG1, and BIK, respectively. These single-nucleotide polymorphisms (SNP) were significantly associated with altered expression of the corresponding genes in primary bronchial epithelial cells. In addition, rs3730859 in LIG1 was also moderately associated with increased risk for lung cancer among Caucasian smokers. Together, our findings suggest that genetic variation in DNA replication and apoptosis pathways impacts the propensity for gene promoter hypermethylation in the aerodigestive tract of smokers. The incorporation of genetic biomarkers for gene promoter hypermethylation with clinical and somatic markers may improve risk assessment models for lung cancer. Cancer Res; 72(3); 707–15. ©2011 AACR.
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- 2023
114. Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA
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Erik N. Bergstrom, Jens Luebeck, Mia Petljak, Azhar Khandekar, Mark Barnes, Tongwu Zhang, Christopher D. Steele, Nischalan Pillay, Maria Teresa Landi, Vineet Bafna, Paul S. Mischel, Reuben S. Harris, and Ludmil B. Alexandrov
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Genome ,Multidisciplinary ,INDEL Mutation ,Mutagenesis ,Neoplasms ,Mutation ,Humans ,APOBEC Deaminases - Abstract
Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions1–5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7–9. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer10. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.
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- 2022
115. Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer
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Jinyoung Byun, Younghun Han, Yafang Li, Jun Xia, Erping Long, Jiyeon Choi, Xiangjun Xiao, Meng Zhu, Wen Zhou, Ryan Sun, Yohan Bossé, Zhuoyi Song, Ann Schwartz, Christine Lusk, Thorunn Rafnar, Kari Stefansson, Tongwu Zhang, Wei Zhao, Rowland W. Pettit, Yanhong Liu, Xihao Li, Hufeng Zhou, Kyle M. Walsh, Ivan Gorlov, Olga Gorlova, Dakai Zhu, Susan M. Rosenberg, Susan Pinney, Joan E. Bailey-Wilson, Diptasri Mandal, Mariza de Andrade, Colette Gaba, James C. Willey, Ming You, Marshall Anderson, John K. Wiencke, Demetrius Albanes, Stephan Lam, Adonina Tardon, Chu Chen, Gary Goodman, Stig Bojeson, Hermann Brenner, Maria Teresa Landi, Stephen J. Chanock, Mattias Johansson, Thomas Muley, Angela Risch, H.-Erich Wichmann, Heike Bickeböller, David C. Christiani, Gad Rennert, Susanne Arnold, John K. Field, Sanjay Shete, Loic Le Marchand, Olle Melander, Hans Brunnstrom, Geoffrey Liu, Angeline S. Andrew, Lambertus A. Kiemeney, Hongbing Shen, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil Caporaso, Angela Cox, Yun-Chul Hong, Jian-Min Yuan, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Alpa Patel, Qing Lan, Nathaniel Rothman, Fiona Taylor, Linda Kachuri, John S. Witte, Lori C. Sakoda, Margaret Spitz, Paul Brennan, Xihong Lin, James McKay, Rayjean J. Hung, and Christopher I. Amos
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Lung Neoplasms ,Quantitative Trait Loci ,Human Genome ,RNA-Binding Proteins ,Single Nucleotide ,Biological Sciences ,Polymorphism, Single Nucleotide ,Medical and Health Sciences ,Article ,DNA-Binding Proteins ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Genetics ,Humans ,2.1 Biological and endogenous factors ,Genetic Predisposition to Disease ,Polymorphism ,Aetiology ,Lung ,Genome-Wide Association Study ,Cancer ,Developmental Biology - Abstract
To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.
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- 2022
116. Characterizing the tumor microenvironment in rare renal cancer histological types
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Scott M. Lawrence, Máire A. Duggan, Carla Azzurra Amoreo, Manuela Costantini, Giuseppe Simone, Mengying Li, Steno Sentinelli, Malgorzata Ewa Dabrowska, Maria Luana Poeta, Yelena G. Golubeva, Naoise C Synnott, Vito Michele Fazio, Mustapha Abubakar, Mary E. Olanich, Ruth M. Pfeiffer, Petra Lenz, Edoardo Pescarmona, Maria Teresa Landi, Karun Mutreja, and Michele Gallucci
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Pathology ,medicine.medical_specialty ,papillary renal cell carcinoma ,Pathology and Forensic Medicine ,Biomarkers, Tumor ,Humans ,tumor microenvironment ,RB1-214 ,Medicine ,Carcinoma, Renal Cell ,CD20 ,Tumor microenvironment ,Papillary renal cell carcinomas ,biology ,business.industry ,CD68 ,rare cancer ,Endothelial Cells ,kidney cancer ,Cancer ,Original Articles ,medicine.disease ,Kidney Neoplasms ,Tumor progression ,biology.protein ,Immunohistochemistry ,Original Article ,digital pathology ,business ,Kidney cancer - Abstract
The tumor microenvironment (TME), including immune cells, cancer‐associated fibroblasts, endothelial cells, adjacent normal cells, and others, plays a crucial role in influencing tumor behavior and progression. Here, we characterized the TME in 83 primary renal tumors and matched metastatic or recurrence tissue samples (n = 15) from papillary renal cell carcinoma (pRCC) types 1 (n = 20) and 2 (n = 49), collecting duct carcinomas (CDC; n = 14), and high‐grade urothelial carcinomas (HGUC; n = 5). We investigated 10 different markers of immune infiltration, vasculature, cell proliferation, and epithelial‐to‐mesenchymal transition by using machine learning image analysis in conjunction with immunohistochemistry. Marker expression was compared by Mann–Whitney and Kruskal–Wallis tests and correlations across markers using Spearman's rank correlation coefficient. Multivariable Poisson regression analysis was used to compare marker expression between histological types, while accounting for variation in tissue size. Several immune markers showed different rates of expression across histological types of renal carcinoma. Using pRCC1 as reference, the incidence rate ratio (IRR) of CD3+ T cells (IRR [95% confidence interval, CI] = 2.48 [1.53–4.01]) and CD20+ B cells (IRR [95% CI] = 4.38 [1.22–5.58]) was statistically significantly higher in CDC. In contrast, CD68+ macrophages predominated in pRCC1 (IRR [95% CI] = 2.35 [1.42–3.9]). Spatial analysis revealed CD3+ T‐cell and CD20+ B‐cell expressions in CDC to be higher at the proximal (p
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- 2021
117. Massively parallel reporter assays and variant scoring identified functional variants and target genes for melanoma loci and highlighted cell-type specificity
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Erping Long, Jinhu Yin, Karen M. Funderburk, Mai Xu, James Feng, Alexander Kane, Tongwu Zhang, Timothy Myers, Alyxandra Golden, Rohit Thakur, Hyunkyung Kong, Lea Jessop, Eun Young Kim, Kristine Jones, Raj Chari, Mitchell J. Machiela, Kai Yu, Mark M. Iles, Maria Teresa Landi, Matthew H. Law, Stephen J. Chanock, Kevin M. Brown, and Jiyeon Choi
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Skin Neoplasms ,Genetics ,Humans ,Biological Assay ,Melanoma ,Genetics (clinical) ,Article ,Genome-Wide Association Study ,Transcription Factors ,Receptors, G-Protein-Coupled - Abstract
The most recent genome-wide association study (GWAS) of cutaneous melanoma identified 54 risk-associated loci, but functional variants and their target genes for most have not been established. Here, we performed massively parallel reporter assays (MPRAs) by using malignant melanoma and normal melanocyte cells and further integrated multi-layer annotation to systematically prioritize functional variants and susceptibility genes from these GWAS loci. Of 1,992 risk-associated variants tested in MPRAs, we identified 285 from 42 loci (78% of the known loci) displaying significant allelic transcriptional activities in either cell type (FDR
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- 2022
118. Gene-Level Associations in Patients With and Without Pathogenic Germline Variants in
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Esteban, Astiazaran-Symonds, Cole, Graham, Jung, Kim, Margaret A, Tucker, Christian, Ingvar, Hildur, Helgadottir, Lorenza, Pastorino, Remco, van Doorn, Joshua N, Sampson, Bin, Zhu, William, Bruno, Paola, Queirolo, Giuseppe, Fornarini, Stefania, Sciallero, Brian, Carter, Belynda, Hicks, Amy, Hutchinson, Kristine, Jones, Douglas R, Stewart, Stephen J, Chanock, Neal D, Freedman, Maria Teresa, Landi, Veronica, Höiom, Susana, Puig, Nelleke, Gruis, Xiaohong R, Yang, Paola, Ghiorzo, and Alisa M, Goldstein
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Pancreatic Neoplasms ,Germ Cells ,Humans ,Genetic Predisposition to Disease ,Cyclin-Dependent Kinase Inhibitor p16 ,Carcinoma, Pancreatic Ductal ,Cyclin-Dependent Kinase Inhibitor Proteins - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) inWe analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with (In RVA tests,These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in
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- 2022
119. Time to first cigarette and its impact on lung tumorigenesis
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Tongwu Zhang, Jian Sang, Neil Caporaso, Fangyi Gu, Amy Hutchinson, Dario Consonni, Angela C. Pesatori, Robert Homer, Stephen Chanock, and Maria Teresa Landi
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Time to first cigarette (TTFC) in the morning has been identified as the best indicator of nicotine dependence and is associated with lung cancer risk beyond other measures of tobacco smoking. Using deep whole genome sequencing of 218 lung cancers from smokers, we show that TTFC is the strongest marker of tobacco smoking mutagenicity, with impact on lung tumor mutational burden, mutational signatures, intratumor heterogeneity,KRASmutations and overall survival. These results pave the way for using TTFC as an easily measurable marker of lung tumorigenesis, with plausible therapeutic and prognostic implications.
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- 2022
120. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor
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S.M. Ashiqul Islam, Marcos Díaz-Gay, Yang Wu, Mark Barnes, Raviteja Vangara, Erik N. Bergstrom, Yudou He, Mike Vella, Jingwei Wang, Jon W. Teague, Peter Clapham, Sarah Moody, Sergey Senkin, Yun Rose Li, Laura Riva, Tongwu Zhang, Andreas J. Gruber, Christopher D. Steele, Burçak Otlu, Azhar Khandekar, Ammal Abbasi, Laura Humphreys, Natalia Syulyukina, Samuel W. Brady, Boian S. Alexandrov, Nischalan Pillay, Jinghui Zhang, David J. Adams, Iñigo Martincorena, David C. Wedge, Maria Teresa Landi, Paul Brennan, Michael R. Stratton, Steven G. Rozen, and Ludmil B. Alexandrov
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cancer genomics ,Tobacco Smoke and Health ,Prevention ,Human Genome ,mutational signatures ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Good Health and Well Being ,ddc:570 ,Tobacco ,genomics ,Genetics ,mutagenesis ,Cancer ,Biotechnology - Abstract
Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues. published
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- 2022
121. A UVB-responsive common variant at chromosome band 7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor, AHR
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Lea Jessop, Rebecca C Hennessey, Andrew D. Wells, Alessandra Chesi, Matthew Law, Glenn Merlino, Michael A. Kovacs, Matthew E. Johnson, Stephen J. Chanock, Ashley Jermusyk, Hayley Sowards, Herbert Higson, Tongwu Zhang, Patricia Bunda, Mark M. Iles, Maria Teresa Landi, Jiyeon Choi, Kristine Jones, Raj Chari, Alisa M. Goldstein, Rohit Thakur, Lindsey Mehl, Kevin M. Brown, Helen T. Michael, Mai Xu, Struan F.A. Grant, and Timothy G. Myers
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Polychlorinated Dibenzodioxins ,Skin Neoplasms ,Carcinogenesis ,Ultraviolet Rays ,Primary Cell Culture ,Locus (genetics) ,Genome-wide association study ,Polymorphism, Single Nucleotide ,Article ,Basic Helix-Loop-Helix Transcription Factors ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Promoter Regions, Genetic ,Melanoma ,Alleles ,Genetics (clinical) ,Sunbathing ,integumentary system ,biology ,Genome, Human ,Cell growth ,Environmental exposure ,Aryl hydrocarbon receptor ,medicine.disease ,Phenotype ,Chromatin ,Gene Expression Regulation ,Receptors, Aryl Hydrocarbon ,Genetic Loci ,Carcinoma, Squamous Cell ,biology.protein ,Cancer research ,Melanocytes ,Chromosomes, Human, Pair 7 ,Genome-Wide Association Study - Abstract
Genome-wide association studies (GWASs) have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). Because ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWASs identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. Because AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 introduced via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression and altering melanocyte growth phenotypes upon exposure.
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- 2021
122. Genomic and evolutionary classification of lung cancer in never smokers
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Bin Zhu, Rachel Lokanga, Natalie Saini, Francisco Martínez-Jiménez, Jung Kim, Kevin M. Brown, Laura Mendoza, Kerstin Heselmeyer-Haddad, Andrea Castro, Mengying Li, Amy Hutchinson, Burcak Otlu, Aaron L Moye, Lucia Anna Muscarella, Nathan Cole, Michael Kebede, Neil E. Caporaso, Scott M. Lawrence, Paul Hofman, Dario Consonni, Manuela Costantini, Naser Ansari-Pour, Hannah Carter, Jonas S Almeida, Yohan Bossé, Maria Luana Poeta, Jian Sang, Bonnie E. Gould Rothberg, Mary E. Olanich, Maria Teresa Landi, Philippe Joubert, Jennifer Rosenbaum, Azhar Khandekar, Thomas Ried, Angela Cecilia Pesatori, Qing Lan, Carla F. Kim, Jiyeon Choi, Douglas R. Stewart, Samuel H. Wilson, Dmitry A. Gordenin, Abel Gonzalez-Perez, Tongwu Zhang, Petra Lenz, Montserrat Garcia-Closas, Nuria Lopez-Bigas, David C. Wedge, Daniela Hirsch, Praphulla M S Bhawsar, Matthew B. Schabath, Yves Pommier, Jianxin Shi, Nathaniel Rothman, Ludmil B. Alexandrov, Máire A. Duggan, S M Ashiqul Islam, Iliana Peneva, Stephen J. Chanock, Wei Zhao, Phuc H Hoang, and Leszek J. Klimczak
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Adult ,Male ,Lung Neoplasms ,DNA Copy Number Variations ,Somatic cell ,Genome-wide association study ,Ubiquitin-Activating Enzymes ,Biology ,medicine.disease_cause ,Article ,Germline ,Proto-Oncogene Proteins p21(ras) ,Young Adult ,Risk Factors ,Genetics ,medicine ,Humans ,Progenitor cell ,Lung cancer ,Aged ,Aged, 80 and over ,Smokers ,Genome ,Whole Genome Sequencing ,Smoking ,Cancer ,Non-Smokers ,Middle Aged ,medicine.disease ,Telomere ,ErbB Receptors ,Receptors, Androgen ,Neoplastic Stem Cells ,Cancer research ,Female ,KRAS ,Genome-Wide Association Study - Abstract
Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.
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- 2021
123. Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family
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Jung Kim, Ketty Peris, Kristie Jones, Eduardo Nagore, Alex Stratigos, Paola Ghiorzo, Bin Zhu, Kevin M. Brown, Belynda Hicks, Mai Xu, Hyunbum Jang, Donato Calista, Dario Consonni, Laura Mendoza, Ruth Nussinov, Douglas R. Stewart, Maria Teresa Landi, Xiaohong Rose Yang, Mingzhen Zhang, Nicholas K. Hayward, Thorkell Andresson, Chiara Menin, Maria Concetta Fargnoli, Michael R. Sargen, Alisa M. Goldstein, Margaret A. Tucker, Susana Puig, Angela Cecilia Pesatori, and Tongwu Zhang
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MAPK/ERK pathway ,Proto-Oncogene Proteins B-raf ,Neuroblastoma RAS viral oncogene homolog ,Cancer Research ,Skin Neoplasms ,Familial cancer ,In vitro characterization ,Melanoma ,Molecular modeling ,NRAS gene ,Rare variant ,GTPase ,Biology ,Article ,Germline ,GTP Phosphohydrolases ,Phosphatidylinositol 3-Kinases ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Gene ,Protein kinase B ,Germ-Line Mutation ,Genetics (clinical) ,Exome sequencing ,Membrane Proteins ,medicine.disease ,Human genetics ,Oncology ,Cancer research ,Guanosine Triphosphate ,Settore MED/35 - MALATTIE CUTANEE E VENEREE ,Proto-Oncogene Proteins c-akt - Abstract
While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations, we identified a novel NRAS variant (c.170A>C, p.D57A) in a melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11 273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2+ binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A>C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.
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- 2021
124. Abstract 5909: Characterization of the lung cancer microbiome using whole genome sequencing
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John McElderry, Tongwu Zhang, Jianxin Shi, and Maria Teresa Landi
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Cancer Research ,Oncology - Abstract
Microbiome studies have been rapidly increasing over the last decade, providing valuable insights into the commensal bacterial contribution to human physiology and disease, including human cancer. Many studies have demonstrated the important roles of the microbiome in cancer progression, anti-tumor immunity, resistance to therapies, metastasis formation, and in some rare cases even cancer development through the production of genotoxins. However, relatively few studies have analyzed the lung cancer microbiome, and both its composition and role in cancer progression are largely unknown. To characterize the microbiome of tumor and matched normal lung tissues, we performed whole-genome sequencing (WGS) in 872 never smokers using the Kraken pipeline. At the phylum level, WGS analyses of tumor and normal samples showed predominantly Proteobacteria and Actinobacteria (58% and 32%, respectively). Notably, we found overall similar microbiome composition in tumor and normal lung tissue samples. At the genus level, Cutibacterium, Klebsiella, Pseudomonas, Sphingomonas, Staphylococcus, and Acinetobacter genera were among the most abundant bacteria in tumor and normal tissues, alike, and the genera Prevotella, Corynebacterium, and Streptococcus were more abundant in tumor samples compared to normal lung tissue. Comparison of alpha diversity at the genus level between tumors and normal samples showed no substantial difference. We are currently investigating whether the microbiome composition varies by lung tumor anatomical location, sex, histology, study subjects’ geographical location, and immune microenvironment. We will also investigate whether the tumor microbiome composition varies in relation to important genomic features, like cancer driver genes and mutational signatures. Finally, we have 16s rRNA seq data from 771 tumor and normal lung tissues from never smokers and we will compare bacterial microbiome composition and diversity based on WGS and 16s rRNA seq for the same samples. This study, based on the largest analysis of lung microbiome to date, is poised to provide important insights into the role of commensal microbiota in shaping lung tumor development and progression. Citation Format: John McElderry, Tongwu Zhang, Jianxin Shi, Maria Teresa Landi. Characterization of the lung cancer microbiome using whole genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5909.
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- 2023
125. Abstract 1166: APOBEC deaminases compete with tobacco smoking mutagenesis and affect age at onset of lung cancer
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Tongwu Zhang, Jian Sang, Phuc H. Hoang, Wei Zhao, Jennifer Rosenbaum, Leszek J. Klimczak, John McElderry, Alyssa Klein, Christopher Wirth, Erik N. Bergstrom, Marcos Díaz-Gay, Raviteja Vangara, Amy Hutchinson, Scott M. Lawrence, Nathan Cole, Bin Zhu, Teresa M. Przytycka, Jianxin Shi, Neil E. Caporaso, Robert Homer, Angela C. Pesatori, Dario Consonni, Stephen J. Chanock, David C. Wedge, Dmitry A. Gordenin, Ludmil B. Alexandrov, Reuben S. Harris, and Maria Teresa Landi
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Cancer Research ,Oncology - Abstract
APOBEC enzymes are part of the innate immunity and are responsible for restricting viruses and retroelements by deaminating cytosine residues. Most solid tumors harbor different levels of somatic mutations attributed to the off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B interact with exogenous mutagenic processes in shaping tumor development is largely unknown. Here, by combining deep whole-genome sequencing with multi-omics profiling of 309 lung cancers from smokers with detailed tobacco smoking information, we identify two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations, whereas HAS for A3A-like mutagenesis and TP53 mutations. Unlike APOBEC3A, APOBEC3B expression is strongly associated with an upregulation of the base excision repair pathway. Hypermutation by unrepaired A3A and tobacco smoking mutagenesis combined with TP53-induced genomic instability can trigger senescence, apoptosis, and cell regeneration, as indicated by telomere shortening, high expression of pulmonary healing signaling pathway and stemness markers in HAS. The expected association of tobacco smoking exposure with genomic/epigenomic changes are not observed in HAS, a plausible consequence of frequent cell senescence or apoptosis. HAS tumors have slower clonal expansion and older age at onset compared to LAS, particularly in heavy smokers, consistent with high proportions of newly generated, unmutated cells in HAS. These findings show how heterogeneity in mutational burden across competing mutational processes and cell types contributes to tumor development, with important clinical implications. Citation Format: Tongwu Zhang, Jian Sang, Phuc H. Hoang, Wei Zhao, Jennifer Rosenbaum, Leszek J. Klimczak, John McElderry, Alyssa Klein, Christopher Wirth, Erik N. Bergstrom, Marcos Díaz-Gay, Raviteja Vangara, Amy Hutchinson, Scott M. Lawrence, Nathan Cole, Bin Zhu, Teresa M. Przytycka, Jianxin Shi, Neil E. Caporaso, Robert Homer, Angela C. Pesatori, Dario Consonni, Stephen J. Chanock, David C. Wedge, Dmitry A. Gordenin, Ludmil B. Alexandrov, Reuben S. Harris, Maria Teresa Landi. APOBEC deaminases compete with tobacco smoking mutagenesis and affect age at onset of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1166.
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- 2023
126. Abstract 2088: gCNV-Seeker: A comprehensive germline CNV calling pipeline based on whole genome sequencing data
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Jian Sang, Tongwu Zhang, David Wedge, and Maria Teresa Landi
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Cancer Research ,Oncology - Abstract
Germline Copy Number Variation (gCNV) is a type of genomic structural alteration including deletion or duplication of small genomic regions (50bp to 1MB) and can have an important role into cancer etiology. Whole genome sequencing (WGS) has been considered to be the most effective technology for genome-wide identification of gCNVs. However, an easy-to-use gCNV calling pipeline based on WGS data is still lacking. Here, we present the gCNV-Seeker, a user-friendly, rigorous computational pipeline to detect gCNV events based on WGS with standardized quality control and data visualization features. gCNV-Seeker initially adopts GATK probabilistic algorithms to detect a set of raw gCNV events and subsequently applies Binary Segmentation and Pruned Exact Linear Time (PELT) algorithms for re-segmentation and boundary revision of the gCNV candidates, respectively. In addition, gCNV-Seeker is built with several functionalities, including quality control, filtration, annotation and visualization to identify the gCNV regions (gCNVRs) of interest. We applied gCNV-Seeker to the WGS data from 872 lung cancers in never smokers from the Sherlock-Lung study and 3202 WGS data from the 1000 Genomes Project (1KGP) (reference) and identified CNVRs associated with lung cancer risk in never smokers. For example, in comparison to WGS data from 1KGP, we identified several CNVR candidates overlapping with known LC susceptible genes, e.g., the GSTM1/2 homozygous deletion (OR = 1.64, 95% CI=1.43-1.88, P < 0.01) and CYP2A6/7 homozygous or heterozygous deletion (OR = 1.59, 95% CI=1.24-2.03, P < 0.01). To evaluate its performance, we also carried out a comprehensive comparison of gCNV calling results between gCNV-Seeker and the 1KGP structural variant calling pipelines (PMID: 36055201) for common gCNVRs in the 1KGP WGS data. gCNV-Seeker showed a significant improvement on specificity and sensitivity for gCNVR detection compared with the 1KGP pipeline. In terms of specificity, 1315 out of 2692 (HGSV_9692) GSTM1/2 heterozygous deletion events (48.85%) originally identified by 1KGP were detected as homozygous deletions by gCNV-Seeker. These results were further confirmed by manual check. In terms of sensitivity, gCNV-Seeker detected total 299 deletion events in CYP2A6/7 regions, which were also manually confirmed. This corresponds to an increase of 48.02% compared to the 202 deletion events (HGSV_232739 & HGSV_232740) originally identified by the 1KGP pipeline. gCNV-Seeker will be a publicly available cross-platform (Linux and IOS) pipeline accessible in GitHub. Citation Format: Jian Sang, Tongwu Zhang, David Wedge, Maria Teresa Landi. gCNV-Seeker: A comprehensive germline CNV calling pipeline based on whole genome sequencing data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2088.
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- 2023
127. Abstract 5722: The mutational signatures of 100,477 targeted sequenced tumors
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Donghyuk Lee, Min Hua, Difei Wang, Lei Song, Tongwu Zhang, Kai Yu, Xiaohong R. Yang, Jianxin Shi, Stephen J. Chanock, Maria Teresa Landi, and Bin Zhu
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Cancer Research ,Oncology - Abstract
Mutational signatures, the footprints of somatic mutations, are associated with the causes of cancer and have been well-studied for tumors with whole exome or genome sequencing. However, due to the low number of detected mutations, mutational signatures were insufficiently explored for many tumors sequenced by targeted panels in clinics. It impedes the clinical application of mutational signatures. Here, we present a new method, SALMON (Signature Analyzer for Low Mutation cOuNts), to identify mutational signatures in targeted sequenced tumors based on tumor mutational burden. SALMON adjusts for panel size differences and uses a large number of targeted sequenced tumors rather than a large number of mutations per tumor (as with whole exome or genome sequencing) to overcome the challenges of mutational signature analysis for targeted sequencing. Extensive simulations and pseudo-targeted sequenced data show that SALMON can accurately detect spiky or common signatures. We applied SALMON to investigate the pan-cancer patterns of mutational signatures for 100,477 targeted sequenced tumors in AACR Project GENIE, including 14,428 lung and 11,389 breast tumors. We detected well-established signatures in tumor types that have not previously been associated with these signatures, such as the smoking signature in ovarian tumors. Interestingly, analysis of thousands of tumors per cancer type from diverse populations revealed gender discrepancies, self-described race differences, subtype heterogeneity, and metastatic enrichment of mutational signatures. For instance, most sex-biased signatures are more frequently present in males for non-gender-specific cancers. Thiopurine treatment-induced signature in glioma is enriched in Black patients. And endometrioid ovarian or uterine cancers have a higher prevalence of polymerase epsilon (POLE) deficiency-related signatures than non-endometrioid ovarian or uterine cancers, respectively. Our study demonstrates the feasibility and utility of mutational signature analysis for targeted sequenced tumors, enabling precision applications of mutational signatures in the clinical setting. Citation Format: Donghyuk Lee, Min Hua, Difei Wang, Lei Song, Tongwu Zhang, Kai Yu, Xiaohong R. Yang, Jianxin Shi, Stephen J. Chanock, Maria Teresa Landi, Bin Zhu. The mutational signatures of 100,477 targeted sequenced tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5722.
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- 2023
128. A Robust Test for Additive Gene-Environment Interaction Under the Trend Effect of Genotype Using an Empirical Bayes-Type Shrinkage Estimator
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Nilotpal Sanyal, Nilanjan Chatterjee, Valerio Napolioni, Michael E. Belloy, Michael D. Greicius, Neil E. Caporaso, Maria Teresa Landi, Summer S. Han, and Matthieu de Rochemonteix
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Shrinkage estimator ,Lung Neoplasms ,Genotype ,Statistical assumption ,Practice of Epidemiology ,Epidemiology ,Apolipoprotein E4 ,Empirical Research ,Polymorphism, Single Nucleotide ,Bayes' theorem ,Alzheimer Disease ,Risk Factors ,Genetic model ,Statistics ,Humans ,Genetic Predisposition to Disease ,Independence (probability theory) ,Retrospective Studies ,Statistical hypothesis testing ,Mathematics ,Likelihood Functions ,Models, Statistical ,Smoking ,Estimator ,Bayes Theorem ,Gene-Environment Interaction ,Type I and type II errors - Abstract
Evaluating gene by environment (G × E) interaction under an additive risk model (i.e., additive interaction) has gained wider attention. Recently, statistical tests have been proposed for detecting additive interaction, utilizing an assumption on gene-environment (G-E) independence to boost power, that do not rely on restrictive genetic models such as dominant or recessive models. However, a major limitation of these methods is a sharp increase in type I error when this assumption is violated. Our goal was to develop a robust test for additive G × E interaction under the trend effect of genotype, applying an empirical Bayes-type shrinkage estimator of the relative excess risk due to interaction. The proposed method uses a set of constraints to impose the trend effect of genotype and builds an estimator that data-adaptively shrinks an estimator of relative excess risk due to interaction obtained under a general model for G-E dependence using a retrospective likelihood framework. Numerical study under varying levels of departures from G-E independence shows that the proposed method is robust against the violation of the independence assumption while providing an adequate balance between bias and efficiency compared with existing methods. We applied the proposed method to the genetic data of Alzheimer disease and lung cancer.
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- 2021
129. Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma
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Tongtong Hong, Christopher I. Amos, Shan Zienolddiny, Hongxia Ma, Matthew B. Schabath, John K. Field, David C. Christiani, Hongbing Shen, Angela Risch, Lambertus A. Kiemeney, Sanjay Shete, Chu Chen, Maria Teresa Landi, Susanne M. Arnold, H-Erich Wichmann, Neil E. Caporaso, Adonina Tardón, Mikael Johansson, Philip Lazarus, Meng Zhu, Heike Bickeböller, Penella J. Woll, Kjell Grankvist, Mattias Johansson, Rayjean J. Hung, Stig E. Bojesen, Gary E. Goodman, Guangfu Jin, Hans Brunnström, Stephen Lam, Juncheng Dai, Victoria L. Stevens, Na Qin, Yuancheng Li, Zhibin Hu, Cheng Wang, Gadi Rennert, Demetrius Albanes, Geoffrey Liu, Loic Le Marchand, Angeline S. Andrew, Melinda C. Aldrich, Olle Melander, and Paul Brennan
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0301 basic medicine ,Lung Neoplasms ,Adenocarcinoma of Lung ,Genome-wide association study ,Computational biology ,Biology ,Polymorphism, Single Nucleotide ,Article ,Transcriptome ,Genetic Heterogeneity ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Genotype ,medicine ,Humans ,Genetic Predisposition to Disease ,Gene ,Epigenomics ,Genetic association ,Genetic heterogeneity ,General Medicine ,medicine.disease ,030104 developmental biology ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Adenocarcinoma ,Genome-Wide Association Study - Abstract
Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
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- 2021
130. Tracing Lung Cancer Risk Factors Through Mutational Signatures in Never-Smokers
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Jiyeon Choi, Wei Zhao, David C. Wedge, Tongwu Zhang, Stephen J. Chanock, Jian Sang, Laura Mendoza, Dmitry A. Gordenin, Michael Kebede, Neil E. Caporaso, Montserrat Garcia-Closas, Marwil Pacheco, Ludmil B. Alexandrov, Mustapha Abubakar, Bin Zhu, Qing Lan, Maria Teresa Landi, Jennifer Rosenbaum, Belynda Hicks, Jianxin Shi, Nathaniel Rothman, and Naoise C Synnott
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Lung Neoplasms ,Epidemiology ,DNA Mutational Analysis ,Computational biology ,Biology ,medicine.disease_cause ,Risk Assessment ,Genome ,DNA sequencing ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,medicine ,Humans ,Genetic Predisposition to Disease ,Microbiome ,Lung cancer ,Retrospective Studies ,030304 developmental biology ,Whole genome sequencing ,0303 health sciences ,Mutation ,Study Design ,Whole Genome Sequencing ,Cancer ,medicine.disease ,Causality ,030220 oncology & carcinogenesis ,Cancer Etiology - Abstract
Epidemiologic studies often rely on questionnaire data, exposure measurement tools, and/or biomarkers to identify risk factors and the underlying carcinogenic processes. An emerging and promising complementary approach to investigate cancer etiology is the study of somatic “mutational signatures” that endogenous and exogenous processes imprint on the cellular genome. These signatures can be identified from a complex web of somatic mutations thanks to advances in DNA sequencing technology and analytical algorithms. This approach is at the core of the Sherlock-Lung study (2018–ongoing), a retrospective case-only study of over 2,000 lung cancers in never-smokers (LCINS), using different patterns of mutations observed within LCINS tumors to trace back possible exposures or endogenous processes. Whole genome and transcriptome sequencing, genome-wide methylation, microbiome, and other analyses are integrated with data from histological and radiological imaging, lifestyle, demographic characteristics, environmental and occupational exposures, and medical records to classify LCINS into subtypes that could reveal distinct risk factors. To date, we have received samples and data from 1,370 LCINS cases from 17 study sites worldwide and whole-genome sequencing has been completed on 1,257 samples. Here, we present the Sherlock-Lung study design and analytical strategy, also illustrating some empirical challenges and the potential for this approach in future epidemiologic studies.
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- 2020
131. A Penalized Regression Framework for Building Polygenic Risk Models Based on Summary Statistics From Genome-Wide Association Studies and Incorporating External Information
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Ting Huei Chen, Jianxin Shi, Nilanjan Chatterjee, and Maria Teresa Landi
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Statistics and Probability ,Penalized regression ,Computer science ,business.industry ,05 social sciences ,Genome-wide association study ,Machine learning ,computer.software_genre ,01 natural sciences ,Summary statistics ,Article ,010104 statistics & probability ,Lasso (statistics) ,0502 economics and business ,Genetic Pleiotropy ,Polygenic risk score ,Artificial intelligence ,0101 mathematics ,Statistics, Probability and Uncertainty ,business ,computer ,Predictive modelling ,050205 econometrics ,Genetic association - Abstract
Large-scale genome-wide association (GWAS) studies provide opportunities for developing genetic risk prediction models that have the potential to improve disease prevention, intervention or treatment. The key step is to develop polygenic risk score (PRS) models with high predictive performance for a given disease, which typically requires a large training data set for selecting truly associated single nucleotide polymorphisms (SNPs) and estimating effect sizes accurately. Here, we develop a comprehensive penalized regression for fitting l(1) regularized regression models to GWAS summary statistics. We propose incorporating Pleiotropy and ANnotation information into PRS (PANPRS) development through suitable formulation of penalty functions and associated tuning parameters. Extensive simulations show that PANPRS performs equally well or better than existing PRS methods when no functional annotation or pleiotropy is incorporated. When functional annotation data and pleiotropy are informative, PANPRS substantially outperforms existing PRS methods in simulations. Finally, we applied our methods to build PRS for type 2 diabetes and melanoma and found that incorporating relevant functional annotations and GWAS of genetically related traits improved prediction of these two complex diseases.
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- 2020
132. Genome-wide interaction analysis identified low-frequency variants with sex disparity in lung cancer risk
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Chu Chen, Rayjean J. Hung, Colette Gaba, Mikael Johansson, David C. Christiani, Sanjay Shete, Ping Yang, Yun-Chul Hong, Gad Rennert, Angeline S. Andrew, Maria Teresa Landi, Jinyoung Byun, Michael P.A. Davies, Xiangjun Xiao, Yohan Bossé, John K. Field, James McKay, Shanbeh Zienolddiny, Gary E. Goodman, Christopher I. Amos, Neil E. Caporaso, Stephen Lam, Yanhong Liu, Paul Brennan, Matthew B. Schabath, Younghun Han, Mattias Johansson, Susanne M. Arnold, Erich Wichmann, James Willey, Susan M. Pinney, Philip Lazarus, Ryan Sun, Hongbing Shen, Yafang Li, Kristen Purrington, Dawn Teare, Diptasri Mandal, Kjell Grankvist, Angela Risch, Chao Cheng, Ann G. Schwartz, Heike Bickeböller, Jianrong Li, Adonina Tardón, Stig E. Bojesen, Hans Brunnström, Ivan P. Gorlov, Loic Le Marchand, Melinda C. Aldrich, Olle Melander, Lambertus A. Kiemeney, Demetrius Albanes, Geoffrey Liu, and Joan E. Bailey-Wilson
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Male ,Lung Neoplasms ,Computational biology ,Biology ,Polymorphism, Single Nucleotide ,Genome ,Text mining ,medicine ,Genetics ,Humans ,Genetic Predisposition to Disease ,Lung cancer ,Lung ,Molecular Biology ,Genetics (clinical) ,Medicinsk genetik ,business.industry ,General Medicine ,respiratory system ,medicine.disease ,Case-Control Studies ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Female ,business ,Medical Genetics ,Genome-Wide Association Study - Abstract
Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene–sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency
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- 2022
133. A Large-Scale Genome-Wide Gene-Gene Interaction Study of Lung Cancer Susceptibility in Europeans With a Trans-Ethnic Validation in Asians
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Ruyang Zhang, Sipeng Shen, Yongyue Wei, Ying Zhu, Yi Li, Jiajin Chen, Jinxing Guan, Zoucheng Pan, Yuzhuo Wang, Meng Zhu, Junxing Xie, Xiangjun Xiao, Dakai Zhu, Yafang Li, Demetrios Albanes, Maria Teresa Landi, Neil E. Caporaso, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D. McKay, John K. Field, Sanjay S. Shete, Loic Le Marchand, Geoffrey Liu, Angeline S. Andrew, Lambertus A. Kiemeney, Shan Zienolddiny-Narui, Annelie Behndig, Mikael Johansson, Angela Cox, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Juncheng Dai, Hongxia Ma, Yang Zhao, Zhibin Hu, Rayjean J. Hung, Christopher I. Amos, Hongbing Shen, Feng Chen, and David C. Christiani
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Pulmonary and Respiratory Medicine ,Lung Neoplasms ,Genetic screening model ,Polymorphism, Single Nucleotide ,Single nucleotide polymorphism ,Cancer risk ,Oncology ,Carcinoma, Non-Small-Cell Lung ,Case-Control Studies ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Humans ,GWAS ,Genetic Predisposition to Disease ,Lung cancer ,Gene-gene interaction ,Medical Genetics ,Early Detection of Cancer ,Genome-Wide Association Study ,Medicinsk genetik - Abstract
IntroductionAlthough genome-wide association studies have been conducted to investigate genetic variation of lung tumorigenesis, little is known about gene-gene (G × G) interactions that may influence the risk of non-small cell lung cancer (NSCLC).MethodsLeveraging a total of 445,221 European-descent participants from the International Lung Cancer Consortium OncoArray project, Transdisciplinary Research in Cancer of the Lung and UK Biobank, we performed a large-scale genome-wide G × G interaction study on European NSCLC risk by a series of analyses. First, we used BiForce to evaluate and rank more than 58 billion G × G interactions from 340,958 single-nucleotide polymorphisms (SNPs). Then, the top interactions were further tested by demographically adjusted logistic regression models. Finally, we used the selected interactions to build lung cancer screening models of NSCLC, separately, for never and ever smokers.ResultsWith the Bonferroni correction, we identified eight statistically significant pairs of SNPs, which predominantly appeared in the 6p21.32 and 5p15.33 regions (e.g., rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.17, p = 6.57 × 10-13; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.17, p = 2.43 × 10-13; rs2858859HLA-DQA1 and rs9275572HLA-DQA2, ORinteraction = 1.15, p = 2.84 × 10-13; rs2853668TERT and rs62329694CLPTM1L, ORinteraction = 0.73, p = 2.70 × 10-13). Notably, even with much genetic heterogeneity across ethnicities, three pairs of SNPs in the 6p21.32 region identified from the European-ancestry population remained significant among an Asian population from the Nanjing Medical University Global Screening Array project (rs521828C6orf10 and rs204999PRRT1, ORinteraction = 1.13, p = 0.008; rs3135369BTNL2 and rs2858859HLA-DQA1, ORinteraction = 1.11, p = 5.23 × 10-4; rs3135369BTNL2 and rs9271300HLA-DQA1, ORinteraction = 0.89, p = 0.006). The interaction-empowered polygenetic risk score that integrated classical polygenetic risk score and G × G information score was remarkable in lung cancer risk stratification.ConclusionsImportant G × G interactions were identified and enriched in the 5p15.33 and 6p21.32 regions, which may enhance lung cancer screening models.
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- 2022
134. An efficient stochastic search for Bayesian variable selection with high-dimensional correlated predictors.
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Deukwoo Kwon, Maria Teresa Landi, Marina Vannucci, Haleem J. Issaq, DaRue Prieto, and Ruth M. Pfeiffer
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- 2011
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135. Histologic features of melanoma associated with germline mutations of CDKN2A, CDK4, and POT1 in melanoma-prone families from the United States, Italy, and Spain
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Michael R. Sargen, Ruth M. Pfeiffer, Daniela Massi, Cristina Carrera, Donato Calista, Maria Teresa Landi, Emily Y. Chu, Paula Aguilera, Rosalie Elenitsas, Margaret A. Tucker, Alisa M. Goldstein, Xiaohong R. Yang, Miriam Potrony, David E. Elder, Llucia Alos, and Susana Puig
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Adult ,Male ,Oncology ,Heterozygote ,medicine.medical_specialty ,Skin Neoplasms ,Telomere-Binding Proteins ,Telomere dysfunction ,Dermatology ,medicine.disease_cause ,Article ,Shelterin Complex ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,CDKN2A ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Neoplasm Invasiveness ,Melanoma ,neoplasms ,Cyclin-Dependent Kinase Inhibitor p16 ,Germ-Line Mutation ,Skin ,Mutation ,business.industry ,Tumor-infiltrating lymphocytes ,Cyclin-Dependent Kinase 4 ,Odds ratio ,Middle Aged ,medicine.disease ,United States ,Italy ,Spain ,030220 oncology & carcinogenesis ,Female ,Histopathology ,business - Abstract
BACKGROUND: CDKN2A, CDK4, and POT1 are well-established melanoma-susceptibility genes. OBJECTIVE: We evaluated melanoma histopathology for individuals with germline mutations of CDKN2A, CDK4, and POT1. METHODS: We assessed histopathology for melanomas diagnosed in melanoma-prone families (≥2 individuals with melanoma) from the United States, Italy, and Spain. Comparisons between mutation carriers and non-carriers (no mutation) were adjusted for age, sex, Breslow depth, and correlations among individuals within the same family. RESULTS: Histologic slides were evaluated for 290 melanomas (139 from 132 non-carriers, 122 from 68 CDKN2A carriers, 10 from 6 CDK4 carriers, 19 from 16 POT1 carriers). Superficial spreading was the predominant subtype for all groups. Spitzoid morphology (>25% of tumor) was observed in the majority of invasive melanomas from POT1 carriers (10 of 15 [67%], P
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- 2020
136. Association Analysis of Driver Gene–Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls
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Neil E. Caporaso, Paul Brennan, Juncheng Dai, Hongxia Ma, Hongbing Shen, Gad Rennert, Ivan P. Gorlov, Adonina Tardón, Philip Lazarus, Yuzhuo Wang, Shanbeh Zienolddiny, Zhibin Hu, Meng Zhu, David C. Christiani, Gary E. Goodman, Stephen Lam, Rayjean J. Hung, Chu Chen, Heike Bickeböller, Matthew B. Schabath, Sanjay Shete, Maria Teresa Landi, Olga Y. Gorlova, Mikael Johansson, Susanne M. Arnold, Lambertus A. Kiemeney, Demetrius Albanes, H. E. Wichmann, Christopher I. Amos, Penella J. Woll, Angela Risch, Geoffrey Liu, Guangfu Jin, Stig E. Bojesen, Hans Brunnström, Kjell Grankvist, Victoria L. Stevens, Loic Le Marchand, Angeline S. Andrew, Mattias Johansson, Melinda C. Aldrich, Olle Melander, and John K. Field
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Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,Epidemiology ,Genome-wide association study ,Single-nucleotide polymorphism ,Biology ,Article ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,Internal medicine ,Genetic variation ,medicine ,Humans ,Genetic Predisposition to Disease ,Lung cancer ,Genetic association ,Case-control study ,Genetic Variation ,Middle Aged ,respiratory system ,medicine.disease ,Lung cancer susceptibility ,respiratory tract diseases ,3. Good health ,030104 developmental biology ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Case-Control Studies ,030220 oncology & carcinogenesis ,Medical genetics ,Female ,Genome-Wide Association Study - Abstract
Background: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated. Methods: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project. Results: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 × 10−6). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 × 10−3). Conclusions: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. Impact: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.
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- 2020
137. Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma
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Neil E. Caporaso, Bin Zhu, Dario Consonni, Lei Song, David C. Wedge, Angela Cecilia Pesatori, Joshua Sampson, Tongwu Zhang, Jianxin Shi, Belynda Hicks, Mingyi Wang, Xing Hua, Kristine Jones, Maria Teresa Landi, and Wei Zhao
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0301 basic medicine ,Male ,Lung Neoplasms ,General Physics and Astronomy ,Kaplan-Meier Estimate ,SCNA ,Epigenesis, Genetic ,0302 clinical medicine ,Cancer genomics ,lcsh:Science ,Aged, 80 and over ,Multidisciplinary ,Manchester Cancer Research Centre ,Methylation ,Middle Aged ,Treatment Outcome ,030220 oncology & carcinogenesis ,DNA methylation ,Adenocarcinoma ,Female ,Lung cancer ,DNA Copy Number Variations ,Tumour heterogeneity ,Science ,Adenocarcinoma of Lung ,Biology ,Polymorphism, Single Nucleotide ,General Biochemistry, Genetics and Molecular Biology ,Article ,Evolution, Molecular ,03 medical and health sciences ,Genetic Heterogeneity ,medicine ,Humans ,Epigenetics ,Aged ,Genetic heterogeneity ,Point mutation ,ResearchInstitutes_Networks_Beacons/mcrc ,Cancer ,General Chemistry ,DNA Methylation ,medicine.disease ,030104 developmental biology ,Mutation ,Cancer research ,lcsh:Q ,CpG Islands - Abstract
Intratumor heterogeneity (ITH) of genomic alterations may impact prognosis of lung adenocarcinoma (LUAD). Here, we investigate ITH of somatic copy number alterations (SCNAs), DNA methylation, and point mutations in lung cancer driver genes in 292 tumor samples from 84 patients with LUAD. LUAD samples show substantial SCNA and methylation ITH, and clonal architecture analyses present congruent evolutionary trajectories for SCNAs and DNA methylation aberrations. Methylation ITH mapping to gene promoter areas or tumor suppressor genes is low. Moreover, ITH composed of genetic and epigenetic mechanisms altering the same cancer driver genes is shown in several tumors. To quantify ITH for valid statistical association analyses, we develope an average pairwise ITH index (APITH), which does not depend on the number of samples per tumor. Both APITH indexes for SCNAs and methylation aberrations show significant associations with poor prognosis. This study further establishes the important clinical implications of genetic and epigenetic ITH in LUAD., Many tumors are known to be heterogeneous. Here, the authors examined multiple samples from 84 patients with lung adenocarcinoma and demonstrate that the intratumor heterogeneity of methylation and copy number associates with poor prognosis.
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- 2020
138. DNA Methylation in Lung Cancer: Mechanisms and Associations with Histological Subtypes, Molecular Alterations, and Major Epidemiological Factors
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Phuc H. Hoang and Maria Teresa Landi
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Cancer Research ,Oncology - Abstract
Lung cancer is the major leading cause of cancer-related mortality worldwide. Multiple epigenetic factors—in particular, DNA methylation—have been associated with the development of lung cancer. In this review, we summarize the current knowledge on DNA methylation alterations in lung tumorigenesis, as well as their associations with different histological subtypes, common cancer driver gene mutations (e.g., KRAS, EGFR, and TP53), and major epidemiological risk factors (e.g., sex, smoking status, race/ethnicity). Understanding the mechanisms of DNA methylation regulation and their associations with various risk factors can provide further insights into carcinogenesis, and create future avenues for prevention and personalized treatments. In addition, we also highlight outstanding questions regarding DNA methylation in lung cancer to be elucidated in future studies
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- 2021
139. Gene-gene Interaction of AhR with and within the Wnt Cascade Affects Susceptibility to Lung Cancer
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Albert Rosenberger, Nils Muttray, Rayjean J Hung, David C Christiani, Neil E Caporaso, Geoffrey Liu, Stig E Bojesen, Loic Le Marchand, Demetrios Albanes, Melinda C Aldrich, Adonina Tardon, Guillermo Fernández-Tardón, Gad Rennert, John K Field, Michael P.A. Davies, Triantafillos Liloglou, Lambertus A Kiemeney, Philip Lazarus, Bernadette Wendel, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Matthew B Schabath, Angeline S Andrew, Eric J Duell, Susanne M Arnold, Gary E Goodman, Chu Chen, Jennifer A Doherty, Fiona Taylor, Angela Cox, Penella J Woll, Angela Risch, Thomas R Muley, Mikael Johansson, Paul Brennan, Maria Teresa Landi, Sanjay S Shete, Christopher I Amos, Heike Bickeböller, and INTEGRAL-ILCCO consortium
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respiratory tract diseases - Abstract
Background Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Further, decision trees were created to investigate variant x variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g. maker rs2722278 SFRP4; OR = 1.20; 95%-CI: 1.13–1.27; p = 5.6 10− 10) and never smokers (e.g. maker rs1133683 Axin2; OR = 1.27; 95%-CI: 1.19–1.35; p = 1.0 10− 12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants Conclusions The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.
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- 2021
140. A COPULA-MODEL BASED SEMIPARAMETRIC INTERACTION TEST UNDER THE CASE-CONTROL DESIGN
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Jing Qin, Neil E. Caporaso, Kai Yu, Maria Teresa Landi, and Hong Zhang
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Statistics and Probability ,Engineering ,Statistical assumption ,business.industry ,Logistic regression ,Article ,Copula (probability theory) ,Joint probability distribution ,Statistics ,Econometrics ,Statistics, Probability and Uncertainty ,Marginal distribution ,business ,Statistical hypothesis testing ,Parametric statistics ,Type I and type II errors - Abstract
It is important to study the interaction between two risk factors in molecular epidemiology studies. To improve the power for the detection of interaction, some statistical testing procedures have been proposed in the literature by incorporating certain assumptions on the underlying joint distribution of the two risk factors. For example, the well known case-only test used in genetic epidemiology studies is derived under the assumption of independency between the two considered risk factors. However, those testing procedures could have detrimental effects on both false positive and false negative rates when the assumptions are not met. We propose to use a parametric copula function to model the joint distribution while leaving the marginal distributions for the two risk factors totally unspecified. A unified approach is proposed to estimate/test the interaction effect. This approach is very flexible and can be applied to study the interaction between two risk factors that are continuous or discrete. A simulation study demonstrates that the proposed approach is generally more powerful than the traditional robust test derived under the standard logistic regression without specifying the relationship between the two risk factors. The performance of the proposed approach is comparable with the case-only test when the two risk factors are indeed independent in the control population. Unlike the case-only test, the proposed test can still maintain the correct type I error rate when the independence assumption is not valid. The application of the proposed procedure is demonstrated through two cancer epidemiology studies.
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- 2021
141. Accounting for EGFR Mutations in Epidemiologic Analyses of Non-Small Cell Lung Cancers: Examples Based on the International Lung Cancer Consortium Data
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Sabine Schmid, Mei Jiang, M. Catherine Brown, Aline Fares, Miguel Garcia, Joelle Soriano, Mei Dong, Sera Thomas, Takashi Kohno, Leticia Ferro Leal, Nancy Diao, Juntao Xie, Zhichao Wang, David Zaridze, Ivana Holcatova, Jolanta Lissowska, Beata Świątkowska, Dana Mates, Milan Savic, Angela S. Wenzlaff, Curtis C. Harris, Neil E. Caporaso, Hongxia Ma, Guillermo Fernandez-Tardon, Matthew J. Barnett, Gary Goodman, Michael P.A. Davies, Mónica Pérez-Ríos, Fiona Taylor, Eric J. Duell, Ben Schoettker, Hermann Brenner, Angeline Andrew, Angela Cox, Alberto Ruano-Ravina, John K. Field, Loic Le Marchand, Ying Wang, Chu Chen, Adonina Tardon, Sanjay Shete, Matthew B. Schabath, Hongbing Shen, Maria Teresa Landi, Brid M. Ryan, Ann G. Schwartz, Lihong Qi, Lori C. Sakoda, Paul Brennan, Ping Yang, Jie Zhang, David C. Christiani, Rui Manuel Reis, Kouya Shiraishi, Rayjean J. Hung, Wei Xu, and Geoffrey Liu
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Lung Neoplasms ,Epidemiology ,Prevention ,Carcinoma ,Lung Cancer ,Medical and Health Sciences ,Survival Analysis ,Article ,ErbB Receptors ,Oncology ,Carcinoma, Non-Small-Cell Lung ,Mutation ,Humans ,Non-Small-Cell Lung ,Lung ,Cancer - Abstract
Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.
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- 2021
142. SUITOR: Selecting the number of mutational signatures through cross-validation
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Difei Wang, Jianxin Shi, Dong-Hyuk Lee, Bin Zhu, Maria Teresa Landi, and Xiaohong Yang
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Ecology ,Computer science ,In silico ,Genomics ,Breast Neoplasms ,Computational biology ,Overfitting ,Cross-validation ,Cellular and Molecular Neuroscience ,Computational Theory and Mathematics ,Modeling and Simulation ,Neoplasms ,Mutation ,Genetics ,Humans ,Computer Simulation ,Female ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics - Abstract
For de novo mutational signature analysis, the critical first step is to decide how many signatures should be expected in a cancer genomics study. An incorrect number could mislead downstream analyses. Here we present SUITOR (Selecting the nUmber of mutatIonal signaTures thrOugh cRoss-validation), an unsupervised cross-validation method that requires little assumptions and no numerical approximations to select the optimal number of signatures without overfitting the data. In vitro studies and in silico simulations demonstrated that SUITOR can correctly identify signatures, some of which were missed by other widely used methods. Applied to 2,540 whole-genome sequenced tumors across 22 cancer types, SUITOR selected signatures with the smallest prediction errors and almost all signatures of breast cancer selected by SUITOR were validated in an independent breast cancer study. SUITOR is a powerful tool to select the optimal number of mutational signatures, facilitating downstream analyses with etiological or therapeutic importance.
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- 2021
143. Gene-gene Interaction of AhR With and Within the Wnt Cascade Affects Susceptibility to Lung Cancer
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Paul Brennan, Matthew B. Schabath, Gad Rennert, Guillermo Fernández-Tardón, Triantafillos Liloglou, Neil E. Caporaso, Shanbeh Zienolddiny, Melinda C. Aldrich, Mikael Johansson, Jennifer A. Doherty, Susanne M. Arnold, Angela Risch, Geoffrey Liu, Albert Rosenberger, Lambertus A. Kiemeney, Nils Muttray, Angela Cox, Angeline S. Andrew, Sanjay Shete, John K. Field, Demetrios Albanes, Christopher I. Amos, Thomas Muley, David C. Christiani, Philip Lazarus, Heike Bickeböller, Aage Haugen, Chu Chen, Adonina Tardón, Gary E. Goodman, Fiona Taylor, Stephen Lam, Eric J. Duell, Bernadette Wendel, Loic Le Marchand, Penella J. Woll, Stig E. Bojesen, Rayjean J. Hung, Maria Teresa Landi, and Michael P.A. Davies
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Text mining ,Gene interaction ,business.industry ,Cancer research ,Wnt signaling pathway ,medicine ,respiratory system ,Biology ,business ,Lung cancer ,medicine.disease ,Gene ,respiratory tract diseases - Abstract
Introduction: Aberrant Wnt signalling, regulating cell development and stemness, is observed in many cancer entities. Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated to lung cancer susceptibility. Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods: Odds ratios (OR) were estimated for genomic variants assigned to the genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2 and other lung cancer-related genes. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer. Further, decision trees were created to investigate variant x variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results: No association with overall lung cancer was observed, but within the subgroups of ever smokers (e.g. maker rs2722278 SFRP4; OR=1.20; 95%-CI: 1.13-1.27; p=5.6 10-10) and never smokers. Although predictability is poor, AhR/Wnt-variants are unexpected overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkable, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants, no assigned to any CHRN gene. Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.
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- 2021
144. Uncovering novel mutational signatures by
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S M Ashiqul, Islam, Marcos, Díaz-Gay, Yang, Wu, Mark, Barnes, Raviteja, Vangara, Erik N, Bergstrom, Yudou, He, Mike, Vella, Jingwei, Wang, Jon W, Teague, Peter, Clapham, Sarah, Moody, Sergey, Senkin, Yun Rose, Li, Laura, Riva, Tongwu, Zhang, Andreas J, Gruber, Christopher D, Steele, Burçak, Otlu, Azhar, Khandekar, Ammal, Abbasi, Laura, Humphreys, Natalia, Syulyukina, Samuel W, Brady, Boian S, Alexandrov, Nischalan, Pillay, Jinghui, Zhang, David J, Adams, Iñigo, Martincorena, David C, Wedge, Maria Teresa, Landi, Paul, Brennan, Michael R, Stratton, Steven G, Rozen, and Ludmil B, Alexandrov
- Abstract
Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for
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- 2021
145. Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals
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Christopher I. Amos, Christopher A. Haiman, Rosalind A. Eeles, Rayjean J. Hung, Stacey J. Winham, Richard S. Houlston, Robert B. Jenkins, Alison P. Klein, Valerie Gaborieau, Corina Lesseur, Bogdan Pasaniuc, Brenda Diergaarde, Paul D.P. Pharoah, Puya Gharahkhani, Hongjie Chen, Stephen J. Chanock, Siddhartha Kar, Constance Turman, Joe Dennis, Arunabha Majumdar, Melissa L. Bondy, Paul Brennan, Sara Lindström, Myriam Brossard, Laufey T. Amundadottir, Johannes Schumacher, James McKay, Helian Feng, Stephanie L. Schmit, Matthew Jones, Zsofia Kote-Jarai, Janusz Jankowski, David C. Christiani, Tracy A. O'Mara, Brian M. Wolpin, Mark M. Iles, Lu Wang, Gloria M. Petersen, Andy R Ness, Douglas F. Easton, Beatrice Melin, Timothy Bishop, Matthew Law, Amanda B. Spurdle, Jeroen R. Huyghe, Jonathan Tyrer, Peter Kraft, Jacques Simard, Kevin M. Brown, Mark P. Purdue, Donghui Li, Iona Cheng, Ines Gockel, Andrew F. Olshan, Maria Teresa Landi, Stuart MacGregor, Jonathan Beesley, Fredrick R. Schumacher, Kyriaki Michailidou, Ness, Andy R [0000-0003-3548-9523], Law, Matthew H [0000-0002-4303-8821], and Apollo - University of Cambridge Repository
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Oncology ,CLPTM1L ,medicine.medical_specialty ,TERT ,Estrogen receptor ,Genome-wide association study ,Biology ,QH426-470 ,medicine.disease_cause ,Article ,Prostate cancer ,Prostate ,Internal medicine ,pleiotropy ,medicine ,Genetics ,cancer ,Genetics (clinical) ,Genetic association ,Medicinsk genetik ,Cancer ,Pleiotropy ,Cancer och onkologi ,Melanoma ,Fine-mapping ,5p15.33 region ,medicine.disease ,medicine.anatomical_structure ,fine-mapping ,Cancer and Oncology ,Molecular Medicine ,Carcinogenesis ,Medical Genetics - Abstract
Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
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- 2021
146. Peritoneal mesothelioma and asbestos exposure: a population-based case–control study in Lombardy, Italy
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Maria Teresa Landi, Dario Mirabelli, Roel Vermeulen, Luciano Riboldi, Susan Peters, Barbara Dallari, Dario Consonni, Neil E. Caporaso, Hans Kromhout, Angela Cecilia Pesatori, Cristina Calvi, Carolina Mensi, Sara De Matteis, One Health Chemisch, and dIRAS RA-2
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Adult ,Male ,Mesothelioma ,medicine.medical_specialty ,Lung Neoplasms ,population–based case–control study ,Population ,Cumulative Exposure ,medicine.disease_cause ,Asbestos ,Occupational Exposure ,Internal medicine ,medicine ,Humans ,Risk factor ,Workplace ,education ,Lung cancer ,Peritoneal Neoplasms ,Aged ,Exposure assessment ,Aged, 80 and over ,education.field_of_study ,business.industry ,population-based case-control study ,Environmental and Occupational Health ,Mesothelioma, Malignant ,Public Health, Environmental and Occupational Health ,Environmental Exposure ,Middle Aged ,asbestos ,peritoneum ,medicine.disease ,Italy ,mesothelioma ,Case-Control Studies ,Peritoneal mesothelioma ,Female ,Public Health ,business - Abstract
ObjectivesAsbestos is the main risk factor for peritoneal mesothelioma (PeM). However, due to its rarity, PeM has rarely been investigated in community-based studies. We examined the association between asbestos exposure and PeM risk in a general population in Lombardy, Italy.MethodsFrom the regional mesothelioma registry, we selected PeM cases diagnosed in 2000–2015. Population controls (matched by area, gender and age) came from two case–control studies in Lombardy on lung cancer (2002–2004) and pleural mesothelioma (2014). Assessment of exposure to asbestos was performed through a quantitative job-exposure matrix (SYN-JEM) and expert evaluation based on a standardised questionnaire. We calculated period-specific and gender-specific OR and 90% CI using conditional logistic regression adjusted for age, province of residence and education.ResultsWe selected 68 cases and 2116 controls (2000–2007) and 159 cases and 205 controls (2008–2015). The ORs for ever asbestos exposure (expert-based, 2008–2015 only) were 5.78 (90% CI 3.03 to 11.0) in men and 8.00 (2.56 to 25.0) in women; the ORs for definite occupational exposure were 12.3 (5.62 to 26.7) in men and 14.3 (3.16 to 65.0) in women. The ORs for ever versus never occupational asbestos exposure based on SYN-JEM (both periods) were 2.05 (90% CI 1.39 to 3.01) in men and 1.62 (0.79 to 3.27) in women. In men, clear positive associations were found for duration, cumulative exposure (OR 1.33 (1.19 to 1.48) per fibres/mL-years) and latency.ConclusionsUsing two different methods of exposure assessment we provided evidence of a clear association between asbestos exposure and PeM risk in the general population.
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- 2019
147. Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers
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Xuchen Zong, José Eluf-Neto, Stefania Boccia, Eloiza H. Tajara, Wilbert H.M. Peters, Silvia Franceschi, Vidar Skaug, Brenda Diergaarde, Rayjean J. Hung, Pagona Lagiou, Melinda C. Aldrich, Shanbeh Zienolddiny, Jennifer A. Doherty, Christopher I. Amos, Maria Teresa Landi, Salvatore Panico, Lambertus A. Kiemeney, Demetrius Albanes, Gary E. Goodman, Stephen Lam, Kim Overvad, Erik H.F.M. van der Heijden, Geoffrey Liu, Dana Mates, Martin Lacko, Ghislaine Scelo, Raquel Ayoub Moysés, Neil E. Caporaso, M. Dawn Teare, Andrew F. Olshan, James D. McKay, Loic Le Marchand, June C Carroll, Jelena Stojsic, Corina Lesseur, Antonia Trichopoulou, Adonina Tardón, Andy R Ness, Jonas Manjer, Paolo Vineis, Chu Chen, Angeline S. Andrew, Gary J. Macfarlane, Mattias Johansson, David Zaridze, Angela Risch, George Davey Smith, Anush Mukeriya, Victor Wünsch-Filho, Eric J. Duell, John K. Field, Heike Bickeböller, David C. Christiani, Fábio Daumas Nunes, Aage Haugen, H-Erich Wichmann, Gad Rennert, Paul Brennan, Olli Saarela, Jolanta Lissowska, Ivana Holcatova, Philip Lazarus, Mark C. Weissler, Matthew B. Schabath, Xifeng Wu, Susanne M. Arnold, Stig E. Bojesen, Vladimir Janout, Linda Kachuri, Beata Swiatkowska, MUMC+: MA Keel Neus Oorheelkunde (9), RS: GROW - R2 - Basic and Translational Cancer Biology, Kachuri, Linda, Saarela, Olli, Bojesen, Stig Egil, Davey Smith, George, Liu, Geoffrey, Landi, Maria Teresa, Caporaso, Neil E, Christiani, David C, Johansson, Mattia, Panico, Salvatore, Overvad, Kim, Trichopoulou, Antonia, Vineis, Paolo, Scelo, Ghislaine, Zaridze, David, Wu, Xifeng, Albanes, Demetriu, Diergaarde, Brenda, Lagiou, Pagona, Macfarlane, Gary J, Aldrich, Melinda C, Tardón, Adonina, Rennert, Gad, Olshan, Andrew F, Weissler, Mark C, Chen, Chu, Goodman, Gary E, Doherty, Jennifer A, Ness, Andrew R, Bickeböller, Heike, Wichmann, H-Erich, Risch, Angela, Field, John K, Teare, M Dawn, Kiemeney, Lambertus A, van der Heijden, Erik H F M, Carroll, June C, Haugen, Aage, Zienolddiny, Shanbeh, Skaug, Vidar, Wünsch-Filho, Victor, Tajara, Eloiza H, Ayoub Moysés, Raquel, Daumas Nunes, Fabio, Lam, Stephen, Eluf-Neto, Jose, Lacko, Martin, Peters, Wilbert H M, Le Marchand, Loïc, Duell, Eric J, Andrew, Angeline S, Franceschi, Silvia, Schabath, Matthew B, Manjer, Jona, Arnold, Susanne, Lazarus, Philip, Mukeriya, Anush, Swiatkowska, Beata, Janout, Vladimir, Holcatova, Ivana, Stojsic, Jelena, Mates, Dana, Lissowska, Jolanta, Boccia, Stefania, Lesseur, Corina, Zong, Xuchen, Mckay, James D, Brennan, Paul, Amos, Christopher I, and Hung, Rayjean J
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0301 basic medicine ,Male ,Lung Neoplasms ,0302 clinical medicine ,Mendelian Randomization ,GENETIC-VARIANTS ,Epidemiology of cancer ,Epidemiology ,Leukocytes ,telomere length ,EPIDEMIOLOGY ,European commission ,030212 general & internal medicine ,Head and neck ,Lung Cancer ,Telomere Length ,Chromosome 5p15.33 ,Mediation Analysis ,Tert ,Aged, 80 and over ,CHALLENGES ,0104 Statistics ,General Medicine ,Middle Aged ,Telomere ,Medical research ,3. Good health ,NEVER SMOKERS ,Head and Neck Neoplasms ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Carcinoma, Squamous Cell ,Population study ,Chromosomes, Human, Pair 5 ,Female ,ICEP ,Translational science ,EXTENSION ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,medicine.medical_specialty ,SUSCEPTIBILITY LOCI ,TERT ,Library science ,Adenocarcinoma of Lung ,1117 Public Health and Health Services ,03 medical and health sciences ,Political science ,medicine ,Humans ,GENOME-WIDE ASSOCIATION ,mediation analysis ,Settore MED/42 - IGIENE GENERALE E APPLICATA ,METAANALYSIS ,Aged ,IDENTIFICATION ,chromosome 5p15.33 ,Squamous Cell Carcinoma of Head and Neck ,Cancer ,Telomere Homeostasis ,Mendelian Randomization Analysis ,medicine.disease ,DYSFUNCTION ,lung cancer ,030104 developmental biology - Abstract
L.K. is a fellow in the Canadian Institutes of Health Research (CIHR) Strategic Training in Advanced Genetic Epidemiology (STAGE) programme and is supported by the CIHR Doctoral Research Award from the Frederick Banting and Charles Best Canada Graduate Scholarships (GSD-137441). Transdisciplinary Research for Cancer in Lung (TRICL) of the International Lung Cancer Consortium (ILCCO) was supported by the National Institutes of Health (U19-CA148127, CA148127S1). Genotyping for the TRICL-ILCCO OncoArray was supported by in-kind genotyping at Centre for Inherited Disease Research (CIDR) (26820120008i-0–6800068-1). Genotyping for the Head and Neck Cancer OncoArray performed at CIDR was funded by the US National Institute of Dental and Craniofacial Research (NIDCR) grant 1X01HG007780–0. CAPUA study was supported by FIS-FEDER/Spain grant numbers FIS-01/310, FIS-PI03–0365 and FIS-07-BI060604, FICYT/Asturias grant numbers FICYT PB02–67 and FICYT IB09–133, and the University Institute of Oncology (IUOPA), of the University of Oviedo and the Ciber de Epidemiologia y Salud Publica. CIBERESP, SPAIN. The work performed in the CARET study was supported by the National Institute of Health (NIH)/National Cancer Institute (NCI): UM1 CA167462 (PI: Goodman), National Institute of Health UO1-CA6367307 (PIs Omen, Goodman); National Institute of Health R01 CA111703 (PI Chen), National Institute of Health 5R01 CA151989 (PI Doherty). The Liverpool Lung Project is supported by the Roy Castle Lung Cancer Foundation. The Harvard Lung Cancer Study was supported by the NIH (National Cancer Institute) grants CA092824, CA090578 and CA074386. The Multiethnic Cohort Study was partially supported by NIH Grants CA164973, CA033619, CA63464 and CA148127. The work performed in MSH-PMH study was supported by the Canadian Cancer Society Research Institute (020214), Ontario Institute of Cancer and Cancer Care Ontario Chair Award to R.J.H. and G.L. and the Alan Brown Chair and Lusi Wong Programs at the Princess Margaret Hospital Foundation. The Norway study was supported by Norwegian Cancer Society, Norwegian Research Council. The work in TLC study has been supported in part the James & Esther King Biomedical Research Program (09KN-15), National Institutes of Health Specialized Programs of Research Excellence (SPORE) Grant (P50 CA119997) and by a Cancer Center Support Grant (CCSG) at the H. Lee Moffitt Cancer Center and Research Institute, an NCI designated Comprehensive Cancer Center (grant number P30-CA76292). The dataset(s) used for the analyses described were obtained from Vanderbilt University Medical Center’s BioVU, which is supported by institutional funding and by the Vanderbilt CTSA grant UL1 TR000445 from NCATS/NIH. Dr Melinda Aldrich is supported by the by NIH/National Cancer Institute 5K07CA172294. The Copenhagen General Population Study (CGPS) was supported by the Chief Physician Johan Boserup and Lise Boserup Fund, the Danish Medical Research Council and Herlev Hospital. The NELCS study: Grant Number P20RR018787 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). Kentucky Lung Cancer Research Initiative (KLCRI) was supported by the Department of Defense (Congressionally Directed Medical Research Program, U.S. Army Medical Research and Materiel Command Program) under award number: 10153006 (W81XWH-11–1-0781). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense. This research was also supported by unrestricted infrastructure funds from the UK Center for Clinical and Translational Science, NIH grant UL1TR000117 and Markey Cancer Center NCI Cancer Center Support Grant (P30 CA177558) Shared Resource Facilities: Cancer Research Informatics, Biospecimen and Tissue Procurement, and Biostatistics and Bioinformatics. The research undertaken by M.D.T., L.V.W. and M.S.A. was partly funded by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. M.D.T. holds a Medical Research Council Senior Clinical Fellowship (G0902313). The Tampa study was funded by Public Health Service grants P01-CA68384 and R01-DE13158 from the National Institutes of Health. The University of Pittsburgh head and neck cancer case–control study is supported by US National Institutes of Health grants P50 CA097190 and P30 CA047904. The Carolina Head and Neck Cancer Study (CHANCE) was supported by the National Cancer Institute (R01CA90731). The Head and Neck Genome Project (GENCAPO) was supported by the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP; grants 04/12054–9 and 10/51168–0). The authors thank all the members of the GENCAPO team. This publication presents data from the Head and Neck 5000 study. The study was a component of independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme (RP-PG-0707–10034). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Human papillomavirus (HPV) serology was supported by a Cancer Research UK Programme Grant, the Integrative Cancer Epidemiology Programme (grant number: C18281/A19169). The Alcohol-Related Cancers and Genetic Susceptibility Study in Europe (ARCAGE) was funded by the European Commission’s fifth framework programme (QLK1– 2001-00182), the Italian Association for Cancer Research, Compagnia di San Paolo/FIRMS, Region Piemonte and Padova University (CPDA057222). The Rome Study was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) awards IG 2011 10491 and IG 2013 14220 to S.B. and by Fondazione Veronesi to S.B. The IARC Latin American study was funded by the European Commission INCO-DC programme (IC18-CT97–0222), with additional funding from Fondo para la Investigacion Cientifica y Tecnologica (Argentina) and the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (01/01768–2). The IARC Central Europe study was supported by the European Commission’s INCO-COPERNICUS Program (IC15-CT98–0332), US NIH/National Cancer Institute grant CA92039 and World Cancer Research Foundation grant WCRF 99A28. The IARC Oral Cancer Multicenter study was funded by grant S06 96 202489 05F02 from Europe against Cancer; grants FIS 97/0024, FIS 97/0662 and BAE 01/5013 from Fondo de Investigaciones Sanitarias, Spain; the UICC Yamagiwa-Yoshida Memorial International Cancer Study; the National Cancer Institute of Canada; Associazione Italiana per la Ricerca sul Cancro; and the Pan-American Health Organization. Coordination of the EPIC study is financially supported by the European Commission (DG SANCO) and the International Agency for Research on Cancer.
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- 2019
148. <scp>POT</scp> 1 germline mutations but not <scp>TERT</scp> promoter mutations are implicated in melanoma susceptibility in a large cohort of Spanish melanoma families
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Josep Malvehy, Carla Daniela Robles-Espinoza, Maria Teresa Landi, David J. Adams, V. Iyer, Susana Puig, Celia Badenas, Joan Anton Puig-Butille, M. Ribera‐Sola, Cristina Carrera, Paula Aguilera, and Miriam Potrony
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Genetics ,education.field_of_study ,Melanoma ,Population ,Dermatology ,Biology ,medicine.disease ,3. Good health ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,CDKN2A ,RNA splicing ,medicine ,Missense mutation ,Family history ,education ,Gene - Abstract
Background: Germline mutations in telomere-related genes such as POT1 and TERT predispose individuals to familial melanoma. Objectives: To evaluate the prevalence of germline mutations in POT1 and TERT in a large cohort of Spanish melanoma-prone families (at least two affected first- or second-degree relatives). Methods: Overall, 228 CDKN2A wild-type melanoma-prone families were included in the study. Screening of POT1 was performed in one affected person from each family and TERT was sequenced in one affected patient from 202 families (26 families were excluded owing to DNA exhaustion/degradation). TERT promoter sequencing was extended to an additional 30 families with CDKN2A mutation and 70 patients with sporadic multiple primary melanoma (MPM) with a family history of other cancers. Results: We identified four families with potentially pathogenic POT1 germline mutations: a missense variant c.233T>C (p.Ile78Thr); a nonsense variant c.1030G>T (p.Glu344*); and two other variants, c.255G>A (r.125_255del) and c.1792G>A (r.1791_1792insAGTA, p.Asp598Serfs*22), which we confirmed disrupted POT1 mRNA splicing. A TERT promoter variant of unknown significance (c.-125C>A) was detected in a patient with MPM, but no germline mutations were detected in TERT promoter in cases of familial melanoma. Conclusions: Overall, 1·7% of our CDKN2A/CDK4-wild type Spanish melanoma-prone families carry probably damaging mutations in POT1. The frequency of TERT promoter germline mutations in families with melanoma in our population is extremely rare.
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- 2019
149. A UVB-responsive common variant at chr7p21.1 confers tanning response and melanoma risk via regulation of the aryl hydrocarbon receptor gene (AHR)
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Kevin M. Brown, Tongwu Zhang, Mai Xu, Grant Sfa, Timothy G. Myers, Mark M. Iles, Helen T. Michael, Andrew D. Wells, Ashley Jermusyk, Jiyeon Choi, Michael A. Kovacs, Matthew Law, Matthew E. Johnson, Rohit Thakur, K.L. Jones, Raj Chari, Rebecca C Hennessey, Patricia Bunda, Maria Teresa Landi, Herbert Higson, Mehl L, Lea Jessop, Alessandra Chesi, Sowards H, Alisa M. Goldstein, Glenn Merlino, and S. J. Chanock
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Cell growth ,Melanoma ,medicine ,Cancer research ,Genome-wide association study ,Locus (genetics) ,Environmental exposure ,Biology ,Allele ,medicine.disease ,Phenotype ,Chromatin - Abstract
Genome-wide association studies have identified a melanoma-associated locus on chromosome band 7p21.1 with rs117132860 as the lead SNP, and a secondary independent signal marked by rs73069846. rs117132860 is also associated with tanning ability and cutaneous squamous cell carcinoma (cSCC). As ultraviolet radiation (UVR) is a key environmental exposure for all three traits, we investigated the mechanisms by which this locus contributes to melanoma risk, focusing on cellular response to UVR. Fine-mapping of melanoma GWAS identified four independent sets of candidate causal variants. A GWAS region-focused Capture-C study of primary melanocytes identified physical interactions between two causal sets and the promoter of the aryl hydrocarbon receptor gene (AHR). Subsequent chromatin state annotation, eQTL, and luciferase assays identified rs117132860 as a functional variant and reinforced AHR as a likely causal gene. As AHR plays critical roles in cellular response to dioxin and UVR, we explored links between this SNP and AHR expression after both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and ultraviolet B (UVB) exposure. Allele-specific AHR binding to rs117132860-G was enhanced following both, consistent with predicted weakened AHR binding to the risk/poor-tanning rs117132860-A allele, and allele-preferential AHR expression driven from the protective rs117132860-G allele was observed following UVB exposure. Small deletions surrounding rs117132860 via CRISPR abrogates AHR binding, reduces melanocyte cell growth, and prolongs growth arrest following UVB exposure. These data suggest AHR is a melanoma susceptibility gene at the 7p21.1 risk locus, and rs117132860 is a functional variant within a UVB-responsive element, leading to allelic AHR expression, and altering melanocyte growth phenotypes upon exposure.
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- 2021
150. Cell-type-specific meQTL extends melanoma GWAS annotation beyond eQTL and informs melanocyte gene regulatory mechanisms
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Jiyeon Choi, Eiríkur Steingrímsson, Berglind Osk Einarsdottir, Mai Xu, Matthew Law, Mark M. Iles, D T Bishop, Michael A. Kovacs, Kevin M. Brown, Tongwu Zhang, K.L. Jones, Ramile Dilshat, Malasky M, Chowdhury S, Alisa M. Goldstein, Jianxin Shi, and Maria Teresa Landi
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Genetics ,medicine.anatomical_structure ,Melanoma ,DNA methylation ,Expression quantitative trait loci ,medicine ,Genome-wide association study ,Melanocyte ,Biology ,Quantitative trait locus ,medicine.disease ,Gene ,Genetic association - Abstract
While expression quantitative trait loci (eQTL) have been powerful in identifying susceptibility genes from genome-wide association studies (GWAS) findings, most trait-associated loci are not explained by eQTL alone. Alternative QTLs including DNA methylation QTL (meQTL) are emerging, but cell-type-specific meQTL using cells of disease origin has been lacking. Here we established an meQTL dataset using primary melanocytes from 106 individuals and identified 1,497,502 significant cis-meQTLs. Multi-QTL colocalization using meQTL, eQTL, and mRNA splice-junction QTL from the same individuals together with imputed methylome-wide and transcriptome-wide association studies identified susceptibility genes at 63% of melanoma GWAS loci. Among three molecular QTLs, meQTLs were the single largest contributor. To compare melanocyte meQTLs with those from malignant melanomas, we performed meQTL analysis on skin cutaneous melanomas from The Cancer Genome Atlas (n = 444). A substantial proportion of meQTL probes (45.9%) in primary melanocytes are preserved in melanomas, while a smaller fraction of eQTL genes is preserved (12.7%). Integration of melanocyte multi-QTL and melanoma meQTL identified candidate susceptibility genes at 72% of melanoma GWAS loci. Beyond GWAS annotation, meQTL-eQTL colocalization in melanocytes suggested that 841 unique genes potentially share a causal variant with a nearby methylation probe in melanocytes. Finally, melanocyte trans-meQTL identified a hotspot for rs12203592, a cis-eQTL of a transcription factor, IRF4, with 131 candidate target CpGs. Motif enrichment and IRF4 ChIPseq analysis demonstrated that these target CpGs are enriched in IRF4 binding sites, suggesting an IRF4-mediated regulatory network. Our study highlights the utility of cell-type-specific meQTL.
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- 2021
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