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1. On the informative value of community‐based indoor radon values in relation to lung cancer

Author

Albert Rosenberger, Heike Bickeböller, David C. Christiani, Geoffrey Liu, Matthew B. Schabath, Luisa F. Duarte, Loic Le Marchand, Christopher Haiman, Teresa Landi, Dario Consonni, John K. Field, Michael P. A. Davies, Demetrios Albanes, Adonina Tardón, Guillermo Fernández‐Tardón, Gad Rennert, Christopher I. Amos, and Rayjean J. Hung

Subjects
histological subtypes, lung cancer, radiation, smoking, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Radon is a radioactive gas and a major risk factor for lung cancer (LC). Methods We investigated the dose–response relationship between radon and LC risk in the International Lung Cancer Consortium with 8927 cases and 5562 controls from Europe, North America, and Israel, conducted between 1992 and 2016. Spatial indoor radon exposure in the residential area (sIR) obtained from national surveys was linked to the participants' residential geolocation. Parametric linear and spline functions were fitted within a logistic regression framework. Results We observed a non‐linear spatial‐dose response relationship for sIR

Published
2024
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2. Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response

Author

Meghana Pagadala, Timothy J. Sears, Victoria H. Wu, Eva Pérez-Guijarro, Hyo Kim, Andrea Castro, James V. Talwar, Cristian Gonzalez-Colin, Steven Cao, Benjamin J. Schmiedel, Shervin Goudarzi, Divya Kirani, Jessica Au, Tongwu Zhang, Teresa Landi, Rany M. Salem, Gerald P. Morris, Olivier Harismendy, Sandip Pravin Patel, Ludmil B. Alexandrov, Jill P. Mesirov, Maurizio Zanetti, Chi-Ping Day, Chun Chieh Fan, Wesley K. Thompson, Glenn Merlino, J. Silvio Gutkind, Pandurangan Vijayanand, and Hannah Carter

Subjects
Science
Abstract

Abstract With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy.

Published
2023
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3. Higher polygenic risk for melanoma is associated with improved survival in a high ultraviolet radiation setting

Author

Mathias Seviiri, Richard A. Scolyer, D. Timothy Bishop, Julia A. Newton-Bishop, Mark M. Iles, Serigne N. Lo, Johnathan R. Stretch, Robyn P. M. Saw, Omgo E. Nieweg, Kerwin F. Shannon, Andrew J. Spillane, Scott D. Gordon, Catherine M. Olsen, David C. Whiteman, Maria Teresa Landi, John F. Thompson, Georgina V. Long, Stuart MacGregor, and Matthew H. Law

Subjects
Melanoma, Melanoma-specific survival, Polygenic risk score, Genome-wide association study, Skin cancer, Medicine
Abstract

Abstract Background The role of germline genetic factors in determining survival from cutaneous melanoma (CM) is not well understood. Objective To perform a genome-wide association study (GWAS) meta-analysis of melanoma-specific survival (MSS), and test whether a CM-susceptibility polygenic risk score (PRS) is associated with MSS. Methods We conducted two Cox proportional-hazard GWAS of MSS using data from the Melanoma Institute Australia, a high ultraviolet (UV) radiation setting (MIA; 5,762 patients with melanoma; 800 melanoma deaths) and UK Biobank (UKB: 5,220 patients with melanoma; 241 melanoma deaths), and combined them in a fixed-effects meta-analysis. Significant (P

Published
2022
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4. Deciphering associations between three RNA splicing-related genetic variants and lung cancer risk

Author

Wenjun Yang, Hongliang Liu, Ruoxin Zhang, Jennifer A. Freedman, Younghun Han, Rayjean J. Hung, Yonathan Brhane, John McLaughlin, Paul Brennan, Heike Bickeboeller, Albert Rosenberger, Richard S. Houlston, Neil E. Caporaso, Maria Teresa Landi, Irene Brueske, Angela Risch, David C. Christiani, Christopher I. Amos, Xiaoxin Chen, Steven R. Patierno, and Qingyi Wei

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Limited efforts have been made in assessing the effect of genome-wide profiling of RNA splicing-related variation on lung cancer risk. In the present study, we first identified RNA splicing-related genetic variants linked to lung cancer in a genome-wide profiling analysis and then conducted a two-stage (discovery and replication) association study in populations of European ancestry. Discovery and validation were conducted sequentially with a total of 29,266 cases and 56,450 controls from both the Transdisciplinary Research in Cancer of the Lung and the International Lung Cancer Consortium as well as the OncoArray database. For those variants identified as significant in the two datasets, we further performed stratified analyses by smoking status and histological type and investigated their effects on gene expression and potential regulatory mechanisms. We identified three genetic variants significantly associated with lung cancer risk: rs329118 in JADE2 (P = 8.80E−09), rs2285521 in GGA2 (P = 4.43E−08), and rs198459 in MYRF (P = 1.60E−06). The combined effects of all three SNPs were more evident in lung squamous cell carcinomas (P = 1.81E−08, P = 6.21E−08, and P = 7.93E−04, respectively) than in lung adenocarcinomas and in ever smokers (P = 9.80E−05, P = 2.70E−04, and P = 2.90E−05, respectively) than in never smokers. Gene expression quantitative trait analysis suggested a role for the SNPs in regulating transcriptional expression of the corresponding target genes. In conclusion, we report that three RNA splicing-related genetic variants contribute to lung cancer susceptibility in European populations. However, additional validation is needed, and specific splicing mechanisms of the target genes underlying the observed associations also warrants further exploration.

Published
2022
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5. Characterizing the tumor microenvironment in rare renal cancer histological types

Author

Naoise C Synnott, Maria Luana Poeta, Manuela Costantini, Ruth M Pfeiffer, Mengying Li, Yelena Golubeva, Scott Lawrence, Karun Mutreja, Carla Amoreo, Malgorzata Dabrowska, Giuseppe Simone, Edoardo Pescarmona, Petra Lenz, Mary Olanich, Maire Duggan, Mustapha Abubakar, Vito Michele Fazio, Michele Gallucci, Steno Sentinelli, and Maria Teresa Landi

Subjects
tumor microenvironment, rare cancer, kidney cancer, digital pathology, papillary renal cell carcinoma, Pathology, RB1-214
Abstract

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

Published
2022
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6. Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

Author

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 The INTEGRAL-ILCCO Consortium

Subjects
Susceptibility, Association, Gene–gene integration, Prediction, Polygenic risk score, Decision trees, Medicine
Abstract

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. Furthermore, decision trees were created to investigate variant × 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.

Published
2022
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7. Application of two job indices for general occupational demands in a pooled analysis of case–control studies on lung cancer

Author

Jan Hovanec, Jack Siemiatycki, David I Conway, Ann Olsson, Pascal Guenel, Danièle Luce, Karl-Heinz Jöckel, Hermann Pohlabeln, Wolfgang Ahrens, Stefan Karrasch, Heinz-Erich Wichmann, Per Gustavsson, Dario Consonni, Franco Merletti, Lorenzo Richiardi, Simonato Lorenzo, Cristina Fortes, Marie-Élise Parent, John R McLaughlin, Paul Demers, Maria Teresa Landi, Neil Caporaso, Guillermo Fernández-Tardón, David Zaridze, Beata Świątkowska, Tamas Pándics, Jolanta Lissowska, Eleonora Fabianova, John K Field, Dana Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Hans Kromhout, Roel Vermeulen, Paolo Boffetta, Kurt Straif, Joachim Schüz, Swaantje Casjens, Beate Pesch, Thomas Brüning, and Thomas Behrens

Subjects
cancer, smoking, lung cancer, psychosocial, job index, case–control, tumor subtype, social prestige, occupational demand, Public aspects of medicine, RA1-1270
Abstract

OBJECTIVES: We investigated general job demands as a risk factor for lung cancer as well as their role in the association between occupational prestige and lung cancer. METHODS: In 13 case–control studies on lung cancer, as part of the international SYNERGY project, we applied indices for physical (PHI) and psychosocial (PSI) job demands – each with four categories (high to low). We estimated odds ratios (OR) and 95% confidence intervals (CI) for lung cancer by unconditional logistic regression, separately for men and women and adjusted for study centre, age, smoking behavior, and former employment in occupations with potential exposure to carcinogens. Further, we investigated, whether higher risks among men with low occupational prestige (Treiman’s Standard International Occupational Prestige Scale) were affected by adjustment for the job indices. RESULTS: In 30 355 men and 7371 women, we found increased risks (OR) for lung cancer with high relative to low job demands in both men [PHI 1.74 (95% CI 1.56–1.93), PSI 1.33 (95% CI 1.17–1.51)] and women [PHI 1.62 (95% CI 1.24–2.11), PSI 1.31 (95% CI 1.09–1.56)]. OR for lung cancer among men with low occupational prestige were slightly reduced when adjusting for PHI [low versus high prestige OR from 1.44 (95% CI 1.32–1.58) to 1.30 (95% CI 1.17–1.45)], but not PSI. CONCLUSIONS: Higher physical job demands were associated with increased risks of lung cancer, while associations for higher psychosocial demands were less strong. In contrast to physical demands, psychosocial demands did not contribute to clarify the association of occupational prestige and lung cancer.

Published
2021
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8. SUITOR: Selecting the number of mutational signatures through cross-validation.

Author

Donghyuk Lee, Difei Wang, Xiaohong R Yang, Jianxin Shi, Maria Teresa Landi, and Bin Zhu

Subjects
Biology (General), QH301-705.5
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.

Published
2022
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9. Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Author

Yan Dora Zhang, Amber N. Hurson, Haoyu Zhang, Parichoy Pal Choudhury, Douglas F. Easton, Roger L. Milne, Jacques Simard, Per Hall, Kyriaki Michailidou, Joe Dennis, Marjanka K. Schmidt, Jenny Chang-Claude, Puya Gharahkhani, David Whiteman, Peter T. Campbell, Michael Hoffmeister, Mark Jenkins, Ulrike Peters, Li Hsu, Stephen B. Gruber, Graham Casey, Stephanie L. Schmit, Tracy A. O’Mara, Amanda B. Spurdle, Deborah J. Thompson, Ian Tomlinson, Immaculata De Vivo, Maria Teresa Landi, Matthew H. Law, Mark M. Iles, Florence Demenais, Rajiv Kumar, Stuart MacGregor, D. Timothy Bishop, Sarah V. Ward, Melissa L. Bondy, Richard Houlston, John K. Wiencke, Beatrice Melin, Jill Barnholtz-Sloan, Ben Kinnersley, Margaret R. Wrensch, Christopher I. Amos, Rayjean J. Hung, Paul Brennan, James McKay, Neil E. Caporaso, Sonja I. Berndt, Brenda M. Birmann, Nicola J. Camp, Peter Kraft, Nathaniel Rothman, Susan L. Slager, Andrew Berchuck, Paul D. P. Pharoah, Thomas A. Sellers, Simon A. Gayther, Celeste L. Pearce, Ellen L. Goode, Joellen M. Schildkraut, Kirsten B. Moysich, Laufey T. Amundadottir, Eric J. Jacobs, Alison P. Klein, Gloria M. Petersen, Harvey A. Risch, Rachel Z. Stolzenberg-Solomon, Brian M. Wolpin, Donghui Li, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Ali Amin Al Olama, Mark P. Purdue, Ghislaine Scelo, Marlene D. Dalgaard, Mark H. Greene, Tom Grotmol, Peter A. Kanetsky, Katherine A. McGlynn, Katherine L. Nathanson, Clare Turnbull, Fredrik Wiklund, Breast Cancer Association Consortium (BCAC), Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON), Colon Cancer Family Registry (CCFR), Transdisciplinary Studies of Genetic Variation in Colorectal Cancer (CORECT), Endometrial Cancer Association Consortium (ECAC), Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Melanoma Genetics Consortium (GenoMEL), Glioma International Case-Control Study (GICC), International Lung Cancer Consortium (ILCCO), Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Consortium, International Consortium of Investigators Working on Non-Hodgkin’s Lymphoma Epidemiologic Studies (InterLymph), Ovarian Cancer Association Consortium (OCAC), Oral Cancer GWAS, Pancreatic Cancer Case-Control Consortium (PanC4), Pancreatic Cancer Cohort Consortium (PanScan), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL), Renal Cancer GWAS, Testicular Cancer Consortium (TECAC), Stephen J. Chanock, Nilanjan Chatterjee, and Montserrat Garcia-Closas

Subjects
Science
Abstract

In cancer many gene variants may contribute to disease etiology, but the impact of a given gene variant may have varied effect size. Here, the authors analyse summary statistics of genome-wide association studies from fourteen cancers, and show the utility of polygenic risk scores may vary depending on cancer type.

Published
2020
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10. The genomic and epigenomic evolutionary history of papillary renal cell carcinomas

Author

Bin Zhu, Maria Luana Poeta, Manuela Costantini, Tongwu Zhang, Jianxin Shi, Steno Sentinelli, Wei Zhao, Vincenzo Pompeo, Maurizio Cardelli, Boian S. Alexandrov, Burcak Otlu, Xing Hua, Kristine Jones, Seth Brodie, Malgorzata Ewa Dabrowska, Jorge R. Toro, Meredith Yeager, Mingyi Wang, Belynda Hicks, Ludmil B. Alexandrov, Kevin M. Brown, David C. Wedge, Stephen Chanock, Vito Michele Fazio, Michele Gallucci, and Maria Teresa Landi

Subjects
Science
Abstract

Many tumours are heterogenous, which calls into question whether multiple biopsies are required to accurately assess the cancer. Here, the authors show that papillary renal cell carcinoma is clonal in nature, suggesting that in this cancer one biopsy is sufficient for diagnosis and molecular analyses.

Published
2020
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11. Protein-altering germline mutations implicate novel genes related to lung cancer development

Author

Xuemei Ji, Semanti Mukherjee, Maria Teresa Landi, Yohan Bosse, Philippe Joubert, Dakai Zhu, Ivan Gorlov, Xiangjun Xiao, Younghun Han, Olga Gorlova, Rayjean J. Hung, Yonathan Brhane, Robert Carreras-Torres, David C. Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Chu Chen, Jinyoung Byun, Konstantin H. Dragnev, John K. Field, Lambertus FA. Kiemeney, Philip Lazarus, Shan Zienolddiny, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Pier A. Bertazzi, Angela C. Pesatori, Nancy Diao, Li Su, Lei Song, Ruyang Zhang, Natasha Leighl, Jakob S. Johansen, Anders Mellemgaard, Walid Saliba, Christopher Haiman, Lynne Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Erik H. F. M. van der Heijden, Jin Hee Kim, Michael P. A. Davies, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Gary E. Goodman, Angela Cox, Fiona Taylor, Penella Woll, Erich Wichmann, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances Shepherd, Ming-Sound Tsao, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Lesley M. Butler, Kenneth Offit, Preethi Srinivasan, Chaitanya Bandlamudi, Matthew D. Hellmann, David B. Solit, Mark E. Robson, Charles M. Rudin, Zsofia K. Stadler, Barry S. Taylor, Michael F. Berger, Richard Houlston, John McLaughlin, Victoria Stevens, David C. Nickle, Ma’en Obeidat, Wim Timens, María Soler Artigas, Sanjay Shete, Hermann Brenner, Stephen Chanock, Paul Brennan, James D. McKay, and Christopher I. Amos

Subjects
Science
Abstract

In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.

Published
2020
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12. Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma

Author

Xing Hua, Wei Zhao, Angela C. Pesatori, Dario Consonni, Neil E. Caporaso, Tongwu Zhang, Bin Zhu, Mingyi Wang, Kristine Jones, Belynda Hicks, Lei Song, Joshua Sampson, David C. Wedge, Jianxin Shi, and Maria Teresa Landi

Subjects
Science
Abstract

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.

Published
2020
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13. Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility

Author

Linda Kachuri, Mattias Johansson, Sara R. Rashkin, Rebecca E. Graff, Yohan Bossé, Venkata Manem, Neil E. Caporaso, Maria Teresa Landi, David C. Christiani, Paolo Vineis, Geoffrey Liu, Ghislaine Scelo, David Zaridze, Sanjay S. Shete, Demetrius Albanes, Melinda C. Aldrich, Adonina Tardón, Gad Rennert, Chu Chen, Gary E. Goodman, Jennifer A. Doherty, Heike Bickeböller, John K. Field, Michael P. Davies, M. Dawn Teare, Lambertus A. Kiemeney, Stig E. Bojesen, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Loïc Le Marchand, Iona Cheng, Matthew B. Schabath, Eric J. Duell, Angeline S. Andrew, Jonas Manjer, Philip Lazarus, Susanne Arnold, James D. McKay, Nima C. Emami, Matthew T. Warkentin, Yonathan Brhane, Ma’en Obeidat, Richard M. Martin, Caroline Relton, George Davey Smith, Philip C. Haycock, Christopher I. Amos, Paul Brennan, John S. Witte, and Rayjean J. Hung

Subjects
Science
Abstract

The role of impaired lung function in lung cancer etiology is complex due to the relation of cigarette smoking to both conditions. Here, supported by Mendelian randomization analysis the authors find a link between pulmonary function impairment and lung cancer risk beyond smoking, implicating immune-related pathways

Published
2020
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14. Association of germline variants in telomere maintenance genes (POT1, TERF2IP, ACD, and TERT) with spitzoid morphology in familial melanoma: A multi-center case series

Author

Alisa M. Goldstein, Richard Qin, Emily Y. Chu, David E. Elder, Daniela Massi, David J. Adams, Paul W. Harms, Carla Daniela Robles-Espinoza, Julia A. Newton-Bishop, D. Timothy Bishop, Mark Harland, Elizabeth A. Holland, Anne E. Cust, Helen Schmid, Graham J. Mann, Susana Puig, Miriam Potrony, Llucia Alos, Eduardo Nagore, David Millán-Esteban, Nicholas K. Hayward, Natasa Broit, Jane M. Palmer, Vaishnavi Nathan, Elizabeth G. Berry, Esteban Astiazaran-Symonds, Xiaohong R. Yang, Margaret A. Tucker, Maria Teresa Landi, Ruth M. Pfeiffer, and Michael R. Sargen

Subjects
Dermatology
Published
2023

15. Genetic Relationship Between Endometriosis and Melanoma

Author

Fei Yang, Sally Mortlock, Stuart MacGregor, Mark M. Iles, Maria Teresa Landi, Jianxin Shi, Matthew H. Law, and Grant W. Montgomery

Subjects
endometriosis, melanoma, genetic correlation, genetic risk, mendelian randomization, Reproduction, QH471-489, Medicine (General), R5-920
Abstract

Epidemiological studies have observed that risk of endometriosis is associated with history of cutaneous melanoma and vice versa. Evidence for shared biological mechanisms between the two traits is limited. The aim of this study was to investigate the genetic correlation and causal relationship between endometriosis and melanoma. Summary statistics from genome-wide association meta-analyses (GWAS) for endometriosis and melanoma were used to estimate the genetic correlation between the traits and Mendelian randomization was used to test for a causal association. When using summary statistics from separate female and male melanoma cohorts we identified a significant positive genetic correlation between melanoma in females and endometriosis (rg = 0.144, se = 0.065, p = 0.025). However, we find no evidence of a correlation between endometriosis and melanoma in males or a combined melanoma dataset. Endometriosis was not genetically correlated with skin color, red hair, childhood sunburn occasions, ease of skin tanning, or nevus count suggesting that the correlation between endometriosis and melanoma in females is unlikely to be influenced by pigmentary traits. Mendelian Randomization analyses also provided evidence for a relationship between the genetic risk of melanoma in females and endometriosis. Colocalization analysis identified 27 genomic loci jointly associated with the two diseases regions that contain different causal variants influencing each trait independently. This study provides evidence of a small genetic correlation and relationship between the genetic risk of melanoma in females and endometriosis. Genetic risk does not equate to disease occurrence and differences in the pathogenesis and age of onset of both diseases means it is unlikely that occurrence of melanoma causes endometriosis. This study instead provides evidence that having an increased genetic risk for melanoma in females is related to increased risk of endometriosis. Larger GWAS studies with increased power will be required to further investigate these associations.

Published
2021
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16. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R. Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H. M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2019
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17. Shared heritability and functional enrichment across six solid cancers

Author

Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström

Subjects
Science
Abstract

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Published
2019
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18. Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls

Author

Jung Kim, Wen Luo, Mingyi Wang, Talia Wegman-Ostrosky, Megan N. Frone, Jennifer J. Johnston, Michael L. Nickerson, Melissa Rotunno, Shengchao A. Li, Maria I. Achatz, Seth A. Brodie, Michael Dean, Kelvin C. de Andrade, Fernanda P. Fortes, Matthew Gianferante, Payal Khincha, Mary L. McMaster, Lisa J. McReynolds, Alexander Pemov, Maisa Pinheiro, Karina M. Santiago, Blanche P. Alter, Neil E. Caporaso, Shahinaz M. Gadalla, Lynn R. Goldin, Mark H. Greene, Jennifer Loud, Xiaohong R. Yang, Neal D. Freedman, Susan M. Gapstur, Mia M. Gaudet, Donato Calista, Paola Ghiorzo, Maria Concetta Fargnoli, Eduardo Nagore, Ketty Peris, Susana Puig, Maria Teresa Landi, Belynda Hicks, Bin Zhu, Jia Liu, Joshua N. Sampson, Stephen J. Chanock, Lisa J. Mirabello, Lindsay M. Morton, Leslie G. Biesecker, Margaret A. Tucker, Sharon A. Savage, Alisa M. Goldstein, and Douglas R. Stewart

Subjects
ACMG secondary findings, Familial cancer exome, Population study, Variant classification, Medicine, Genetics, QH426-470
Abstract

Abstract Background Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8–5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982). Methods We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS). Results In the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers. Conclusion The 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls.

Published
2018
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19. Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

Author

Corina Lesseur, Aida Ferreiro-Iglesias, James D McKay, Yohan Bossé, Mattias Johansson, Valerie Gaborieau, Maria Teresa Landi, David C Christiani, Neil C Caporaso, Stig E Bojesen, Christopher I Amos, Sanjay Shete, Geoffrey Liu, Gadi Rennert, Demetrius Albanes, Melinda C Aldrich, Adonina Tardon, Chu Chen, Liloglou Triantafillos, John K Field, Marion Dawn Teare, Lambertus A Kiemeney, Brenda Diergaarde, Robert L Ferris, Shanbeh Zienolddiny, Stephen Lam, Andrew F Olshan, Mark C Weissler, Martin Lacko, Angela Risch, Heike Bickeböller, Andy R Ness, Steve Thomas, Loic Le Marchand, Matthew B Schabath, Victor Wünsch-Filho, Eloiza H Tajara, Angeline S Andrew, Gary M Clifford, Philip Lazarus, Kjell Grankvist, Mikael Johansson, Susanne Arnold, Olle Melander, Hans Brunnström, Stefania Boccia, Gabriella Cadoni, Wim Timens, Ma'en Obeidat, Xiangjun Xiao, Richard S Houlston, Rayjean J Hung, and Paul Brennan

Subjects
Genetics, QH426-470
Abstract

Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta

Published
2021
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20. Sub-multiplicative interaction between polygenic risk score and household coal use in relation to lung adenocarcinoma among never-smoking women in Asia

Author

Batel Blechter, Jason Y.Y. Wong, Chao Agnes Hsiung, H.Dean Hosgood, Zhihua Yin, Xiao-Ou Shu, Han Zhang, Jianxin Shi, Lei Song, Minsun Song, Wei Zheng, Zhaoming Wang, Neil Caporaso, Laurie Burdette, Meredith Yeager, Sonja I. Berndt, Maria Teresa Landi, Chien-Jen Chen, Gee-Chen Chang, Chin-Fu Hsiao, Ying-Huang Tsai, Kuan-Yu Chen, Ming-Shyan Huang, Wu-Chou Su, Yuh-Min Chen, Li-Hsin Chien, Chung-Hsing Chen, Tsung-Ying Yang, Chih-Liang Wang, Jen-Yu Hung, Chien-Chung Lin, Reury-Perng Perng, Chih-Yi Chen, Kun-Chieh Chen, Yao-Jen Li, Chong-Jen Yu, Yi-Song Chen, Ying-Hsiang Chen, Fang-Yu Tsai, Wei Jie Seow, Bryan A. Bassig, Wei Hu, Bu-Tian Ji, Wei Wu, Peng Guan, Qincheng He, Yu-Tang Gao, Qiuyin Cai, Wong-Ho Chow, Yong-Bing Xiang, Dongxin Lin, Chen Wu, Yi-Long Wu, Min-Ho Shin, Yun-Chul Hong, Keitaro Matsuo, Kexin Chen, Maria Pik Wong, Daru Lu, Li Jin, Jiu-Cun Wang, Adeline Seow, Tangchun Wu, Hongbing Shen, Joseph F. Fraumeni, Pan-Chyr Yang, I-Shou Chang, Baosen Zhou, Stephen J. Chanock, Nathaniel Rothman, Nilanjan Chatterjee, and Qing Lan

Subjects
Lung adenocarcinoma, Polygenic risk score, Gene-environment interaction, Household coal use, Never-smoking women in Asia, Environmental sciences, GE1-350
Abstract

We previously identified 10 lung adenocarcinoma susceptibility loci in a genome-wide association study (GWAS) conducted in the Female Lung Cancer Consortium in Asia (FLCCA), the largest genomic study of lung cancer among never-smoking women to date. Furthermore, household coal use for cooking and heating has been linked to lung cancer in Asia, especially in Xuanwei, China. We investigated the potential interaction between genetic susceptibility and coal use in FLCCA. We analyzed GWAS-data from Taiwan, Shanghai, and Shenyang (1472 cases; 1497 controls), as well as a separate study conducted in Xuanwei (152 cases; 522 controls) for additional analyses. We summarized genetic susceptibility using a polygenic risk score (PRS), which was the weighted sum of the risk-alleles from the 10 previously identified loci. We estimated associations between a PRS, coal use (ever/never), and lung adenocarcinoma with multivariable logistic regression models, and evaluated potential gene-environment interactions using likelihood ratio tests. There was a strong association between continuous PRS and lung adenocarcinoma among never coal users (Odds Ratio (OR) = 1.69 (95% Confidence Interval (CI) = 1.53, 1.87), p=1 × 10−26). This effect was attenuated among ever coal users (OR = 1.24 (95% CI: 1.03, 1.50), p = 0.02, p-interaction = 6 × 10−3). We observed similar attenuation among coal users from Xuanwei. Our study provides evidence that genetic susceptibility to lung adenocarcinoma among never-smoking Asian women is weaker among coal users. These results suggest that lung cancer pathogenesis may differ, at least partially, depending on exposure to coal combustion products. Notably, these novel findings are among the few instances of sub-multiplicative gene-environment interactions in the cancer literature.

Published
2021
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21. Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity

Author

Aida Ferreiro-Iglesias, Corina Lesseur, James McKay, Rayjean J. Hung, Younghun Han, Xuchen Zong, David Christiani, Mattias Johansson, Xiangjun Xiao, Yafang Li, David C. Qian, Xuemei Ji, Geoffrey Liu, Neil Caporaso, Ghislaine Scelo, David Zaridze, Anush Mukeriya, Milica Kontic, Simona Ognjanovic, Jolanta Lissowska, Małgorzata Szołkowska, Beata Swiatkowska, Vladimir Janout, Ivana Holcatova, Ciprian Bolca, Milan Savic, Miodrag Ognjanovic, Stig Egil Bojesen, Xifeng Wu, Demetrios Albanes, Melinda C. Aldrich, Adonina Tardon, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Loic Le Marchand, Gadi Rennert, Chu Chen, Jennifer Doherty, Gary Goodman, Heike Bickeböller, H-Erich Wichmann, Angela Risch, Albert Rosenberger, Hongbing Shen, Juncheng Dai, John K. Field, Michael Davies, Penella Woll, M. Dawn Teare, Lambertus A. Kiemeney, Erik H. F. M. van der Heijden, Jian-Min Yuan, Yun-Chul Hong, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Ming-Sound Tsao, Mikael Johansson, Kjell Grankvist, Matthew B. Schabath, Angeline Andrew, Eric Duell, Olle Melander, Hans Brunnström, Philip Lazarus, Susanne Arnold, Stacey Slone, Jinyoung Byun, Ahsan Kamal, Dakai Zhu, Maria Teresa Landi, Christopher I. Amos, and Paul Brennan

Subjects
Science
Abstract

Abstract Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA–tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.

Published
2018
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22. Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

Author

Xuemei Ji, Yohan Bossé, Maria Teresa Landi, Jiang Gui, Xiangjun Xiao, David Qian, Philippe Joubert, Maxime Lamontagne, Yafang Li, Ivan Gorlov, Mariella de Biasi, Younghun Han, Olga Gorlova, Rayjean J. Hung, Xifeng Wu, James McKay, Xuchen Zong, Robert Carreras-Torres, David C. Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Chu Chen, M. Dawn Teare, John K. Field, Lambertus A. Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Hongbing Shen, Yun-Chul Hong, Jian-Min Yuan, Pier A. Bertazzi, Angela C. Pesatori, Yuanqing Ye, Nancy Diao, Li Su, Ruyang Zhang, Yonathan Brhane, Natasha Leighl, Jakob S. Johansen, Anders Mellemgaard, Walid Saliba, Christopher Haiman, Lynne Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Erik H. F. M. van der Heijden, Jin Hee Kim, Juncheng Dai, Zhibin Hu, Michael P. A. Davies, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Jennifer Doherty, Gary E. Goodman, Angela Cox, Fiona Taylor, Penella Woll, Irene Brüske, Judith Manz, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances Shepherd, Ming-Sound Tsao, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Shanbeh Zienolddiny, Eric J. Duell, Lesley M. Butler, Woon-Puay Koh, Yu-Tang Gao, Richard Houlston, John McLaughlin, Victoria Stevens, David C. Nickle, Ma’en Obeidat, Wim Timens, Bin Zhu, Lei Song, María Soler Artigas, Martin D. Tobin, Louise V. Wain, Fangyi Gu, Jinyoung Byun, Ahsan Kamal, Dakai Zhu, Rachel F. Tyndale, Wei-Qi Wei, Stephen Chanock, Paul Brennan, and Christopher I. Amos

Subjects
Science
Abstract

The chromosome 15q25.1 locus is a leading susceptibility region for lung cancer. Here, the authors interrogate three GWAS cohorts with 42,901 individuals to investigate potential pathological pathways such as gated channel activity and neuroactive ligand receptor interaction in lung cancer etiology.

Published
2018
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23. Weak sharing of genetic association signals in three lung cancer subtypes: evidence at the SNP, gene, regulation, and pathway levels

Author

Timothy D. O’Brien, Peilin Jia, Neil E. Caporaso, Maria Teresa Landi, and Zhongming Zhao

Subjects
GWAS, eQTL, Enhancer, Lung cancer subtype, Functional genomics, Pathway analysis, Medicine, Genetics, QH426-470
Abstract

Abstract Background There are two main types of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC has many subtypes, but the two most common are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These subtypes are mainly classified by physiological and pathological characteristics, although there is increasing evidence of genetic and molecular differences as well. Although some work has been done at the somatic level to explore the genetic and biological differences among subtypes, little work has been done that interrogates these differences at the germline level to characterize the unique and shared susceptibility genes for each subtype. Methods We used single-nucleotide polymorphisms (SNPs) from a genome-wide association study (GWAS) of European samples to interrogate the similarity of the subtypes at the SNP, gene, pathway, and regulatory levels. We expanded these genotyped SNPs to include all SNPs in linkage disequilibrium (LD) using data from the 1000 Genomes Project. We mapped these SNPs to several lung tissue expression quantitative trait loci (eQTL) and enhancer datasets to identify regulatory SNPs and their target genes. We used these genes to perform a biological pathway analysis for each subtype. Results We identified 8295, 8734, and 8361 SNPs with moderate association signals for LUAD, LUSC, and SCLC, respectively. Those SNPs had p < 1 × 10− 3 in the original GWAS or were within LD (r 2 > 0.8, Europeans) to the genotyped SNPs. We identified 215, 320, and 172 disease-associated genes for LUAD, LUSC, and SCLC, respectively. Only five genes (CHRNA5, IDH3A, PSMA4, RP11-650 L12.2, and TBC1D2B) overlapped all subtypes. Furthermore, we observed only two pathways from the Kyoto Encyclopedia of Genes and Genomes shared by all subtypes. At the regulatory level, only three eQTL target genes and two enhancer target genes overlapped between all subtypes. Conclusions Our results suggest that the three lung cancer subtypes do not share much genetic signal at the SNP, gene, pathway, or regulatory level, which differs from the common subtype classification based upon histology. However, three (CHRNA5, IDH3A, and PSMA4) of the five genes shared between the subtypes are well-known lung cancer genes that may act as general lung cancer genes regardless of subtype.

Published
2018
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24. Tumor Mutational Burden by Whole-Genome Sequencing in Resected NSCLC of Never Smokers

Author

Louis-Jacques Ruel, Zhonglin Li, Nathalie Gaudreault, Cyndi Henry, Victoria Saavedra Armero, Dominique K. Boudreau, Tongwu Zhang, Maria Teresa Landi, Catherine Labbé, Christian Couture, Patrice Desmeules, Philippe Joubert, and Yohan Bossé

Subjects
Lung Neoplasms, Smokers, Oncology, Epidemiology, Carcinoma, Non-Small-Cell Lung, Exome Sequencing, Biomarkers, Tumor, Humans
Abstract

Background: Data are scarce about tumor mutational burden (TMB) as a biomarker in never smokers with non–small cell lung cancer (NSCLC). Methods: TMB was assessed by whole-genome sequencing (WGS) and compared with in silico reduced whole-exome sequencing (WES) and targeted commercial next-generation sequencing (NGS) gene panels in 92 paired tumor-normal samples from never smokers who underwent NSCLC resection with curative intent. Analyses were performed to test for association with survival after surgery and to identify the optimal prognostic TMB cutoff. Results: Tumors of never smokers with NSCLC had low TMB scores (median 1.57 mutations/Mb; range, 0.13–17.94). A TMB cutoff of 1.70 mutations/Mb was associated with a 5-year overall survival of 58% in the high-TMB (42% of cases) compared with 86% in low-TMB patients (Wald P = 0.0029). TMB scores from WGS and WES were highly correlated (Spearman ρ = 0.93, P < 2.2e−16). TMB scores from NGS panels demonstrated high intraindividual fluctuations and identified high-TMB patients with 65% concordance in average compared with WGS. Conclusions: In resected NSCLC of never smokers, high TMB was associated with worse prognosis. WES provided a good estimate of TMB while targeted NGS panels seem to lack adequate depth and resolution in the setting of low mutation burden. Impact: TMB is a prognostic indicator of survival in resected NSCLC from individuals who never smoked. In this setting of low mutation counts, TMB can be accurately measured by WGS or WES, but not NGS panels.

Published
2022

25. Functional characterization of a multi-cancer risk locus on chr5p15.33 reveals regulation of TERT by ZNF148

Author

Jun Fang, Jinping Jia, Matthew Makowski, Mai Xu, Zhaoming Wang, Tongwu Zhang, Jason W. Hoskins, Jiyeon Choi, Younghun Han, Mingfeng Zhang, Janelle Thomas, Michael Kovacs, Irene Collins, Marta Dzyadyk, Abbey Thompson, Maura O'Neill, Sudipto Das, Qi Lan, Roelof Koster, PanScan Consortium, TRICL Consortium, GenoMEL Consortium, Rachael S. Stolzenberg-Solomon, Peter Kraft, Brian M. Wolpin, Pascal W. T. C. Jansen, Sara Olson, Katherine A. McGlynn, Peter A. Kanetsky, Nilanjan Chatterjee, Jennifer H. Barrett, Alison M. Dunning, John C. Taylor, Julia A. Newton-Bishop, D. Timothy Bishop, Thorkell Andresson, Gloria M. Petersen, Christopher I. Amos, Mark M. Iles, Katherine L. Nathanson, Maria Teresa Landi, Michiel Vermeulen, Kevin M. Brown, and Laufey T. Amundadottir

Subjects
Science
Abstract

Genetic variants at multiple loci of chr5p15.33 have been associated with susceptibility to numerous cancers. Here the authors show that the association of one of these loci may be explained by a variant, rs36115365, influencing telomerase reverse transcriptase (TERT) expression via ZNF148.

Published
2017
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26. Genetic variants of PTPN2 are associated with lung cancer risk: a re-analysis of eight GWASs in the TRICL-ILCCO consortium

Author

Yun Feng, Yanru Wang, Hongliang Liu, Zhensheng Liu, Coleman Mills, Younghun Han, Rayjean J. Hung, Yonathan Brhane, John McLaughlin, Paul Brennan, Heike Bickeboeller, Albert Rosenberger, Richard S. Houlston, Neil E. Caporaso, Maria Teresa Landi, Irene Brueske, Angela Risch, Yuanqing Ye, Xifeng Wu, David C. Christiani, Christopher I. Amos, and Qingyi Wei

Subjects
Medicine, Science
Abstract

Abstract The T-cell protein tyrosine phosphatase (TCPTP) pathway consists of signaling events mediated by TCPTP. Mutations and genetic variants of some genes in the TCPTP pathway are associated with lung cancer risk and survival. In the present study, we first investigated associations of 5,162 single nucleotide polymorphisms (SNPs) in 43 genes of this TCPTP pathway with lung cancer risk by using summary data of six published genome-wide association studies (GWAS) of 12,160 cases and 16,838 controls. We identified 11 independent SNPs in eight genes after correction for multiple comparisons by a false discovery rate

Published
2017
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27. Proceedings of the fifth international Molecular Pathological Epidemiology (MPE) meeting

Author

Song Yao, Peter T. Campbell, Tomotaka Ugai, Gretchen Gierach, Mustapha Abubakar, Viktor Adalsteinsson, Jonas Almeida, Paul Brennan, Stephen Chanock, Todd Golub, Samir Hanash, Curtis Harris, Cassandra A. Hathaway, Karl Kelsey, Maria Teresa Landi, Faisal Mahmood, Christina Newton, John Quackenbush, Scott Rodig, Nikolaus Schultz, Guillermo Tearney, Shelley S. Tworoger, Molin Wang, Xuehong Zhang, Montserrat Garcia-Closas, Timothy R. Rebbeck, Christine B. Ambrosone, and Shuji Ogino

Subjects
Cancer Research, Oncology, Neoplasms, Mutation, Tumor Microenvironment, Humans, Pathology, Molecular
Abstract

Cancer heterogeneities hold the key to a deeper understanding of cancer etiology and progression and the discovery of more precise cancer therapy. Modern pathological and molecular technologies offer a powerful set of tools to profile tumor heterogeneities at multiple levels in large patient populations, from DNA to RNA, protein and epigenetics, and from tumor tissues to tumor microenvironment and liquid biopsy. When coupled with well-validated epidemiologic methodology and well-characterized epidemiologic resources, the rich tumor pathological and molecular tumor information provide new research opportunities at an unprecedented breadth and depth. This is the research space where Molecular Pathological Epidemiology (MPE) emerged over a decade ago and has been thriving since then. As a truly multidisciplinary field, MPE embraces collaborations from diverse fields including epidemiology, pathology, immunology, genetics, biostatistics, bioinformatics, and data science. Since first convened in 2013, the International MPE Meeting series has grown into a dynamic and dedicated platform for experts from these disciplines to communicate novel findings, discuss new research opportunities and challenges, build professional networks, and educate the next-generation scientists. Herein, we share the proceedings of the Fifth International MPE meeting, held virtually online, on May 24 and 25, 2021. The meeting consisted of 21 presentations organized into the three main themes, which were recent integrative MPE studies, novel cancer profiling technologies, and new statistical and data science approaches. Looking forward to the near future, the meeting attendees anticipated continuous expansion and fruition of MPE research in many research fronts, particularly immune-epidemiology, mutational signatures, liquid biopsy, and health disparities.

Published
2022

28. Rare germline deleterious variants increase susceptibility for lung cancer

Author

Jian Sang, Tongwu Zhang, Jung Kim, Mengying Li, Angela C Pesatori, Dario Consonni, Lei Song, Jia Liu, Wei Zhao, Phuc H Hoang, Dave S Campbell, James Feng, Monica E D’Arcy, Naoise Synnott, Yingxi Chen, Zeni Wu, Bin Zhu, Xiaohong R Yang, Kevin M Brown, Jiyeon Choi, Jianxin Shi, and Maria Teresa Landi

Subjects
Germ Cells, Lung Neoplasms, DNA Repair, Genetics, Humans, Original Article, Genetic Predisposition to Disease, General Medicine, Molecular Biology, Genetics (clinical), Genome-Wide Association Study
Abstract

Although multiple common susceptibility loci for lung cancer (LC) have been identified by genome-wide association studies, they can explain only a small portion of heritability. The etiological contribution of rare deleterious variants (RDVs) to LC risk is not fully characterized and may account for part of the missing heritability. Here, we sequenced the whole exomes of 2777 participants from the Environment and Genetics in Lung cancer Etiology study, a homogenous population including 1461 LC cases and 1316 controls. In single-variant analyses, we identified a new RDV, rs77187983 [EHBP1, odds ratio (OR) = 3.13, 95% confidence interval (CI) = 1.34–7.30, P = 0.008] and replicated two previously reported RDVs, rs11571833 (BRCA2, OR = 2.18; 95% CI = 1.25–3.81, P = 0.006) and rs752672077 (MPZL2, OR = 3.70, 95% CI = 1.04–13.15, P = 0.044). In gene-based analyses, we confirmed BRCA2 (P = 0.007) and ATM (P = 0.014) associations with LC risk and identified TRIB3 (P = 0.009), involved in maintaining genome stability and DNA repair, as a new candidate susceptibility gene. Furthermore, cases were enriched with RDVs in homologous recombination repair [carrier frequency (CF) = 22.9% versus 19.5%, P = 0.017] and Fanconi anemia (CF = 12.5% versus 10.2%, P = 0.036) pathways. Our results were not significant after multiple testing corrections but were enriched in cases versus controls from large scale public biobank resources, including The Cancer Genome Atlas, FinnGen and UK Biobank. Our study identifies novel candidate genes and highlights the importance of RDVs in DNA repair-related genes for LC susceptibility. These findings improve our understanding of LC heritability and may contribute to the development of risk stratification and prevention strategies.

Published
2022

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

Author

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

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

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

Published
2016
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30. Contribution of Common Genetic Variants to Familial Aggregation of Disease and Implications for Sequencing Studies.

Author

Andrew Schlafly, Ruth M Pfeiffer, Eduardo Nagore, Susana Puig, Donato Calista, Paola Ghiorzo, Chiara Menin, Maria Concetta Fargnoli, Ketty Peris, Lei Song, Tongwu Zhang, Jianxin Shi, Maria Teresa Landi, and Joshua Neil Sampson

Subjects
Genetics, QH426-470
Abstract

Despite genetics being accepted as the primary cause of familial aggregation for most diseases, it is still unclear whether afflicted families are likely to share a single highly penetrant rare variant, many minimally penetrant common variants, or a combination of the two types of variants. We therefore use recent estimates of SNP heritability and the liability threshold model to estimate the proportion of afflicted families likely to carry a rare, causal variant. We then show that Polygenic Risk Scores (PRS) may be useful for identifying families likely to carry such a rare variant and therefore for prioritizing families to include in sequencing studies with that aim. Specifically, we introduce a new statistic that estimates the proportion of individuals carrying causal rare variants based on the family structure, disease pattern, and PRS of genotyped individuals. Finally, we consider data from the MelaNostrum consortium and show that, despite an estimated PRS heritability of only 0.05 for melanoma, families carrying putative causal variants had a statistically significantly lower PRS, supporting the idea that PRS prioritization may be a useful future tool. However, it will be important to evaluate whether the presence of rare mendelian variants are generally associated with the proposed test statistic or lower PRS in future and larger studies.

Published
2019
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31. SATS: A mutational signature analyzer of targeted sequenced tumors

Author

Donghyuk Lee, Min Hua, Difei Wang, Lei Song, Tongwu Zhang, Kai Yu, Xiaohong R. Yang, Stephen J. Chanock, Jianxin Shi, Maria Teresa Landi, and Bin Zhu

Abstract

Tumor mutational signatures are important in clinical decision-making and are typically analyzed using whole exome or genome sequencing (WES/WGS). However, targeted sequencing is more commonly used in clinical settings, posing challenges in mutational signature analysis due to sparse mutation data and non-overlapping targeted gene panels. We introduce SATS (Signature Analyzer for Targeted Sequencing), an analytical method that identifies mutational signatures in targeted sequenced tumors by analyzing tumor mutational burdens and accounting for different gene panels. We demonstrate through simulations and pseudo-targeted sequencing data (generated by down-sampling WES/WGS data) that SATS can accurately detect common mutational signatures with distinct profiles. Using SATS, we created a pan-cancer catalog of mutational signatures specifically tailored to targeted sequencing by analyzing 100,477 targeted sequenced tumors from the AACR Project GENIE. The catalog allows SATS to estimate signature activities even within a single sample, providing new opportunities for applying mutational signatures in clinical settings.

Published
2023

32. Data from Tumor Mutational Burden by Whole-Genome Sequencing in Resected NSCLC of Never Smokers

Author

Yohan Bossé, Philippe Joubert, Patrice Desmeules, Christian Couture, Catherine Labbé, Maria Teresa Landi, Tongwu Zhang, Dominique K. Boudreau, Victoria Saavedra Armero, Cyndi Henry, Nathalie Gaudreault, Zhonglin Li, and Louis-Jacques Ruel

Abstract

Background:Data are scarce about tumor mutational burden (TMB) as a biomarker in never smokers with non–small cell lung cancer (NSCLC).Methods:TMB was assessed by whole-genome sequencing (WGS) and compared with in silico reduced whole-exome sequencing (WES) and targeted commercial next-generation sequencing (NGS) gene panels in 92 paired tumor-normal samples from never smokers who underwent NSCLC resection with curative intent. Analyses were performed to test for association with survival after surgery and to identify the optimal prognostic TMB cutoff.Results:Tumors of never smokers with NSCLC had low TMB scores (median 1.57 mutations/Mb; range, 0.13–17.94). A TMB cutoff of 1.70 mutations/Mb was associated with a 5-year overall survival of 58% in the high-TMB (42% of cases) compared with 86% in low-TMB patients (Wald P = 0.0029). TMB scores from WGS and WES were highly correlated (Spearman ρ = 0.93, P < 2.2e−16). TMB scores from NGS panels demonstrated high intraindividual fluctuations and identified high-TMB patients with 65% concordance in average compared with WGS.Conclusions:In resected NSCLC of never smokers, high TMB was associated with worse prognosis. WES provided a good estimate of TMB while targeted NGS panels seem to lack adequate depth and resolution in the setting of low mutation burden.Impact:TMB is a prognostic indicator of survival in resected NSCLC from individuals who never smoked. In this setting of low mutation counts, TMB can be accurately measured by WGS or WES, but not NGS panels.

Published
2023

33. Supplementary Figure from Tumor Mutational Burden by Whole-Genome Sequencing in Resected NSCLC of Never Smokers

Author

Yohan Bossé, Philippe Joubert, Patrice Desmeules, Christian Couture, Catherine Labbé, Maria Teresa Landi, Tongwu Zhang, Dominique K. Boudreau, Victoria Saavedra Armero, Cyndi Henry, Nathalie Gaudreault, Zhonglin Li, and Louis-Jacques Ruel

Abstract

Supplementary Figure from Tumor Mutational Burden by Whole-Genome Sequencing in Resected NSCLC of Never Smokers

Published
2023

34. Supplementary Material 2 from A Gene Expression Signature from Peripheral Whole Blood for Stage I Lung Adenocarcinoma

Author

Maria Teresa Landi, Phil R. Taylor, Neil E. Caporaso, Joanna Shih, Sholom Wacholder, Pier Alberto Bertazzi, Angela C. Pesatori, Dario Consonni, Andrew W. Bergen, Alisa M. Goldstein, Chaoyu Wang, Hua Su, Nan Hu, and Melissa Rotunno

Abstract

PDF file - 132K, Affymetrix Probesets Differentially Expressed in Stage I Lung Adenocarcinoma Cases Compared to Controls in Current Smokers and All Subjects Combined, Italy, 2002-2005.

Published
2023

35. Data from A Gene Expression Signature from Peripheral Whole Blood for Stage I Lung Adenocarcinoma

Author

Maria Teresa Landi, Phil R. Taylor, Neil E. Caporaso, Joanna Shih, Sholom Wacholder, Pier Alberto Bertazzi, Angela C. Pesatori, Dario Consonni, Andrew W. Bergen, Alisa M. Goldstein, Chaoyu Wang, Hua Su, Nan Hu, and Melissa Rotunno

Abstract

Affordable early screening in subjects with high risk of lung cancer has great potential to improve survival from this deadly disease. We measured gene expression from lung tissue and peripheral whole blood (PWB) from adenocarcinoma cases and controls to identify dysregulated lung cancer genes that could be tested in blood to improve identification of at-risk patients in the future. Genome-wide mRNA expression analysis was conducted in 153 subjects (73 adenocarcinoma cases, 80 controls) from the Environment And Genetics in Lung cancer Etiology study using PWB and paired snap-frozen tumor and noninvolved lung tissue samples. Analyses were conducted using unpaired t tests, linear mixed effects, and ANOVA models. The area under the receiver operating characteristic curve (AUC) was computed to assess the predictive accuracy of the identified biomarkers. We identified 50 dysregulated genes in stage I adenocarcinoma versus control PWB samples (false discovery rate ≤0.1, fold change ≥1.5 or ≤0.66). Among them, eight (TGFBR3, RUNX3, TRGC2, TRGV9, TARP, ACP1, VCAN, and TSTA3) differentiated paired tumor versus noninvolved lung tissue samples in stage I cases, suggesting a similar pattern of lung cancer–related changes in PWB and lung tissue. These results were confirmed in two independent gene expression analyses in a blood-based case–control study (n = 212) and a tumor–nontumor paired tissue study (n = 54). The eight genes discriminated patients with lung cancer from healthy controls with high accuracy (AUC = 0.81, 95% CI = 0.74–0.87). Our finding suggests the use of gene expression from PWB for the identification of early detection markers of lung cancer in the future. Cancer Prev Res; 4(10); 1599–608. ©2011 AACR.

Published
2023

36. Supplementary Material 1 from A Gene Expression Signature from Peripheral Whole Blood for Stage I Lung Adenocarcinoma

Author

Maria Teresa Landi, Phil R. Taylor, Neil E. Caporaso, Joanna Shih, Sholom Wacholder, Pier Alberto Bertazzi, Angela C. Pesatori, Dario Consonni, Andrew W. Bergen, Alisa M. Goldstein, Chaoyu Wang, Hua Su, Nan Hu, and Melissa Rotunno

Abstract

PDF file - 222K, Affymetrix Quality Assessment for the Gene Expression Data from Peripheral Whole Blood in Cases and Controls, Italy, 2002-2005.

Published
2023

37. Supplementary Methods, Figure 1, Tables 1-6 from Inherited Variation at Chromosome 12p13.33, Including RAD52, Influences the Risk of Squamous Cell Lung Carcinoma

Author

Maria Teresa Landi, Richard S. Houlston, Christopher I. Amos, Stephen J. Chanock, Neil E. Caporaso, Pier Alberto Bertazzi, Margaret R. Spitz, Michael Thun, Demetrius Albanes, Qiong Dong, Wei Chen, Zhaoming Wang, Timothy Eisen, Marc Henrion, Peter Broderick, William Wheeler, Peng Li, Dario Consonni, Angela C. Pesatori, Yufei Wang, Melissa Rotunno, Nilanjan Chatterjee, and Jianxin Shi

Abstract

PDF file - 386K

Published
2023

38. Supplementary Table S1 from Common TDP1 Polymorphisms in Relation to Survival among Small Cell Lung Cancer Patients: A Multicenter Study from the International Lung Cancer Consortium

Author

Chu Chen, Noel S. Weiss, Gary E. Goodman, Xuchen Zong, Ruyang Zhang, Kazushi Yoshida, Ping Yang, Adonina Tardón, Stacey A. Slone, Kouya Shiraishi, Matthew B. Schabath, Grainne M. O'Kane, Michael W. Marcus, Yi Liu, Geoffrey Liu, Maria Teresa Landi, Takashi Kohno, Rayjean J. Hung, Eric B. Haura, John K. Field, Michael P.A. Davies, David C. Christiani, Susanne M. Arnold, Christopher I. Amos, Lori C. Sakoda, and Pawadee Lohavanichbutr

Abstract

List of tag SNPs for the TDP1 gene region

Published
2023

39. Data from Influence of Quercetin-Rich Food Intake on microRNA Expression in Lung Cancer Tissues

Author

Maria Teresa Landi, Ena Wang, Neil E. Caporaso, Pier Alberto Bertazzi, Angela Pesatori, Francesco Marincola, Yingdong Zhao, Stephanie Shao, and Tram K. Lam

Abstract

Background: Epidemiologic studies have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. A quercetin-rich diet might modulate microRNA (miR) expression; however, this mechanism has not been fully examined.Methods: miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. In individual-miR–based analyses, we compared the expression of miRs (n = 198) between lung cancer cases consuming high versus low quercetin-rich food intake using multivariate ANOVA tests. In family-miR–based analyses, we used Functional Class Scoring (FCS) to assess differential effect on biologically functional miR families. We accounted for multiple testing using 10,000 global permutations (significance at Pglobal < 0.10). All multivariate analyses were conducted separately by histology and by smoking status (former and current smokers).Results: Family-based analyses showed that a quercetin-rich diet differentiated miR expression profiles of the tumor suppressor let-7 family among adenocarcinomas (PFCS < 0.001). Other significantly differentiated miR families included carcinogenesis-related miR-146, miR-26, and miR-17 (PFCS < 0.05). In individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest and lowest quercetin-rich food consumers (23 expected by chance; Pglobal = 0.047).Conclusions: We observed differential expression of key biologically functional miRs between high versus low consumers of quercetin-rich foods in adenocarcinoma cases.Impact: Our findings provide preliminary evidence on the mechanism underlying quercetin-related lung carcinogenesis. Cancer Epidemiol Biomarkers Prev; 21(12); 2176–84. ©2012 AACR.

Published
2023

40. Supplemental Table 5 from Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk

Author

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

Abstract

LD between nine functional CYP2A6 variants and top six overlapping associations between MEC & TRICL - among Whites and Overall MEC sample

Published
2023

42. Supplementary Information from Assessing Lung Cancer Absolute Risk Trajectory Based on a Polygenic Risk Model

Author

Christopher I. Amos, Paul Brennan, James D. McKay, Matthew B. Schabath, Angela Risch, Heike Bickeböller, Melinda C. Aldrich, Susanne M. Arnold, Angeline S. Andrew, Stephen Lam, Shanbeth Zienolddiny, Philip Lazarus, Lambertus A. Kiemeney, John K. Field, Chu Chen, Stig E. Bojesen, Gad Rennert, Adonina Tardon, Loic Le Marchand, Demetrius Albanes, Mattias Johansson, Geoffrey Liu, Neil E. Caporaso, Maria Teresa Landi, David C. Christiani, Nilanjan Chatterjee, Yonathan Brhane, Matthew T. Warkentin, and Rayjean J. Hung

Abstract

Supplementary materials, Tables and Figures

Published
2023

43. Supplemental Table 2 from Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk

Author

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

Abstract

List of 226 overlapping associations for CYP2A6 in the TRICL & MEC Studies

Published
2023

45. Data from Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk

Author

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

Abstract

Metabolism of nicotine by cytochrome P450 2A6 (CYP2A6) is a suspected determinant of smoking dose and, consequently, lung cancer risk. We conducted a genome-wide association study (GWAS) of CYP2A6 activity, as measured by the urinary ratio of trans-3′-hydroxycotinine and its glucuronide conjugate over cotinine (total 3HCOT/COT), among 2,239 smokers in the Multiethnic Cohort (MEC) study. We identified 248 CYP2A6 variants associated with CYP2A6 activity (P < 5 × 10−8). CYP2A6 activity was correlated (r = 0.32; P < 0.0001) with total nicotine equivalents (a measure of nicotine uptake). When we examined the effect of these variants on lung cancer risk in the Transdisciplinary Research in Cancer of the Lung (TRICL) consortium GWAS dataset (13,479 cases and 43,218 controls), we found that the vast majority of these individual effects were directionally consistent and associated with an increased lung cancer risk. Two hundred and twenty-six of the 248 variants associated with CYP2A6 activity in the MEC were available in TRICL. Of them, 81% had directionally consistent risk estimates, and six were globally significantly associated with lung cancer. When conditioning on nine known functional variants and two deletions, the top two SNPs (rs56113850 in MEC and rs35755165 in TRICL) remained significantly associated with CYP2A6 activity in MEC and lung cancer in TRICL. The present data support the hypothesis that a greater CYP2A6 activity causes smokers to smoke more extensively and be exposed to higher levels of carcinogens, resulting in an increased risk for lung cancer. Although the variants identified in these studies may be used as risk prediction markers, the exact causal variants remain to be identified. Cancer Res; 76(19); 5768–76. ©2016 AACR.

Published
2023

46. Supplemental Table 1 from Novel Association of Genetic Markers Affecting CYP2A6 Activity and Lung Cancer Risk

Author

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

Abstract

List of 251 globally significant associations (p < 5E-8) for CYP2A6 in the MEC Cohort

Published
2023

48. Supplementary Table 2 and Supplemental Figures from Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

Author

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

Abstract

Table S2: Odds ratio and 95% confidence limits for cancers associated with variants with pleiotropic associations. Figure S1: Flowchart showing analysis steps. Figure S2. Manhattan plots by chromosome for individual cancer sites. Figure S3. Results for rs11571833. Figure S4: Conditional QQ-plots.

Published
2023

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