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1. 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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2. Data 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

Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

Published
2023
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3. 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

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

Funding sources, acknowledgements, consortia involved in study and bioinformatics tools used

Published
2023
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4. Supplementary Table 1 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

Variants selected for replication

Published
2023
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5. Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer.

Author

Jian Gong, Carolyn M Hutter, Polly A Newcomb, Cornelia M Ulrich, Stephanie A Bien, Peter T Campbell, John A Baron, Sonja I Berndt, Stephane Bezieau, Hermann Brenner, Graham Casey, Andrew T Chan, Jenny Chang-Claude, Mengmeng Du, David Duggan, Jane C Figueiredo, Steven Gallinger, Edward L Giovannucci, Robert W Haile, Tabitha A Harrison, Richard B Hayes, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Jihyoun Jeon, Mark A Jenkins, Jonathan Kocarnik, Sébastien Küry, Loic Le Marchand, Yi Lin, Noralane M Lindor, Reiko Nishihara, Shuji Ogino, John D Potter, Anja Rudolph, Robert E Schoen, Petra Schrotz-King, Daniela Seminara, Martha L Slattery, Stephen N Thibodeau, Mark Thornquist, Reka Toth, Robert Wallace, Emily White, Shuo Jiao, Mathieu Lemire, Li Hsu, Ulrike Peters, and CCFR and GECCO

Subjects
Genetics, QH426-470
Abstract

Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10-8; permuted p-value 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74-0.91]; P = 2.1×10-4) and TT genotypes (OR,0.62 [95% CI, 0.51-0.75]; P = 1.3×10-6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk.

Published
2016
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6. Fine-Mapping of Common Genetic Variants Associated with Colorectal Tumor Risk Identified Potential Functional Variants.

Author

Mengmeng Du, Shuo Jiao, Stephanie A Bien, Manish Gala, Goncalo Abecasis, Stephane Bezieau, Hermann Brenner, Katja Butterbach, Bette J Caan, Christopher S Carlson, Graham Casey, Jenny Chang-Claude, David V Conti, Keith R Curtis, David Duggan, Steven Gallinger, Robert W Haile, Tabitha A Harrison, Richard B Hayes, Michael Hoffmeister, John L Hopper, Thomas J Hudson, Mark A Jenkins, Sébastien Küry, Loic Le Marchand, Suzanne M Leal, Polly A Newcomb, Deborah A Nickerson, John D Potter, Robert E Schoen, Fredrick R Schumacher, Daniela Seminara, Martha L Slattery, Li Hsu, Andrew T Chan, Emily White, Sonja I Berndt, and Ulrike Peters

Subjects
Medicine, Science
Abstract

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).

Published
2016
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7. Histone H3.3 beyond cancer: Germline mutations in

Author

Laura, Bryant, Dong, Li, Samuel G, Cox, Dylan, Marchione, Evan F, Joiner, Khadija, Wilson, Kevin, Janssen, Pearl, Lee, Michael E, March, Divya, Nair, Elliott, Sherr, Brieana, Fregeau, Klaas J, Wierenga, Alexandrea, Wadley, Grazia M S, Mancini, Nina, Powell-Hamilton, Jiddeke, van de Kamp, Theresa, Grebe, John, Dean, Alison, Ross, Heather P, Crawford, Zoe, Powis, Megan T, Cho, Marcia C, Willing, Linda, Manwaring, Rachel, Schot, Caroline, Nava, Alexandra, Afenjar, Davor, Lessel, Matias, Wagner, Thomas, Klopstock, Juliane, Winkelmann, Claudia B, Catarino, Kyle, Retterer, Jane L, Schuette, Jeffrey W, Innis, Amy, Pizzino, Sabine, Lüttgen, Jonas, Denecke, Tim M, Strom, Kristin G, Monaghan, Zuo-Fei, Yuan, Holly, Dubbs, Renee, Bend, Jennifer A, Lee, Michael J, Lyons, Julia, Hoefele, Roman, Günthner, Heiko, Reutter, Boris, Keren, Kelly, Radtke, Omar, Sherbini, Cameron, Mrokse, Katherine L, Helbig, Sylvie, Odent, Benjamin, Cogne, Sandra, Mercier, Stephane, Bezieau, Thomas, Besnard, Sebastien, Kury, Richard, Redon, Karit, Reinson, Monica H, Wojcik, Katrin, Õunap, Pilvi, Ilves, A Micheil, Innes, Kristin D, Kernohan, Gregory, Costain, M Stephen, Meyn, David, Chitayat, Elaine, Zackai, Anna, Lehman, Hilary, Kitson, Martin G, Martin, Julian A, Martinez-Agosto, Stan F, Nelson, Christina G S, Palmer, Jeanette C, Papp, Neil H, Parker, Janet S, Sinsheimer, Eric, Vilain, Jijun, Wan, Amanda J, Yoon, Allison, Zheng, Elise, Brimble, Giovanni Battista, Ferrero, Francesca Clementina, Radio, Diana, Carli, Sabina, Barresi, Alfredo, Brusco, Marco, Tartaglia, Jennifer Muncy, Thomas, Luis, Umana, Marjan M, Weiss, Garrett, Gotway, K E, Stuurman, Michelle L, Thompson, Kirsty, McWalter, Constance T R M, Stumpel, Servi J C, Stevens, Alexander P A, Stegmann, Kristian, Tveten, Arve, Vøllo, Trine, Prescott, Christina, Fagerberg, Lone Walentin, Laulund, Martin J, Larsen, Melissa, Byler, Robert Roger, Lebel, Anna C, Hurst, Joy, Dean, Samantha A, Schrier Vergano, Jennifer, Norman, Saadet, Mercimek-Andrews, Juanita, Neira, Margot I, Van Allen, Nicola, Longo, Elizabeth, Sellars, Raymond J, Louie, Sara S, Cathey, Elly, Brokamp, Delphine, Heron, Molly, Snyder, Adeline, Vanderver, Celeste, Simon, Xavier, de la Cruz, Natália, Padilla, J Gage, Crump, Wendy, Chung, Benjamin, Garcia, Hakon H, Hakonarson, and Elizabeth J, Bhoj

Subjects
endocrine system, SciAdv r-articles, Forkhead Transcription Factors, Neurodegenerative Diseases, Zebrafish Proteins, Histones, fluids and secretions, mental disorders, Genetics, Animals, Humans, Molecular Biology, reproductive and urinary physiology, Germ-Line Mutation, Zebrafish, Research Articles, Research Article
Abstract

Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome., Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.

Published
2020

8. Nationwide French Study of RET Variants Detected from 2003 to 2013 Suggests a Possible Influence of Polymorphisms as Modifiers

Author

Anne-Paule Gimenez-Roqueplo, Maylis Lebeault, Marie Chabbert, Chantal Delvincourt, Stéphane Pinson, Pauline Romanet, Nathalie Bouzamondo, Véronique Barbu, Anne Barlier, Vincent Rohmer, Patrick Saulnier, Jean-Marc Rey, Françoise Borson-Chazot, Julien Blin, Pascal Pigny, Stephane Bezieau, Charlotte Veyrat-Durebex, Alain Carrie, Sophie Giraud, Marine Guillaud-Bataille, Delphine Mirebeau-Prunier, Amira Mohamed, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Laboratoire de génétique humaine [CHU Herriot], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Référence des Maladies Rares - Maladies Inflammatoires des Voies Biliaires et Service d’Hépatologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Centre Hospitalier Universitaire de Reims (CHU Reims), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ingénierie de la vectorisation particulaire, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut national du cancer [Boulogne] (INCA), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Health Service and Performance Research (HESPER), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Stress Oxydant et Pathologies Métaboliques (SOPAM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Barlier, Anne

Subjects
Adult, Male, endocrine system, endocrine system diseases, Endocrinology, Diabetes and Metabolism, Adrenal Gland Neoplasms, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Multiple Endocrine Neoplasia Type 2a, medullary thyroid cancer (MTC), Pheochromocytoma, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, [SDV.CAN] Life Sciences [q-bio]/Cancer, Gene Frequency, Rearranged during transfection, Humans, Genetic Predisposition to Disease, Thyroid Neoplasms, Gene, Aged, Retrospective Studies, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Genetics, genetic variants, multiple endocrine neoplasia type 2 (MEN2), Proto-Oncogene Proteins c-ret, Genetic variants, Exons, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Middle Aged, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, 030220 oncology & carcinogenesis, Carcinoma, Medullary, RET oncogene, Female, Ret oncogene, France, pheochromocytoma (PHEO)
Abstract

International audience; Background: The presence of single nucleotide polymorphisms (SNPs) in the REarranged during Transfection (RET) gene has been investigated with regard to their potential role in the development or progression of medullary thyroid cancer or pheochromocytomas (PHEO) in patients with the multiple endocrine neoplasia type 2 (MEN2) syndrome. The aim of this study was to evaluate the spectrum of RET variants in France between 2003 and 2013, and to evaluate the impact of SNPs on the MEN2 A phenotype.Methods: In this retrospective cohort study, RET variants were screened in 5109 index cases, and RET pathogenic variants were screened in 2214 relatives. Exons 5, 8, 10, 11, 13, 14, 15, and 16 were characterized by Sanger sequencing. RET pathogenic variants, RET variants with unknown functional significance (VUS), and four RET SNP variants—G691S (rs1799939), L769L (rs1800861), S836S (rs1800862), and S904S (rs1800863)—were characterized and are reported in index cases. In silico analysis and classification following the recommendation of the American College of Medical Genetics and Genomics was performed for RET VUS. Each patient's age at the time of diagnosis, sex, and the endocrine neoplasias present at molecular diagnosis were recorded.Results: Twenty-six single VUS in RET without any well-defined risk profiles were found in 33 patients. Nine of these were considered probably pathogenic, 11 of uncertain significance, and six as probably benign. Three double pathogenic variants found in three patients were classified as pathogenic. A study of the entire cohort showed that patients carrying pathogenic variants or VUS in RET together with PHEO were diagnosed earlier than the others. The presence of the G691S SNP, or a combination of SNPs, increased the risk of developing PHEO but did not modify the date of the diagnosis. No association was found between SNPs and medullary thyroid cancer or hyperparathyroidism.Conclusions: The findings propose a classification of 15 of the 26 VUS in RET without any well-defined risk profiles and suggest that the G691S SNP, or a combination of SNPs, may be associated with the development of PHEO.

Published
2017
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9. Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia

Author

Fangyi, Gu, Han, Zhang, Paula L, Hyland, Sonja, Berndt, Susan M, Gapstur, William, Wheeler, The, Ellipse Consortium, Christopher I, Amos, Stephane, Bezieau, Heike, Bickeböller, Hermann, Brenner, Paul, Brennan, Jenny, Chang-Claude, David V, Conti, Jennifer Anne, Doherty, Stephen B, Gruber, Tabitha A, Harrison, Richard B, Hayes, Michael, Hoffmeister, Richard S, Houlston, Rayjean J, Hung, Mark A, Jenkins, Peter, Kraft, Kate, Lawrenson, James, McKay, Sarah, Markt, Lorelei, Mucci, Catherine M, Phelan, Conghui, Qu, Angela, Risch, Mary Anne, Rossing, H-Erich, Wichmann, Jianxin, Shi, Eva, Schernhammer, Kai, Yu, Maria Teresa, Landi, Neil E, Caporaso, and Apollo - University of Cambridge Repository

Subjects
circadian rhythm, Male, Ovarian Neoplasms, Lung Neoplasms, Carcinogenesis, Cancer, Circadian Rhythm, Melatonin, Prostate Cancer, education, Prostatic Neoplasms, melatonin, Nerve Tissue Proteins, prostate cancer, Arylalkylamine N-Acetyltransferase, Polymorphism, Single Nucleotide, Article, Basic Helix-Loop-Helix Transcription Factors, cancer, Humans, Female, Genetic Predisposition to Disease, Colorectal Neoplasms, health care economics and organizations, Genetic Association Studies, Signal Transduction
Abstract

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (p pathway < 0.00625). The two most significant genes were NPAS2 (p gene =0.0062) and AANAT (p gene =0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (p pathway =0.021); this association was not confirmed in GECCO (p pathway =0.76) or the combined data (p pathway =0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.

Published
2017

10. Familial Medullary Thyroid Carcinoma with Noncysteine RET Mutations: Phenotype-Genotype Relationship in a Large Series of Patients

Author

Vincent Rohmer, Marie-Laure Kottler, Béatrice Maes, Arnaud Murat, Gérard Chabrier, Sophie Giraud, Sophie Morange, Line Baldet, Patricia Niccoli-Sire, Stephane Bezieau, Bernard Conte-Devolx, Sylvia Franc, and Frédérique Savagner

Subjects
Male, Pathology, endocrine system diseases, Genetic Linkage, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Clinical Biochemistry, Thyroid Gland, Biochemistry, Endocrinology, Drosophila Proteins, Genetic Carrier Screening, Thyroid, Exons, Middle Aged, Phenotype, medicine.anatomical_structure, Databases as Topic, Medullary carcinoma, Carcinoma, Medullary, Lymphatic Metastasis, Thyroidectomy, Female, Pentagastrin, France, Adult, Calcitonin, endocrine system, medicine.medical_specialty, Genotype, Medullary cavity, Thyroid carcinoma, Germline mutation, Proto-Oncogene Proteins, Internal medicine, Proto-Oncogenes, medicine, Humans, Cysteine, Thyroid Neoplasms, Hyperplasia, business.industry, Proto-Oncogene Proteins c-ret, Biochemistry (medical), Receptor Protein-Tyrosine Kinases, medicine.disease, C-Cell Hyperplasia, business
Abstract

Familial medullary thyroid carcinoma only is related to germline mutations in the protooncogene RET, mainly in exons 10, whereas noncysteine mutations (exons 13-15) are considered infrequent. We analyzed 148 patients from 47 familial medullary thyroid carcinoma only families, and we found noncysteine RET mutations in 59.5% of these families. Of the index cases with noncysteine mutations, 43.4% presented with a multinodular goiter and high basal calcitonin; they were older at diagnosis than those with mutation in exon 10 and had more multifocal medullary thyroid carcinoma, but no difference in size, bilaterality, presence of C cell hyperplasia, or nodal metastases was found. Gene carriers with noncysteine RET mutations had a lower incidence of medullary thyroid carcinoma (78.2% vs. 94.1%) than those with mutation in exon 10; 20.2% had C cell hyperplasia only, although thyroidectomized at an older age. In conclusion, familial medullary thyroid carcinoma with noncysteine RET mutations are not infrequent and are overrepresented in presumed sporadic medullary thyroid carcinoma, suggesting that RET analysis should routinely be extended to exons 13, 14, and 15. The phenotype is characterized by a late onset of the disease, suggesting a delayed appearance of C cell disease rather than a less aggressive form. In familial medullary thyroid carcinoma gene carriers, the optimal timing for thyroidectomy remains controversial. Based on these data, we propose that surgery should be performed before elevation of the basal calcitonin level, potentially as soon as the pentagastrin test becomes abnormal.

Published
2001
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