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1. Final analysis of the phase 3 randomized clinical trial comparing HD201 vs. referent trastuzumab in patients with ERBB2-positive breast cancer treated in the neoadjuvant setting

Author: Xavier Pivot, Alexey Georgievitch Manikhas, Volodymyr Shamrai, Giorgi Dzagnidze, Hwoei Fen Soo Hoo, Viriya Kaewkangsadan, Fausto Petrelli, Cristian Villanueva, Jamie Kim, Sumita Pradhan, Litha Jaison, Peggy Feyaerts, Leonard Kaufman, Marie-Paule Derde, Filip Deforce, and David G. Cox
Subjects: Trastuzumab, Biosimilar, HD201, Breast cancer, Neoadjuvant, HER2, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background The TROIKA trial established that HD201 and trastuzumab were equivalent in terms of primary endpoints (total pathological complete response) following neoadjuvant treatment. The objective of the present analysis was to compare survival outcomes and final safety. Methods In the TROIKA trial, patients with ERBB2-positive early breast cancer were randomized and treated with either HD201 or the referent trastuzumab. Eligible patients received 8 cycles of either HD201 or referent trastuzumab (loading dose, 8 mg/kg; maintenance dose, 6 mg/kg) every 3 weeks in combination with 8 cycles of chemotherapy (4 cycles of docetaxel, 75 mg/m2, followed by 4 cycles of epirubicin, 75 mg/m2, and cyclophosphamide, 500 mg/m2) in the neoadjuvant setting. The patients then underwent surgery followed by 10 cycles of adjuvant HD201 or referent trastuzumab according to their initial randomization to complete one year of trastuzumab-directed therapy. Event-free and overall survival rates were calculated using Kaplan–Meier analysis. The hazard ratio for event-free survival was estimated by Cox proportional hazards regression. Results The final analysis was performed after all patients completed the study at a median follow-up of 37.7 months (Q1-Q3, 37.3–38.1 months). A total of 502 randomized patients received either HD201 or the referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. In this population, the 3-year event-free survival rates were 85.6% (95% CI: 80.28–89.52) and 84.9% (95% CI: 79.54–88.88) in the HD201 and referent trastuzumab groups, respectively (log rank p = 0.938) (HR 1.02, 95% CI: 0.63–1.63; p = 0.945). The 3-year overall survival rates were comparable between the HD201 (95.6%; 95% CI: 91.90–97.59) and referent trastuzumab treatment groups (96.0%, 95% CI: 92.45–97.90) (log rank p = 0.606). During the posttreatment follow-up period, adverse events were reported for 64 (27.4%) and 72 (29.8%) patients in the HD201 and the reference trastuzumab groups, respectively. Serious adverse events were rare and none of which were related to the study treatment. Conclusions This final analysis of the TROIKA trial further confirms the comparable efficacy and safety of HD201 and trastuzumab. Trial registration ClinicalTrials.gov identifier: NCT03013504.
Published: 2023
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2. Outcome of lung oligometastatic patients treated with stereotactic body irradiation

Author: Guillaume Virbel, David G. Cox, Anne Olland, Pierre-Emmanuel Falcoz, Clara Le Fevre, Roland Schott, Delphine Antoni, and Georges Noel
Subjects: lung, metastases, oligometastatic, stereotactic body radiotherapy, SBRT, SABR, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: PurposeThe oligometastatic stage is an intermediate stage of cancer between the localized stage and polymetastatic stage. The prognosis of patients in this stage also appears to be intermediate. Lung stereotactic body radiotherapy is a possible tool for treating oligometastatic lung sites. The objective of our study was to evaluate the clinical outcomes in terms of local control, progression-free survival, overall survival, and toxicity of SBRT in oligometastatic patients with lung metastases from any solid primary tumor.Materials and methodsClinical records of consecutive lung oligometastatic patients treated between January 2010 and December 2020 for lung SBRT at 60 Gy in 3- or 8-fraction schedules and a controlled primary tumor were retrospectively analyzed.ResultsAfter a median follow-up of 20.3 months, local failure occurred for 14 lesions, 57 patients experienced lung progression, and 64 patients experienced disease progression. Overall survival rates at 1 and 2 years were 85.6 and 69.7%, respectively. Fifty-two patients experienced radiation pneumonitis, but only 2 patients were symptomatic and presented grade 2 late pneumonitis. No grade 3-4 toxicity was observed. ECOG 0 was the only prognostic factor for overall survival (HR = 3.5; 95% CI 3.2-3.8; p < 0.01).ConclusionSBRT with a 60-Gy schedule in 8 fractions is an effective and well-tolerated treatment for patients with lung oligometastases from any solid primary tumor.
Published: 2022
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3. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author: Mitchell J. Machiela, Thomas G. P. Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetete-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Nathalie Gaspar, Udo Kontny, Anna González-Neira, Piero Picci, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Perrine Marec Bérard, Neal D. Freedman, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdett, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G. Cox, Robert N. Hoover, Javed Khan, Gregory T. Armstrong, Wendy M. Leisenring, Smita Bhatia, Leslie L. Robison, Andreas E. Kulozik, Jennifer Kriebel, Thomas Meitinger, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lindsay M. Morton, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Stephen J. Chanock, and Olivier Delattre
Subjects: Science
Abstract: Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.
Published: 2018
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4. A GWAS in uveal melanoma identifies risk polymorphisms in the CLPTM1L locus

Author: Lenha Mobuchon, Aude Battistella, Claire Bardel, Ghislaine Scelo, Alexia Renoud, Alexandre Houy, Nathalie Cassoux, Maud Milder, Géraldine Cancel-Tassin, Olivier Cussenot, Olivier Delattre, Céline Besse, Anne Boland, Jean-François Deleuze, David G. Cox, and Marc-Henri Stern
Subjects: Medicine, Genetics, QH426-470
Abstract: Cancer: Risk allele identified for melanoma of the eye Researchers have discovered an important genetic risk variant linked to uveal melanoma, a rare malignant tumor of the eye. Marc-Henri Stern from Institut Curie in Paris, France, and colleagues compared more than 860,000 single DNA variants covering the entire genome, from the genomes of 259 people with uveal melanoma and 401 healthy controls, all of whom were of European ancestry. The researchers found that a series of closely linked gene variants on the short arm of chromosome 5 were significantly more common in the melanoma patients. They confirmed the association between this genomic region and disease risk in an independent cohort of 276 cancer cases and 184 controls. Expression analyses showed that the CLPTM1L gene contained in this region was more expressed in people with the risk variants, pointing to CLPTM1L playing a role in tumor development.
Published: 2017
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5. Genetically Determined Height and Risk of Non-hodgkin Lymphoma

Author: Amy Moore, Eleanor Kane, Zhaoming Wang, Orestis A. Panagiotou, Lauren R. Teras, Alain Monnereau, Nicole Wong Doo, Mitchell J. Machiela, Christine F. Skibola, Susan L. Slager, Gilles Salles, Nicola J. Camp, Paige M. Bracci, Alexandra Nieters, Roel C. H. Vermeulen, Joseph Vijai, Karin E. Smedby, Yawei Zhang, Claire M. Vajdic, Wendy Cozen, John J. Spinelli, Henrik Hjalgrim, Graham G. Giles, Brian K. Link, Jacqueline Clavel, Alan A. Arslan, Mark P. Purdue, Lesley F. Tinker, Demetrius Albanes, Giovanni M. Ferri, Thomas M. Habermann, Hans-Olov Adami, Nikolaus Becker, Yolanda Benavente, Simonetta Bisanzi, Paolo Boffetta, Paul Brennan, Angela R. Brooks-Wilson, Federico Canzian, Lucia Conde, David G. Cox, Karen Curtin, Lenka Foretova, Susan M. Gapstur, Hervé Ghesquières, Martha Glenn, Bengt Glimelius, Rebecca D. Jackson, Qing Lan, Mark Liebow, Marc Maynadie, James McKay, Mads Melbye, Lucia Miligi, Roger L. Milne, Thierry J. Molina, Lindsay M. Morton, Kari E. North, Kenneth Offit, Marina Padoan, Alpa V. Patel, Sara Piro, Vignesh Ravichandran, Elio Riboli, Silvia de Sanjose, Richard K. Severson, Melissa C. Southey, Anthony Staines, Carolyn Stewart, Ruth C. Travis, Elisabete Weiderpass, Stephanie Weinstein, Tongzhang Zheng, Stephen J. Chanock, Nilanjan Chatterjee, Nathaniel Rothman, Brenda M. Birmann, James R. Cerhan, and Sonja I. Berndt
Subjects: non-Hodgkin lymphoma, height, genetics, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Although the evidence is not consistent, epidemiologic studies have suggested that taller adult height may be associated with an increased risk of some non-Hodgkin lymphoma (NHL) subtypes. Height is largely determined by genetic factors, but how these genetic factors may contribute to NHL risk is unknown. We investigated the relationship between genetic determinants of height and NHL risk using data from eight genome-wide association studies (GWAS) comprising 10,629 NHL cases, including 3,857 diffuse large B-cell lymphoma (DLBCL), 2,847 follicular lymphoma (FL), 3,100 chronic lymphocytic leukemia (CLL), and 825 marginal zone lymphoma (MZL) cases, and 9,505 controls of European ancestry. We evaluated genetically predicted height by constructing polygenic risk scores using 833 height-associated SNPs. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) for association between genetically determined height and the risk of four NHL subtypes in each GWAS and then used fixed-effect meta-analysis to combine subtype results across studies. We found suggestive evidence between taller genetically determined height and increased CLL risk (OR = 1.08, 95% CI = 1.00–1.17, p = 0.049), which was slightly stronger among women (OR = 1.15, 95% CI: 1.01–1.31, p = 0.036). No significant associations were observed with DLBCL, FL, or MZL. Our findings suggest that there may be some shared genetic factors between CLL and height, but other endogenous or environmental factors may underlie reported epidemiologic height associations with other subtypes.
Published: 2020
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6. Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma.

Author: Shu-Hong Lin, Joshua N Sampson, Thomas G P Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetête-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Udo Kontny, Anna González-Neira, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Perrine Marec Bérard, Jeremy Miller, Neal D Freedman, Nathaniel Rothman, Brian D Carter, Casey L Dagnall, Laurie Burdett, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G Cox, Robert N Hoover, Javed Khan, Gregory T Armstrong, Wendy M Leisenring, Smita Bhatia, Leslie L Robison, Andreas E Kulozik, Jennifer Kriebel, Thomas Meitinger, Markus Metzler, Manuela Krumbholz, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Uta Dirksen, Lisa Mirabello, Margaret A Tucker, Franck Tirode, Lindsay M Morton, Stephen J Chanock, Olivier Delattre, and Mitchell J Machiela
Subjects: Medicine, Science
Abstract: BackgroundEwing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherited variants with minor allele frequencies below 5% due to limited genotyped cases of this rare tumor.MethodsWe investigated the contribution of rare and low-frequency variation to EwS susceptibility in the largest EwS genome-wide association study to date (733 EwS cases and 1,346 unaffected controls of European ancestry).ResultsWe identified two low-frequency variants, rs112837127 and rs2296730, on chromosome 20 that were associated with EwS risk (OR = 0.186 and 2.038, respectively; P-value < 5×10-8) and located near previously reported common susceptibility loci. After adjusting for the most associated common variant at the locus, only rs112837127 remained a statistically significant independent signal (OR = 0.200, P-value = 5.84×10-8).ConclusionsThese findings suggest rare variation residing on common haplotypes are important contributors to EwS risk.ImpactMotivate future targeted sequencing studies for a comprehensive evaluation of low-frequency and rare variation around common EwS susceptibility loci.
Published: 2020
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7. Constitutional variants are not associated with HER2-positive breast cancer: results from the SIGNAL/PHARE clinical cohort

Author: Xavier Pivot, Gilles Romieu, Pierre Fumoleau, Maria Rios, Hervé Bonnefoi, Thomas Bachelot, Patrick Soulié, Christelle Jouannaud, Hugues Bourgeois, Thierry Petit, Isabelle Tennevet, David Assouline, Marie-Christine Mathieu, Jean-Philippe Jacquin, Sandrine Lavau-Denes, Ariane Darut-Jouve, Jean-Marc Ferrero, Carole Tarpin, Christelle Lévy, Valérie Delecroix, Véronique Trillet-Lenoir, Oana Cojocarasu, Jérôme Meunier, Jean-Yves Pierga, Cécile Agostini, Pierre Kerbrat, Céline Faure-Mercier, Hélène Blanché, Mourad Sahbatou, Anne Boland, Delphine Bacq, Céline Besse, Fabien Calvo, Alexia Renaud, Jean-François Deleuze, Iris Pauporté, Gilles Thomas, and David G. Cox
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Genetics: heredity does not explain HER2 expression A large gene-finding study failed to identify any hereditary factors linked to HER2 expression among women with breast cancer. A team in France led by Xavier Pivot from the University Hospital Center of Besançon, France, analyzed more than 500,000 single DNA letters from a cohort of 8703 patients with breast cancer, 3230 of whom had tumors with high expression of human epidermal growth factor receptor 2 (HER2) and are thus treated with for anti-HER2 targeted therapies. The researchers searched for DNA variants associated with HER2 status, but none reached the threshold for statistical significance. The findings reveal a high level of genetic diversity in women with HER2-positive breast cancer and suggest that HER2 amplification may have more to do with the intrinsic nature of the tumor than with the genetics of the patient.
Published: 2017
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8. Supplemental Table from HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author: Christine F. Skibola, Patricia Hartge, Nathaniel Rothman, Stephen J. Chanock, Peter Kraft, Yawei Zhang, Anne Kricker, Eve Roman, Martyn T. Smith, Angela Brooks-Wilson, Qing Lan, Richard K. Severson, Scott Davis, Anthony Staines, Lenka Foretova, Paulo Bofetta, Gilles Salles, Hervé Ghesquières, David G. Cox, Alain Monnereau, Jacqueline Clavel, Karen Curtin, Martha Glenn, Nicola J. Camp, Lucia Conde, Bengt Glimelius, Mads Melbye, Hans-Olov Adami, Mark P. Purdue, Alan A. Arslan, Jacob Musinsky, Kenneth Offit, Roger L. Milne, Melissa C. Southey, Graham G. Giles, Nicole Wong Doo, Andrew L. Feldman, Giancarlo Latte, Maria Grazia Ennas, Corrado Magnani, Brian K. Link, Marie-Hélène Delfau-Larue, James McKay, Paul Brennan, Yolanda Benavente, Elio Riboli, Rudolph Kaaks, Ruth C. Travis, Stephanie J. Lax, W. Ryan Diver, Lauren R. Teras, Stephanie J. Weinstein, Demetrius Albanes, Pierluigi Cocco, Marc Maynadie, Dennis Weisenburger, Eleanor Kane, Elizabeth A. Holly, Nikolaus Becker, Christopher R. Flowers, Brenda M. Birmann, Tongzhang Zheng, John J. Spinelli, Jennifer Turner, Elizabeth E. Brown, Wendy Cozen, Silvia de Sanjose, Alexandra Nieters, Martha S. Linet, Claire M. Vajdic, Ora Paltiel, Roel Vermeulen, Lindsay M. Morton, Joseph Vijai, Henrik Hjalgrim, Karin E. Smedby, James R. Cerhan, Jenna Voutsinas, Paige M. Bracci, Susan L. Slager, Sonja I. Berndt, Mary Carrington, and Sophia S. Wang
Abstract: SUPPLEMENTAL TABLE: Effect of homozygosity at the three HLA class I loci -A, -B and -C and five HLA class I loci -DRB1, DQA1, DQB1, DPA1, and DPB1 on susceptibility to four NHL subtypes (DLBCL, FL, CLL/SLL, and MZL) stratified by GWAS platform (analyses adjusted for sex, age, and ancestry/principal components)
Published: 2023
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9. Supplementary notes from Genome-Wide Association Study of Prostate Cancer–Specific Survival

Author: Fredrik Wiklund, Sara Lindström, Johanna Schleutker, Lovise Maehle, David G. Cox, Anne Tjønneland, Bas H. Bueno-de-Mesquita, Antonia Trichopoulou, Stephanie J. Weinstein, Victoria L. Stevens, Meir J. Stampfer, Kathryn L. Penney, Alison M. Mondul, Jing Ma, Loic Le Marchand, Peter Kraft, David J. Hunter, Edward L. Giovannucci, Susan M. Gapstur, Stephen Chanock, Sonja I. Berndt, Gerald L. Andriole, Demetrius Albanes, Judith A. Clements, Jyotsna Batra, Andrzej Kierzek, Agnieszka Michael, Hardev Pandha, Sofia Maia, Paula Paulo, Manuel R. Teixeira, Amanda Spurdle, Vanio I. Mitev, Radka P. Kaneva, Chavdar Slavov, Hui-Yi Lim, Thomas A. Sellers, Jong Y. Park, Bernd Holleczek, Volker Herrmann, Hermann Brenner, Lisa Cannon-Albright, Wojciech Kluźniak, Jan Lubiński, Cezary Cybulski, Adam S. Kibel, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Christiane Maier, Daniel J. Schaid, Shannon K. McDonnell, Stephen N. Thibodeau, Janet L. Stanford, Kay-Tee Khaw, Nora Pashayan, Paul D.P. Pharoah, Freddie C. Hamdy, Jenny L. Donovan, David E. Neal, Ruth C. Travis, Timothy J. Key, Børge G. Nordestgaard, Teuvo L.J. Tammela, Csilla Sipeky, Christopher A. Haiman, Fredrick R. Schumacher, Brian E. Henderson, Liesel M. FitzGerald, Melissa C. Southey, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind A. Eeles, Henrik Gronberg, Markus Aly, Thomas Whitington, Robert Karlsson, and Robert Szulkin
Abstract: Supplementary acknowledgments.
Published: 2023
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10. Data from HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author: Christine F. Skibola, Patricia Hartge, Nathaniel Rothman, Stephen J. Chanock, Peter Kraft, Yawei Zhang, Anne Kricker, Eve Roman, Martyn T. Smith, Angela Brooks-Wilson, Qing Lan, Richard K. Severson, Scott Davis, Anthony Staines, Lenka Foretova, Paulo Bofetta, Gilles Salles, Hervé Ghesquières, David G. Cox, Alain Monnereau, Jacqueline Clavel, Karen Curtin, Martha Glenn, Nicola J. Camp, Lucia Conde, Bengt Glimelius, Mads Melbye, Hans-Olov Adami, Mark P. Purdue, Alan A. Arslan, Jacob Musinsky, Kenneth Offit, Roger L. Milne, Melissa C. Southey, Graham G. Giles, Nicole Wong Doo, Andrew L. Feldman, Giancarlo Latte, Maria Grazia Ennas, Corrado Magnani, Brian K. Link, Marie-Hélène Delfau-Larue, James McKay, Paul Brennan, Yolanda Benavente, Elio Riboli, Rudolph Kaaks, Ruth C. Travis, Stephanie J. Lax, W. Ryan Diver, Lauren R. Teras, Stephanie J. Weinstein, Demetrius Albanes, Pierluigi Cocco, Marc Maynadie, Dennis Weisenburger, Eleanor Kane, Elizabeth A. Holly, Nikolaus Becker, Christopher R. Flowers, Brenda M. Birmann, Tongzhang Zheng, John J. Spinelli, Jennifer Turner, Elizabeth E. Brown, Wendy Cozen, Silvia de Sanjose, Alexandra Nieters, Martha S. Linet, Claire M. Vajdic, Ora Paltiel, Roel Vermeulen, Lindsay M. Morton, Joseph Vijai, Henrik Hjalgrim, Karin E. Smedby, James R. Cerhan, Jenna Voutsinas, Paige M. Bracci, Susan L. Slager, Sonja I. Berndt, Mary Carrington, and Sophia S. Wang
Abstract: A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.
Published: 2023
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11. Data from Genome-Wide Association Study of Prostate Cancer–Specific Survival

Author: Fredrik Wiklund, Sara Lindström, Johanna Schleutker, Lovise Maehle, David G. Cox, Anne Tjønneland, Bas H. Bueno-de-Mesquita, Antonia Trichopoulou, Stephanie J. Weinstein, Victoria L. Stevens, Meir J. Stampfer, Kathryn L. Penney, Alison M. Mondul, Jing Ma, Loic Le Marchand, Peter Kraft, David J. Hunter, Edward L. Giovannucci, Susan M. Gapstur, Stephen Chanock, Sonja I. Berndt, Gerald L. Andriole, Demetrius Albanes, Judith A. Clements, Jyotsna Batra, Andrzej Kierzek, Agnieszka Michael, Hardev Pandha, Sofia Maia, Paula Paulo, Manuel R. Teixeira, Amanda Spurdle, Vanio I. Mitev, Radka P. Kaneva, Chavdar Slavov, Hui-Yi Lim, Thomas A. Sellers, Jong Y. Park, Bernd Holleczek, Volker Herrmann, Hermann Brenner, Lisa Cannon-Albright, Wojciech Kluźniak, Jan Lubiński, Cezary Cybulski, Adam S. Kibel, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Christiane Maier, Daniel J. Schaid, Shannon K. McDonnell, Stephen N. Thibodeau, Janet L. Stanford, Kay-Tee Khaw, Nora Pashayan, Paul D.P. Pharoah, Freddie C. Hamdy, Jenny L. Donovan, David E. Neal, Ruth C. Travis, Timothy J. Key, Børge G. Nordestgaard, Teuvo L.J. Tammela, Csilla Sipeky, Christopher A. Haiman, Fredrick R. Schumacher, Brian E. Henderson, Liesel M. FitzGerald, Melissa C. Southey, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind A. Eeles, Henrik Gronberg, Markus Aly, Thomas Whitington, Robert Karlsson, and Robert Szulkin
Abstract: Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical.Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR).Results: We observed no significant association between genetic variants and prostate cancer survival.Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study.Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes. Cancer Epidemiol Biomarkers Prev; 24(11); 1796–800. ©2015 AACR.
Published: 2023
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12. Supplementary Tables 1S-7S, Figure 1S from Haplotype Analysis of the HSD17B1 Gene and Risk of Breast Cancer: A Comprehensive Approach to Multicenter Analyses of Prospective Cohort Studies

Author: Dimitrios Trichopoulos, Anne Tjonneland, Michael J. Thun, Gilles Thomas, Daniel O. Stram, V. Wendy Setiawan, Elio Riboli, Malcolm C. Pike, Petra H. Peeters, Carmen Navarro, William Modi, Jakob Linseisen, Loic LeMarchand, Peter Kraft, Laurence N. Kolonel, David Hunter, Joel N. Hirschhorn, Richard B. Hayes, Susan E. Hankinson, Christopher A. Haiman, Matthew L. Freedman, W. Ryan Diver, Graham Colditz, Francoise Clavel-Chapelon, Stephen J. Chanock, Eugenia E. Calle, Noel P. Burtt, Julie E. Buring, Sheila Bingham, Franco Berrino, Goran Berglund, David Altshuler, Demetrius Albanes, Brian E. Henderson, Rudolf Kaaks, Sholom Wacholder, Howard M. Cann, David G. Cox, and Heather Spencer Feigelson
Abstract: Supplementary Tables 1S-7S, Figure 1S from Haplotype Analysis of the HSD17B1 Gene and Risk of Breast Cancer: A Comprehensive Approach to Multicenter Analyses of Prospective Cohort Studies
Published: 2023
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13. Supplementary Methods and Tables 1-4 from Genetic Variation at the CYP19A1 Locus Predicts Circulating Estrogen Levels but not Breast Cancer Risk in Postmenopausal Women

Author: Regina G. Ziegler, Sholom Wacholder, Dimitrios Trichopoulos, Ruth Travis, Anne Tjonneland, Elio Riboli, Malcolm C. Pike, Petra H. Peeters, Salvatore Panico, Eiliv Lund, Per Lenner, Loïc Le Marchand, Laurence N. Kolonel, Rudolf Kaaks, David J. Hunter, Robert Hoover, Joel N. Hirschhorn, Brian E. Henderson, Richard B. Hayes, Susan E. Hankinson, Heather Spencer Feigelson, David G. Cox, Graham A. Colditz, Françoise Clavel-Chapelon, Stephen Chanock, Eugenia E. Calle, Noël Burtt, Julie Buring, Heiner Boeing, Eva Ardanaz, David Altshuler, Demetrius Albanes, Michael J. Thun, Gilles Thomas, Alison M. Dunning, Daniel O. Stram, V. Wendy Setiawan, Laure Dossus, and Christopher A. Haiman
Abstract: Supplementary Methods and Tables 1-4 from Genetic Variation at the CYP19A1 Locus Predicts Circulating Estrogen Levels but not Breast Cancer Risk in Postmenopausal Women
Published: 2023
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14. Data from Genetic Variation at the CYP19A1 Locus Predicts Circulating Estrogen Levels but not Breast Cancer Risk in Postmenopausal Women

Author: Regina G. Ziegler, Sholom Wacholder, Dimitrios Trichopoulos, Ruth Travis, Anne Tjonneland, Elio Riboli, Malcolm C. Pike, Petra H. Peeters, Salvatore Panico, Eiliv Lund, Per Lenner, Loïc Le Marchand, Laurence N. Kolonel, Rudolf Kaaks, David J. Hunter, Robert Hoover, Joel N. Hirschhorn, Brian E. Henderson, Richard B. Hayes, Susan E. Hankinson, Heather Spencer Feigelson, David G. Cox, Graham A. Colditz, Françoise Clavel-Chapelon, Stephen Chanock, Eugenia E. Calle, Noël Burtt, Julie Buring, Heiner Boeing, Eva Ardanaz, David Altshuler, Demetrius Albanes, Michael J. Thun, Gilles Thomas, Alison M. Dunning, Daniel O. Stram, V. Wendy Setiawan, Laure Dossus, and Christopher A. Haiman
Abstract: The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (≥5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5′ region of CYP19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women [effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 × 10−15]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CYP19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer. [Cancer Res 2007;67(5):1893–7]
Published: 2023
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15. Efficacity of Deep Inspiration Breath Hold and Intensity-Modulated Radiotherapy in Preventing Perfusion Defect for Left Sided Breast Cancer (EDIPE): A Prospective Cohort Study Protocol

Author: Jordan Eber, Cyrille Blondet, Martin Schmitt, David G. Cox, Claire Vit, Clara Le Fèvre, Delphine Antoni, Fabrice Hubele, and Georges Noel
Subjects: Cancer Research, Oncology
Abstract: Breast radiotherapy can lead to radiation-induced cardiac disease, particularly in left breast cancers. Recent studies have shown that subclinical cardiac lesions, such as myocardial perfusion deficits, may occur early after radiotherapy. The primary method for irradiating breast cancer, known as opposite tangential field radiotherapy, can cause the anterior interventricular coronary artery to receive a high dose of radiation during left breast irradiation. To explore alternative approaches that could reduce the risk of myocardial perfusion defects in patients with left breast cancer, we plan to conduct a prospective single-center study using a combination of deep inspiration breath hold radiotherapy and intensity modulated radiation therapy. The study will use stress and, if necessary, resting myocardial scintigraphy to assess myocardial perfusion. The trial aims to show that reducing the cardiac dose with these techniques can prevent the appearance of early (3-month) and medium-term (6- and 12-month) perfusion disorders.
Published: 2023
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16. Targeted Sequencing of the Mitochondrial Genome of Women at High Risk of Breast Cancer without Detectable Mutations in BRCA1/2.

Author: Sophie Blein, Laure Barjhoux, GENESIS investigators, Francesca Damiola, Marie-Gabrielle Dondon, Séverine Eon-Marchais, Morgane Marcou, Olivier Caron, Alain Lortholary, Bruno Buecher, Philippe Vennin, Pascaline Berthet, Catherine Noguès, Christine Lasset, Marion Gauthier-Villars, Sylvie Mazoyer, Dominique Stoppa-Lyonnet, Nadine Andrieu, Gilles Thomas, Olga M Sinilnikova, and David G Cox
Subjects: Medicine, Science
Abstract: Breast Cancer is a complex multifactorial disease for which high-penetrance mutations have been identified. Approaches used to date have identified genomic features explaining about 50% of breast cancer heritability. A number of low- to medium penetrance alleles (per-allele odds ratio < 1.5 and 4.0, respectively) have been identified, suggesting that the remaining heritability is likely to be explained by the cumulative effect of such alleles and/or by rare high-penetrance alleles. Relatively few studies have specifically explored the mitochondrial genome for variants potentially implicated in breast cancer risk. For these reasons, we propose an exploration of the variability of the mitochondrial genome in individuals diagnosed with breast cancer, having a positive breast cancer family history but testing negative for BRCA1/2 pathogenic mutations. We sequenced the mitochondrial genome of 436 index breast cancer cases from the GENESIS study. As expected, no pathogenic genomic pattern common to the 436 women included in our study was observed. The mitochondrial genes MT-ATP6 and MT-CYB were observed to carry the highest number of variants in the study. The proteins encoded by these genes are involved in the structure of the mitochondrial respiration chain, and variants in these genes may impact reactive oxygen species production contributing to carcinogenesis. More functional and epidemiological studies are needed to further investigate to what extent variants identified may influence familial breast cancer risk.
Published: 2015
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17. A genome-wide 'pleiotropy scan' does not identify new susceptibility loci for estrogen receptor negative breast cancer.

Author: Daniele Campa, Myrto Barrdahl, Konstantinos K Tsilidis, Gianluca Severi, W Ryan Diver, Afshan Siddiq, Stephen Chanock, Robert N Hoover, Regina G Ziegler, Christine D Berg, Saundra S Buys, Christopher A Haiman, Brian E Henderson, Fredrick R Schumacher, Loïc Le Marchand, Dieter Flesch-Janys, Sara Lindström, David J Hunter, Susan E Hankinson, Walter C Willett, Peter Kraft, David G Cox, Kay-Tee Khaw, Anne Tjønneland, Laure Dossus, Dimitrios Trichopoulos, Salvatore Panico, Carla H van Gils, Elisabete Weiderpass, Aurelio Barricarte, Malin Sund, Mia M Gaudet, Graham Giles, Melissa Southey, Laura Baglietto, Jenny Chang-Claude, Rudolf Kaaks, and Federico Canzian
Subjects: Medicine, Science
Abstract: Approximately 15-30% of all breast cancer tumors are estrogen receptor negative (ER-). Compared with ER-positive (ER+) disease they have an earlier age at onset and worse prognosis. Despite the vast number of risk variants identified for numerous cancer types, only seven loci have been unambiguously identified for ER-negative breast cancer. With the aim of identifying new susceptibility SNPs for this disease we performed a pleiotropic genome-wide association study (GWAS). We selected 3079 SNPs associated with a human complex trait or disease at genome-wide significance level (P
Published: 2014
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18. Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes

Author: Joseph Vijai, Henrik Hjalgrim, Roger L. Milne, Simonetta Bisanzi, Rebecca D. Jackson, Graham G. Giles, Mark Liebow, John J. Spinelli, Stephanie J. Weinstein, Wendy Cozen, Susan M. Gapstur, Michael Dean, Paolo Boffetta, Pierluigi Cocco, Paige M. Bracci, Nicola J. Camp, Amy Moore, Herve Ghesquieres, Federico Canzian, James McKay, Thomas M. Habermann, Nikolaus Becker, Kari E. North, Demetrius Albanes, Alain Monnereau, Marc Maynadié, Lesley F. Tinker, Christine F. Skibola, Vignesh Ravichandran, Susan L. Slager, Karin E. Smedby, Ruth C. Travis, Jacqueline Clavel, Lucia Miligi, Melissa C. Southey, Mary Carrington, Claire M. Vajdic, Karen Curtin, David G. Cox, Roel Vermeulen, Elio Riboli, Eleanor Kane, Weiyin Zhou, Nathaniel Rothman, Mitchell J. Machiela, Yolanda Benavente, Alan A. Arslan, Meredith Yeager, Paul Brennan, Tongzhang Zheng, Elisabete Weiderpass, Moara Machado, Qing Lan, Alpa V. Patel, James R. Cerhan, Sonja I. Berndt, Neil E. Caporaso, Silvia de Sanjosé, Stephen J. Chanock, Nicole Wong Doo, Lauren R. Teras, Sara Piro, Lenka Foretova, Chi Gao, Gilles Salles, Immaculata De Vivo, Alexandra Nieters, Bengt Glimelius, Sophia S. Wang, Richard K. Severson, Mads Melbye, Hans-Olov Adami, Yawei Zhang, Carolyn Stewart, Lucia Conde, Brenda M. Birmann, Angela Brooks-Wilson, Thierry Jo Molina, Kenneth Offit, Brian K. Link, Martha Glenn, Anthony Staines, Moore, Amy, Machiela, Mitchell J, Machado, Moara, Wang, Sophia S, Kane, Eleanor, Slager, Susan L, Zhou, Weiyin, Carrington, Mary, Lan, Qing, Milne, Roger L, Birmann, Brenda M, Adami, Hans-Olov, Albanes, Demetriu, Arslan, Alan A, Becker, Nikolau, Benavente, Yolanda, Bisanzi, Simonetta, Boffetta, Paolo, Bracci, Paige M, Brennan, Paul, Brooks-Wilson, Angela R, Canzian, Federico, Caporaso, Neil, Clavel, Jacqueline, Cocco, Pierluigi, Conde, Lucia, Cox, David G, Cozen, Wendy, Curtin, Karen, De Vivo, Immaculata, de Sanjose, Silvia, Foretova, Lenka, Gapstur, Susan M, Ghesquières, Hervè, Giles, Graham G, Glenn, Martha, Glimelius, Bengt, Gao, Chi, Habermann, Thomas M, Hjalgrim, Henrik, Jackson, Rebecca D, Liebow, Mark, Link, Brian K, Maynadie, Marc, McKay, Jame, Melbye, Mad, Miligi, Lucia, Molina, Thierry J, Monnereau, Alain, Nieters, Alexandra, North, Kari E, Offit, Kenneth, Patel, Alpa V, Piro, Sara, Ravichandran, Vignesh, Riboli, Elio, Salles, Gille, Severson, Richard K, Skibola, Christine F, Smedby, Karin E, Southey, Melissa C, Spinelli, John J, Staines, Anthony, Stewart, Carolyn, Teras, Lauren R, Tinker, Lesley F, Travis, Ruth C, Vajdic, Claire M, Vermeulen, Roel C H, Vijai, Joseph, Weiderpass, Elisabete, Weinstein, Stephanie, Doo, Nicole Wong, Zhang, Yawei, Zheng, Tongzhang, Chanock, Stephen J, Rothman, Nathaniel, Cerhan, James R, Dean, Michael, Camp, Nicola J, Yeager, Meredith, and Berndt, Sonja I
Subjects: Genetics, Chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Follicular lymphoma, Single-nucleotide polymorphism, Runs of Homozygosity, Biology, medicine.disease, marginal zone lymphoma, Article, follicular lymphoma, immune system diseases, hemic and lymphatic diseases, Genetic variation, medicine, chronic lymphocytic leukemia, homozygosity, Diffuse large B-cell lymphoma, Inbreeding, Non-Hodgkin lymphoma, Genetic association
Abstract: Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10 -6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL ( P = 1.0) or MZL ( P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10 -5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.
Published: 2021
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19. Mannose-binding lectin 2 gene and risk of adult glioma.

Author: Dominique S Michaud, Afshan Siddiq, David G Cox, Danielle M Backes, Federico C F Calboli, Michael E Sughrue, J Michael Gaziano, Jing Ma, Meir Stampfer, Shelley S Tworoger, David J Hunter, Carlos A Camargo, and Andrew T Parsa
Subjects: Medicine, Science
Abstract: The immune system is likely to play a key role in the etiology of gliomas. Genetic polymorphisms in the mannose-binding lectin gene, a key activator in the lectin complement pathway, have been associated with risk of several cancers.To examine the role of the lectin complement pathway, we combined data from prospectively collected cohorts with available DNA specimens. Using a nested case-control design, we genotyped 85 single nucleotide polymorphisms (SNPs) in 9 genes in the lectin complement pathway and 3 additional SNPs in MBL2 were tested post hoc). Initial SNPs were selected using tagging SNPs for haplotypes; the second group of SNPs for MBL2 was selected based on functional SNPs related to phenotype. Associations were examined using logistic regression analysis. All statistical tests were two-sided. Nominal p-values are presented and are not corrected for multiple comparisons.A total of 143 glioma cases and 419 controls were available for this analysis. Statistically significant associations were observed for two SNPs in the mannose-binding lectin 2 (ML2) gene and risk of glioma (rs1982266 and rs1800450, test for trend p = 0.003 and p = 0.04, respectively, using the additive model). One of these SNPs, rs1800450, was associated with a 58% increase in glioma risk among those carrying one or two mutated alleles (odds ratio = 1.58, 95% confidence interval = 0.99-2.54), compared to those homozygous for the wild type allele.Overall, our findings suggest that MBL may play a role in the etiology of glioma. Future studies are needed to confirm these findings which may be due to chance, and if reproduced, to determine mechanisms that link glioma pathogenesis with the MBL complement pathway.
Published: 2013
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20. Analysis of the StoRM cohort reveals physical activity to be associated with survival in metastatic breast cancer

Author: Christine M. Friedenreich, Thomas Bachelot, C. Roemer-Becuwe, Sophie Abadie-Lacourtoisie, Céline Segura-Ferlay, Jean-Philippe Jacquin, E. Jacquet, Loic Chaigneau, Frédérique Penault-Llorca, H. Orfeuvre, Jean-Marc Ferrero, Christelle Jouannaud, David G. Cox, Lidia Delrieu, Pierre-Etienne Heudel, Monica Arnedos, N Quenel-Tueux, William Jacot, Isabelle Moullet, Gilles Romieu, Olivier Tredan, Maria Rios, Ellen Blanc, Olivia Febvey-Combes, CHU Grenoble, Université Joseph Fourier, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), and UNICANCER
Subjects: Oncology, Receptor, ErbB-2, [SDV]Life Sciences [q-bio], lcsh:Medicine, Triple Negative Breast Neoplasms, Body Mass Index, Breast cancer, 0302 clinical medicine, Surveys and Questionnaires, Prospective Studies, 030212 general & internal medicine, Neoplasm Metastasis, lcsh:Science, Prospective cohort study, education.field_of_study, Multidisciplinary, Anthropometry, Middle Aged, Prognosis, Metastatic breast cancer, 3. Good health, Survival Rate, Treatment Outcome, Data Interpretation, Statistical, 030220 oncology & carcinogenesis, Cohort, Female, medicine.medical_specialty, Population, Breast Neoplasms, Subgroup analysis, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Internal medicine, medicine, Humans, education, Exercise, Survival rate, Aged, Proportional Hazards Models, business.industry, lcsh:R, medicine.disease, Physical activity level, Multivariate Analysis, lcsh:Q, business
Abstract: Benefits of physical activity are widely demonstrated for early stage cancers but few studies have focused on metastatic disease. The purpose of this study was to determine the impact of physical activity on survival in patients with metastatic breast cancer. We conducted a secondary analysis of the national, multicentric, non-randomized, prospective cohort SNPs to Risk of Metastasis (StoRM) study. The level of physical activity was self-reported at inclusion and divided into three categories of physical activity: light level, moderate level, and vigorous level. Overall, 833 patients (56.2%) completed the physical activity questionnaire at baseline on average physical activity during the previous year: 11.6% had a light level of physical activity, 69.0% achieved moderate levels of physical activity and 19.3% reported vigorous levels of physical activity. After adjustment for confounding, physical activity was not statistically significantly associated with overall survival in the whole population. Subgroup analysis identified that both vigorous and moderate physical activity were associated with statistically significantly improved overall survival compared to light physical activity level only in the HER2 positive subgroup (HR 0.23; 95% CI 0.07–0.70, p = 0.01 and HR 0.38; 95% CI 0.15–0.96, p = 0.04). Physical activity done during the previous year was associated with survival in HER2 positive metastatic breast cancer patients. These results suggest that overall survival in metastatic breast cancer patients could be improved through physical activity which should be considered as a complementary intervention for these individuals. The study showed that moderate/vigorous levels of physical activity were associated with better overall survival, and that these associations remained statistically significant in multivariate analysis in the HER2 positive subgroup. These results have clinical relevance and justify the recommendations for physical activity interventions in metastatic breast cancer.
Published: 2020
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21. Efficacy of HD201 vs Referent Trastuzumab in Patients With ERBB2-Positive Breast Cancer Treated in the Neoadjuvant Setting

Author: Xavier, Pivot, M A, Georgievich, Volodymyr, Shamrai, Giorgi, Dzagnidze, Hwoei Fen, Soo Hoo, Viriya, Kaewkangsadan, Fausto, Petrelli, Cristian, Villanueva, Lipatov O, Nikolaevich, Jocelyn, Hii, Jamie, Kim, Sumita, Pradhan, Litha, Jaison, Peggy, Feyaerts, Leonard, Kaufman, Marie-Paule, Derde, Ghislain M C, Bonamy, Filip, Deforce, and David G, Cox
Subjects: Adult, Aged, 80 and over, Cancer Research, Receptor, ErbB-2, Correction, Antineoplastic Agents, Breast Neoplasms, Middle Aged, Trastuzumab, Neoadjuvant Therapy, Oncology, Humans, Female, Aged
Abstract: The drug HD201 is a biosimilar candidate for breast cancer treatment as the reference trastuzumab.To compare the efficacy of HD201 with referent trastuzumab.This randomized clinical trial (TROIKA) included 502 women with ERBB2-positive early breast cancer treated with either HD201 or referent trastuzumab. It was conducted across 70 centers in 12 countries, including Western and Eastern Europe and Asian countries. Randomization was stratified by tumor hormone receptor status, clinical stage, and geographic region of recruitment. This analysis was conducted on February 12, 2021, after the completion of the adjuvant phase at a median of 31 months (IQR, 28-33 months) of follow-up.Patients with ERBB2-positive early breast cancer were randomly assigned to receive HD201 or referent trastuzumab in the neoadjuvant setting for 8 cycles, concurrently with 4 cycles of docetaxel, which was followed by 4 cycles of epirubicin and cyclophosphamide. Patients then underwent surgery, which was followed by treatment with 10 cycles of adjuvant HD201 or referent trastuzumab.The primary end point was the total pathological complete response (tpCR) assessed after neoadjuvant treatment. Equivalence was concluded if the 95% CI of the absolute difference in tpCR between arms in the per-protocol set was within the margin of more or less than 15%. Other objectives included the breast pathological complete response, overall response, event-free and overall survival, safety, pharmacokinetics, and immunogenicity.A total of 502 female patients (mean [range] age, 53 [26-82] years) were randomized to receive either HD201 or referent trastuzumab, and 474 (94.2%) were eligible for inclusion in the per-protocol set. The baseline characteristics were well balanced between the 2 arms; 195 tumors (38.8%) were hormone receptor-negative , and 213 patients (42.4%) had clinical stage III disease. The tpCR rates were 45% and 48.7% for HD201 and referent trastuzumab, respectively. The difference between the 2 groups was not significant at -3.8% (95% CI, -12.8% to 5.4%) and fell within the predefined equivalence margins. The ratio of the tpCR rates between the 2 arms was 0.92 (95% CI, 0.76 to 1.12). A total of 433 patients (86.1%) presented with 2232 treatment-emergent adverse events of special interest for trastuzumab during the entire treatment period, with 220 (88.0%) and 213 (84.5%) patients in the HD201 and referent trastuzumab groups, respectively.The results of this randomized clinical trial found that HD201 demonstrated equivalence to referent trastuzumab in terms of efficacy for the end point of tpCR, with a similar safety profile.ClinicalTrials.gov Identifier: NCT03013504.
Published: 2022
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22. A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation.

Author: Andrea D Coviello, Robin Haring, Melissa Wellons, Dhananjay Vaidya, Terho Lehtimäki, Sarah Keildson, Kathryn L Lunetta, Chunyan He, Myriam Fornage, Vasiliki Lagou, Massimo Mangino, N Charlotte Onland-Moret, Brian Chen, Joel Eriksson, Melissa Garcia, Yong Mei Liu, Annemarie Koster, Kurt Lohman, Leo-Pekka Lyytikäinen, Ann-Kristin Petersen, Jennifer Prescott, Lisette Stolk, Liesbeth Vandenput, Andrew R Wood, Wei Vivian Zhuang, Aimo Ruokonen, Anna-Liisa Hartikainen, Anneli Pouta, Stefania Bandinelli, Reiner Biffar, Georg Brabant, David G Cox, Yuhui Chen, Steven Cummings, Luigi Ferrucci, Marc J Gunter, Susan E Hankinson, Hannu Martikainen, Albert Hofman, Georg Homuth, Thomas Illig, John-Olov Jansson, Andrew D Johnson, David Karasik, Magnus Karlsson, Johannes Kettunen, Douglas P Kiel, Peter Kraft, Jingmin Liu, Östen Ljunggren, Mattias Lorentzon, Marcello Maggio, Marcello R P Markus, Dan Mellström, Iva Miljkovic, Daniel Mirel, Sarah Nelson, Laure Morin Papunen, Petra H M Peeters, Inga Prokopenko, Leslie Raffel, Martin Reincke, Alex P Reiner, Kathryn Rexrode, Fernando Rivadeneira, Stephen M Schwartz, David Siscovick, Nicole Soranzo, Doris Stöckl, Shelley Tworoger, André G Uitterlinden, Carla H van Gils, Ramachandran S Vasan, H-Erich Wichmann, Guangju Zhai, Shalender Bhasin, Martin Bidlingmaier, Stephen J Chanock, Immaculata De Vivo, Tamara B Harris, David J Hunter, Mika Kähönen, Simin Liu, Pamela Ouyang, Tim D Spector, Yvonne T van der Schouw, Jorma Viikari, Henri Wallaschofski, Mark I McCarthy, Timothy M Frayling, Anna Murray, Steve Franks, Marjo-Riitta Järvelin, Frank H de Jong, Olli Raitakari, Alexander Teumer, Claes Ohlsson, Joanne M Murabito, and John R B Perry
Subjects: Genetics, QH426-470
Abstract: Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
Published: 2012
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23. Genome-wide association study of circulating estradiol, testosterone, and sex hormone-binding globulin in postmenopausal women.

Author: Jennifer Prescott, Deborah J Thompson, Peter Kraft, Stephen J Chanock, Tina Audley, Judith Brown, Jean Leyland, Elizabeth Folkerd, Deborah Doody, Susan E Hankinson, David J Hunter, Kevin B Jacobs, Mitch Dowsett, David G Cox, Douglas F Easton, and Immaculata De Vivo
Subjects: Medicine, Science
Abstract: Genome-wide association studies (GWAS) have successfully identified common genetic variants that contribute to breast cancer risk. Discovering additional variants has become difficult, as power to detect variants of weaker effect with present sample sizes is limited. An alternative approach is to look for variants associated with quantitative traits that in turn affect disease risk. As exposure to high circulating estradiol and testosterone, and low sex hormone-binding globulin (SHBG) levels is implicated in breast cancer etiology, we conducted GWAS analyses of plasma estradiol, testosterone, and SHBG to identify new susceptibility alleles. Cancer Genetic Markers of Susceptibility (CGEMS) data from the Nurses' Health Study (NHS), and Sisters in Breast Cancer Screening data were used to carry out primary meta-analyses among ~1600 postmenopausal women who were not taking postmenopausal hormones at blood draw. We observed a genome-wide significant association between SHBG levels and rs727428 (joint β = -0.126; joint P = 2.09 × 10(-16)), downstream of the SHBG gene. No genome-wide significant associations were observed with estradiol or testosterone levels. Among variants that were suggestively associated with estradiol (P
Published: 2012
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24. Transmission of breast cancer polygenic risk based on single nucleotide polymorphisms

Author: Xavier Pivot, David G. Cox, Julie Henry, Pierre-Etienne Heudel, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Léon Bérard [Lyon], Triangle : action, discours, pensée politique et économique (TRIANGLE), École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Centre Paul Strauss, CRLCC Paul Strauss, Centre National de la Recherche Scientifique (CNRS)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Risk, 0301 basic medicine, Multifactorial Inheritance, media_common.quotation_subject, education, Population, Mothers, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, Risk Assessment, Nuclear Family, 03 medical and health sciences, breast cancer, 0302 clinical medicine, Breast cancer, Humans, Medicine, Genetic Predisposition to Disease, Nuclear family, Allele frequency, Alleles, media_common, Daughter, education.field_of_study, Framingham Risk Score, business.industry, [SHS.PHIL]Humanities and Social Sciences/Philosophy, General Medicine, medicine.disease, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Surgery, business, Risk assessment, Demography
Abstract: Aim The goal of the present study was to further refine how polygenic risk scores may be used in a large population and to quantify the transmission of risk score through generations. Methods Allele frequencies from the 1000 Genomes data for 159 single nucleotide polymorphisms associated with breast cancer risk were used. A breast cancer risk score was calculated among 100,000 people. Choosing two “parents” and the alleles they transmit at random, 100,000 “daughters” were simulated. The population was divided by deciles of risk score. Comparing mean risk score in the mother and daughter populations provided information regarding the general relationship at a population level. By examining the distribution of daughter's risk score within each decile of maternal risk score, the transmission was evaluated at the subject level. Results Mean values of risk score were 85.1 (St Dev = 7.5) and 85.0 (St Dev = 7.5) for the populations of mothers and daughters, respectively (mean absolute difference = 0.02, p = 0.48). When examining the transmission of risk score from mothers to daughters in specific deciles of risk, statistically significant differences were observed in all deciles (ranged between 0.001 and Conclusion The relationship at the subject level will not provide information regarding prevention and screening of offspring based on the knowledge of parents' risk score alone. The present results show that risk estimation by polygenic risk scores is personal, and evaluation of risk score is required for each individual.
Published: 2018
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25. HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Author: Roel Vermeulen, Paulo Bofetta, Nicole Wong Doo, Mark P. Purdue, Eleanor Kane, Gilles Salles, Bengt Glimelius, Christine F. Skibola, Tongzhang Zheng, Graham G. Giles, Scott Davis, Pierluigi Cocco, Karin E. Smedby, Melissa C. Southey, Alexandra Nieters, Elizabeth A. Holly, Corrado Magnani, Paul Brennan, Stephanie J. Lax, David G. Cox, Lindsay M. Morton, Nikolaus Becker, Qing Lan, Elio Riboli, Herve Ghesquieres, Rudolph Kaaks, Jennifer Turner, Martha S. Linet, Anne Kricker, Stephanie J. Weinstein, Christopher R. Flowers, Alain Monnereau, Silvia de Sanjosé, Mary Carrington, John J. Spinelli, Patricia Hartge, Nathaniel Rothman, Yolanda Benavente, Susan L. Slager, Martha Glenn, Richard K. Severson, Ora Paltiel, Yawei Zhang, Ruth C. Travis, Demetrius Albanes, Nicola J. Camp, Paige M. Bracci, Jacqueline Clavel, James R. Cerhan, Marc Maynadié, Maria Grazia Ennas, Marie Hélène Delfau-Larue, Peter Kraft, Henrik Hjalgrim, Roger L. Milne, Alan A. Arslan, Jacob Musinsky, Martyn T. Smith, Anthony Staines, Lauren R. Teras, Jenna M. Voutsinas, Lenka Foretova, Sophia S. Wang, Hans-Olov Adami, Andrew L. Feldman, Wendy Cozen, Angela Brooks-Wilson, Kenneth Offit, Brian K. Link, Brenda M. Birmann, Sonja I. Berndt, Stephen J. Chanock, James McKay, Dennis D. Weisenburger, Claire M. Vajdic, Giancarlo Latte, Karen Curtin, W. Ryan Diver, Mads Melbye, Lucia Conde, Elizabeth E. Brown, Joseph Vijai, Eve Roman, Wang, Sophia S., Carrington, Mary, Berndt, Sonja I., Slager, Susan L., Bracci, Paige M., Voutsinas, Jenna, Cerhan, James R., Smedby, Karin E., Hjalgrim, Henrik, Vijai, Joseph, Morton, Lindsay M., Vermeulen, Roel, Paltiel, Ora, Vajdic, Claire M., Linet, Martha S., Nieters, Alexandra, de Sanjose, Silvia, Cozen, Wendy, Brown, Elizabeth E., Turner, Jennifer, Spinelli, John J., Zheng, Tongzhang, Birmann, Brenda M., Flowers, Christopher R., Becker, Nikolau, Holly, Elizabeth A., Kane, Eleanor, Weisenburger, Denni, Maynadie, Marc, Cocco, Pierluigi, Albanes, Demetriu, Weinstein, Stephanie J., Teras, Lauren R., Diver, W. Ryan, Lax, Stephanie J., Travis, Ruth C., Kaaks, Rudolph, Riboli, Elio, Benavente, Yolanda, Brennan, Paul, McKay, Jame, Delfau-Larue, Marie-Hélène, Link, Brian K., Magnani, Corrado, Ennas, Maria Grazia, Latte, Giancarlo, Feldman, Andrew L., Doo, Nicole Wong, Giles, Graham G., Southey, Melissa C., Milne, Roger L., Offit, Kenneth, Musinsky, Jacob, Arslan, Alan A., Purdue, Mark P., Adami, Hans-Olov, Melbye, Mad, Glimelius, Bengt, Conde, Lucia, Camp, Nicola J., Glenn, Martha, Curtin, Karen, Clavel, Jacqueline, Monnereau, Alain, Cox, David G., Ghesquières, Hervé, Salles, Gille, Boffetta, Paolo, Foretova, Lenka, Staines, Anthony, Davis, Scott, Severson, Richard K., Lan, Qing, Brooks-Wilson, Angela, Smith, Martyn T., Roman, Eve, Kricker, Anne, Zhang, Yawei, Kraft, Peter, Chanock, Stephen J., Rothman, Nathaniel, Hartge, Patricia, and Skibola, Christine F.
Subjects: Male, 0301 basic medicine, Heterozygote, Cancer Research, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Chronic lymphocytic leukemia, EPIDEMIOLOGIC RESEARCH, Genome-wide association study, Human leukocyte antigen, Biology, CLASSIFICATION, ANTIGENS, Article, Genetic Heterogeneity, 03 medical and health sciences, immune system diseases, hemic and lymphatic diseases, Internal medicine, medicine, INTERLYMPH, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Prospective Studies, GENOME-WIDE ASSOCIATION, Allele, HLA Complex, Science & Technology, Hematology, CHRONIC LYMPHOCYTIC-LEUKEMIA, Genetic heterogeneity, Lymphoma, Non-Hodgkin, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, HETEROZYGOTE ADVANTAGE, medicine.disease, 3. Good health, Lymphoma, 030104 developmental biology, Oncology, Case-Control Studies, Immunology, B-VIRUS INFECTION, Female, Life Sciences & Biomedicine, NEOPLASMS, Genome-Wide Association Study
Abstract: A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.
Published: 2018
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26. Genetic variability of the mTOR pathway and prostate cancer risk in the European Prospective Investigation on Cancer (EPIC).

Author: Daniele Campa, Anika Hüsing, Angelika Stein, Lucie Dostal, Heiner Boeing, Tobias Pischon, Anne Tjønneland, Nina Roswall, Kim Overvad, Jane Nautrup Østergaard, Laudina Rodríguez, Núria Sala, Maria-José Sánchez, Nerea Larrañaga, José María Huerta, Aurelio Barricarte, Kay-Tee Khaw, Nicholas Wareham, Ruth C Travis, Naomi E Allen, Pagona Lagiou, Antonia Trichopoulou, Dimitrios Trichopoulos, Domenico Palli, Sabina Sieri, Rosario Tumino, Carlotta Sacerdote, Henk van Kranen, H Bas Bueno-de-Mesquita, Göran Hallmans, Mattias Johansson, Isabelle Romieu, Mazda Jenab, David G Cox, Afshan Siddiq, Elio Riboli, Federico Canzian, and Rudolf Kaaks
Subjects: Medicine, Science
Abstract: The mTOR (mammalian target of rapamycin) signal transduction pathway integrates various signals, regulating ribosome biogenesis and protein synthesis as a function of available energy and amino acids, and assuring an appropriate coupling of cellular proliferation with increases in cell size. In addition, recent evidence has pointed to an interplay between the mTOR and p53 pathways. We investigated the genetic variability of 67 key genes in the mTOR pathway and in genes of the p53 pathway which interact with mTOR. We tested the association of 1,084 tagging SNPs with prostate cancer risk in a study of 815 prostate cancer cases and 1,266 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). We chose the SNPs (n = 11) with the strongest association with risk (p
Published: 2011
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27. The mitochondrial A10398G polymorphism, interaction with alcohol consumption, and breast cancer risk.

Author: Annamaria Pezzotti, Peter Kraft, Susan E Hankinson, David J Hunter, Julie Buring, and David G Cox
Subjects: Medicine, Science
Abstract: Polymorphisms in the mitochondrial genome are hypothesized to be associated with risk of various diseases, including cancer. However, there has been conflicting evidence for associations between a common polymorphism in the mitochondrial genome (A10398G, G10398A in some prior reports) and breast cancer risk. Reactive oxygen species, a by-product of mitochondrial energy production, can lead to oxidative stress and DNA damage in both the mitochondria and their cells. Alcohol consumption, which may also lead to oxidative stress, is associated with breast cancer risk. Therefore, we hypothesized that polymorphisms in the mitochondrial genome interact with alcohol consumption to alter breast cancer risk. We genotyped the A10398G polymorphism in a case-control study nested within the Nurses' Health Study (NHS, 1,561 cases, 2,209 controls). We observed an interaction between alcohol consumption (yes/no) and A10398G on breast cancer risk (p-int = 0.03). The risk associated with alcohol consumption was limited to carriers of the 10398G allele (Odds Ratio 1.52, 95% Confidence Interval 1.10-2.08 comparing drinkers to non-drinkers). However, we were unable to replicate these findings in the Women's Health Study (WHS, 678 cases, 669 controls), although the power to detect this interaction in the WHS was low (power = 0.57). Further examination of this interaction, such as sufficiently powered epidemiological studies of cancer risk or associations with biomarkers of oxidative stress, may provide further evidence for GxE interactions between the A10398G mitochondrial polymorphism and alcohol consumption on breast cancer risk.
Published: 2009
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28. IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3).

Author: Alpa V Patel, Iona Cheng, Federico Canzian, Loïc Le Marchand, Michael J Thun, Christine D Berg, Julie Buring, Eugenia E Calle, Stephen Chanock, Francoise Clavel-Chapelon, David G Cox, Miren Dorronsoro, Laure Dossus, Christopher A Haiman, Susan E Hankinson, Brian E Henderson, Robert Hoover, David J Hunter, Rudolf Kaaks, Laurence N Kolonel, Peter Kraft, Jakob Linseisen, Eiliv Lund, Jonas Manjer, Catherine McCarty, Petra H M Peeters, Malcolm C Pike, Michael Pollak, Elio Riboli, Daniel O Stram, Anne Tjonneland, Ruth C Travis, Dimitrios Trichopoulos, Rosario Tumino, Meredith Yeager, Regina G Ziegler, Heather Spencer Feigelson, and Breast and Prostate Cancer Cohort Consortium
Subjects: Medicine, Science
Abstract: IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.
Published: 2008
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29. Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

Author: Montserrat Garcia-Closas, Per Hall, Heli Nevanlinna, Karen Pooley, Jonathan Morrison, Douglas A Richesson, Stig E Bojesen, Børge G Nordestgaard, Christen K Axelsson, Jose I Arias, Roger L Milne, Gloria Ribas, Anna González-Neira, Javier Benítez, Pilar Zamora, Hiltrud Brauch, Christina Justenhoven, Ute Hamann, Yon-Dschun Ko, Thomas Bruening, Susanne Haas, Thilo Dörk, Peter Schürmann, Peter Hillemanns, Natalia Bogdanova, Michael Bremer, Johann Hinrich Karstens, Rainer Fagerholm, Kirsimari Aaltonen, Kristiina Aittomäki, Karl von Smitten, Carl Blomqvist, Arto Mannermaa, Matti Uusitupa, Matti Eskelinen, Maria Tengström, Veli-Matti Kosma, Vesa Kataja, Georgia Chenevix-Trench, Amanda B Spurdle, Jonathan Beesley, Xiaoqing Chen, Australian Ovarian Cancer Management Group, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Peter Devilee, Christi J van Asperen, Catharina E Jacobi, Rob A E M Tollenaar, Petra E A Huijts, Jan G M Klijn, Jenny Chang-Claude, Silke Kropp, Tracy Slanger, Dieter Flesch-Janys, Elke Mutschelknauss, Ramona Salazar, Shan Wang-Gohrke, Fergus Couch, Ellen L Goode, Janet E Olson, Celine Vachon, Zachary S Fredericksen, Graham G Giles, Laura Baglietto, Gianluca Severi, John L Hopper, Dallas R English, Melissa C Southey, Christopher A Haiman, Brian E Henderson, Laurence N Kolonel, Loic Le Marchand, Daniel O Stram, David J Hunter, Susan E Hankinson, David G Cox, Rulla Tamimi, Peter Kraft, Mark E Sherman, Stephen J Chanock, Jolanta Lissowska, Louise A Brinton, Beata Peplonska, Maartje J Hooning, Han Meijers-Heijboer, J Margriet Collee, Ans van den Ouweland, Andre G Uitterlinden, Jianjun Liu, Low Yen Lin, Li Yuqing, Keith Humphreys, Kamila Czene, Angela Cox, Sabapathy P Balasubramanian, Simon S Cross, Malcolm W R Reed, Fiona Blows, Kristy Driver, Alison Dunning, Jonathan Tyrer, Bruce A J Ponder, Suleeporn Sangrajrang, Paul Brennan, James McKay, Fabrice Odefrey, Valerie Gabrieau, Alice Sigurdson, Michele Doody, Jeffrey P Struewing, Bruce Alexander, Douglas F Easton, and Paul D Pharoah
Subjects: Genetics, QH426-470
Abstract: A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
Published: 2008
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30. 319P A propensity score weighted study comparing two versus four-weekly pegylated liposomal doxorubicin regimen in metastatic breast cancer

Author: H. Bischoff, C. Pflumio, C. Bigot, C. Fischbach, Xavier Pivot, P. Coliat, M. Alt, D. Karouby, M. Kalish Weindling, David G. Cox, L. Bender, L. Pierard, F. Moinard, Thierry Petit, P. Trensz, Jean-Emmanuel Kurtz, and Martin Demarchi
Subjects: Oncology, medicine.medical_specialty, Regimen, business.industry, Internal medicine, Propensity score matching, medicine, Hematology, medicine.disease, business, Metastatic breast cancer, Pegylated Liposomal Doxorubicin
Published: 2021
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31. 286P Outcome of patients with HER2-positive brain metastatic breast cancer: A 10-year retrospective study

Author: Jean-Emmanuel Kurtz, C. Lefevre, Thierry Petit, Xavier Pivot, P. Trensz, L. Bender, M. Alt, C. Bigot, Georges Noël, David G. Cox, C. Fischbach, L. Pierard, Martin Demarchi, M. Kalish Weindling, I. Chambrelant, H. Bischoff, and C. Pflumio
Subjects: Oncology, medicine.medical_specialty, business.industry, Internal medicine, Medicine, Retrospective cohort study, Hematology, business, medicine.disease, Outcome (game theory), Metastatic breast cancer
Published: 2021
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32. LBA11 Individual patient data meta-analysis of 5 non-inferiority RCTs of reduced duration single agent adjuvant trastuzumab in the treatment of HER2 positive early breast cancer

Author: Xavier Pivot, David G. Cox, C. Faure-Mercier, Jacinta Abraham, Janet A. Dunn, V. Georgoulias, Roberto D'Amico, Heikki Joensuu, Valentina Guarneri, Pierfranco Conte, Helena M. Earl, Marc Debled, Louise Hiller, David Miles, T. Huttunen, Andrew M Wardley, Henrik Lindman, David Cameron, Judith Fraser, and Gilles Romieu
Subjects: Oncology, medicine.medical_specialty, business.industry, medicine.medical_treatment, Hematology, Patient data, Non inferiority, Trastuzumab, Meta-analysis, Internal medicine, medicine, Single agent, Duration (project management), business, Adjuvant, Early breast cancer, medicine.drug
Published: 2021
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33. Hands-on engagement online: using a randomised control trial to estimate the impact of an at-home lab kit on student attitudes and achievement in a MOOC

Author: David G. Cox, Casey J Smith, S. Zahra Atiq, Casey Lynn Haney, and Jennifer DeBoer
Subjects: Self-efficacy, Medical education, Online learning, 05 social sciences, Control (management), Distance education, General Engineering, 050301 education, 06 humanities and the arts, 0603 philosophy, ethics and religion, Electronic learning, Education, law.invention, Randomized controlled trial, law, Engineering education, Pedagogy, 060301 applied ethics, Psychology, 0503 education
Abstract: A shortcoming of Massive Open Online Courses (MOOCs) is the lack of substantive integration of hands-on activities into online classrooms. We conducted a randomised control trial (RCT) in a MOOC wh...
Published: 2017
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34. Encoding of 3D Head Orienting Movements in Primary Visual Cortex

Author: Steffen B. E. Wolff, Javier Masís, David G. Cox, and Grigori Guitchounts
Subjects: 0303 health sciences, Movement (music), Efference copy, Sensory system, Visual processing, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Visual cortex, Orientation (mental), medicine, Premovement neuronal activity, Psychology, Neuroscience, 030217 neurology & neurosurgery, 030304 developmental biology, Motor cortex
Abstract: Animals actively sample from the sensory world by generating complex patterns of movement that evolve in three dimensions. At least some of these movements have been shown to influence neural codes in sensory areas. For example, in primary visual cortex (V1), locomotion-related neural activity influences sensory gain, encodes running speed, and predicts the direction of visual flow. As most experiments exploring movement-related modulation of V1 have been performed in head-fixed animals, it remains unclear whether or how the naturalistic movements used to interact with sensory stimuli– like head orienting–influence visual processing. Here we show that 3D head orienting movements modulate V1 neuronal activity in a direction-specific manner that also depends on the presence or absence of light. We identify two largely independent populations of movement-direction-tuned neurons that support this modulation, one of which is direction-tuned in the dark and the other in the light. Finally, we demonstrate that V1 gains access to a motor efference copy related to orientation from secondary motor cortex, which has been shown to control head orienting movements. These results suggest a mechanism through which sensory signals generated by purposeful movement can be distinguished from those arising in the outside world, and reveal a pervasive role of 3D movement in shaping sensory cortical dynamics.
Published: 2020
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35. Low-frequency variation near common germline susceptibility loci are associated with risk of Ewing sarcoma

Author: Sakina Zaidi, Didier Surdez, Javier Alonso, Gregory T. Armstrong, Gaëlle Pierron, Nadège Corradini, Nathaniel Rothman, Markus Metzler, Valérie Laurence, Kathleen Wyatt, Kristine Jones, Heinrich Kovar, Brian D. Carter, Eve Lapouble, Weiyin Zhou, Leslie L. Robison, Rebeca Alba Rubio, Thomas Kirchner, Wendy M. Leisenring, David G. Cox, Manuela Krumbholz, Lisa Mirabello, Smita Bhatia, Olivier Delattre, Casey L. Dagnall, Lindsay M. Morton, Neal D. Freedman, Stéphanie Reynaud, Stelly Ballet, Udo Kontny, Thomas Meitinger, Sandrine Grossetête-Lalami, Robert N. Hoover, Shu-Hong Lin, Ana Patiño-García, Joshua N. Sampson, Margaret A. Tucker, Laurie Burdett, Olivier Mirabeau, Perrine Marec Bérard, Mitchell J. Machiela, Jeremy A. Miller, Stephen J. Chanock, Thomas G. P. Grunewald, Jennifer Kriebel, Jean Michon, Meredith Yeager, Uta Dirksen, Wolfgang Hartmann, Andreas E. Kulozik, Javed Khan, Konstantin Strauch, Franck Tirode, Eric Karlins, Anna González-Neira, Michelle Manning, NIH - National Cancer Institute (NCI) (Estados Unidos), Agence Nationale de la Recherche (Francia), Unión Europea. Comisión Europea. 7 Programa Marco, Deutsche Forschungsgemeinschaft (Alemania), Instituto de Salud Carlos III, Comunidad Foral de Navarra (España), National Cancer Institute (United States), Agence Nationale de la Recherche (France), 7º Programa Marco - Comisión Europea, Deutsche Forschungsgemeinschaft, Instituto de Salud Carlos III - ISCIII, and Gobierno de Navarra
Subjects: 0301 basic medicine, Heredity, Epidemiology, Medizin, Genome-wide association study, Linkage Disequilibrium, 0302 clinical medicine, Medizinische Fakultät, Medicine and Health Sciences, Odds Ratio, Genetics, Multidisciplinary, Cancer Risk Factors, Prostate Cancer, Prostate Diseases, Sarcoma, Genomics, Genetic Mapping, Oncology, 030220 oncology & carcinogenesis, Medicine, Research Article, Urology, Science, Ewing Sarcoma, Locus (genetics), Variant Genotypes, Sarcoma, Ewing, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Genetic variation, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Alleles, Genetic association, Colorectal Cancer, Haplotype, Cancers and Neoplasms, Biology and Life Sciences, Computational Biology, Genetic Variation, Human Genetics, Genome Analysis, Minor allele frequency, Genitourinary Tract Tumors, 030104 developmental biology, Germ Cells, Genetic Loci, Medical Risk Factors, Chromosome 20, Genome-Wide Association Study
Abstract: PLOS ONE 15(9), e0237792 (2020). doi:10.1371/journal.pone.0237792, Published by PLOS, San Francisco, California, US
Published: 2020
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36. Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes

Author: Paul Brennan, M. G. Ennas, Qing Lan, Sasha Bernatsky, Alan A. Arslan, Peter Kraft, Lohith Madireddy, Roel Vermeulen, Kenan Onel, Graham G. Giles, John J. Spinelli, Eleanor Kane, Bengt Glimelius, Alexandra Nieters, David V. Conti, Christine F. Skibola, Pouya Khankhanian, Amy Moore, Ruth C. Travis, Mads Melbye, Sonja I. Berndt, Mark Liebow, Lauren R. Teras, Pierluigi Cocco, Lennox Din, Alain Monnereau, Mark P. Purdue, Lenka Foretova, Stephen J. Chanock, Stephen M. Ansell, Angela Brooks-Wilson, Wendy Cozen, Kenneth Offit, Demetrius Albanes, Anne J. Novak, Melissa C. Southey, Paolo Boffetta, Nicola J. Camp, James R. Cerhan, Rudolph Kaaks, Silvia de Sanjosé, Karen Curtin, Sophia S. Wang, James McKay, Nicole Wong Doo, Hans-Olov Adami, Tongzhang Zheng, Claire M. Vajdic, Nisha Pradhan, Giacomo Muzi, Gilles Salles, Nathaniel Rothman, Yolanda Benavente, Marc Maynadié, Brian K. Link, Delphine Casabonne, Hervé Ghesquières, Joseph Vijai, Karin E. Smedby, Paige M. Bracci, David G. Cox, Brenda M. Birmann, Lucia Miligi, Carolyn Stewart, Lucia Conde, Leonid Padyukov, Eve Roman, Richard K. Severson, Jorge R. Oksenberg, Immaculata De Vivo, Yawei Zhang, Corrado Magnani, Jacqueline Clavel, Lindsay M. Morton, Corinne Haioun, Jonathan N. Hofmann, Karen H. Costenbader, Pierre-Antoine Gourraud, Mohammad Sheikh, Stephanie J. Weinstein, Susan L. Slager, Paolo Vineis, Nikitha Kosaraju, Zachary Taub, Henrik Hjalgrim, Roger L. Milne, Morris Din, Martha Glenn, Nikolaus Becker, Timothy J. Vyse, Thomas M. Mack, Anthony Staines, Department of Medicine, Clinical Epidemiology, McGill University Health Center [Montreal] (MUHC), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Emory University [Atlanta, GA], Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, International Agency for Cancer Research (IACR), Department of Public Health, Vientiane Municipality, Registre des hémopathies malignes de Côte d'Or, Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, GRAPHOS - IFROSS Recherche, Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon, Faculty of Medicine, Section of Rheumatology, Imperial College London, Karolinska Institutet [Stockholm], Epidémiologie environnementale des cancers, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Uppsala Universitet [Uppsala], Carver College of Medicine, University of Iowa, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Cancer Epidemiology and Genetics, National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Health Sciences, University of York [York, UK], Service de Radio-Oncologie [Lyon], Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), University of Melbourne, Centre Léon Bérard [Lyon], Mayo Clinic [Rochester], Occupational and Environmental Epidemiology Branch [Bethesda, Maryland], Division of Cancer Epidemiology and Genetics [Bethesda, Maryland], National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), Memorial Sloane Kettering Cancer Center [New York], Huntsman Cancer Institute, Clinical Genetics Service, ISPO - Cancer Prevention and Research Institute, Unit of Environmental and Occupational Epidemiology, Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], B.B. Brodie Department of Neuroscience, Department of Pathology, Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Unit of Environment Cancer Epidemiology, IARC, University of Torino and CPO-Piemonte, Università degli studi di Torino (UNITO), Department of Epidemiology, Harvard School of Public Health, Wayne State University [Detroit], Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Cancer Epidemiology Centre, Cancer Council Victoria, Cancer Epidemiology Unit, University of Oxford [Oxford], De la Molécule aux Nanos-objets : Réactivité, Interactions et Spectroscopies (MONARIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Catalan Institute of Oncology (ICO), Department of Neurology [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Norris Comprehensive Cancer Center, Masaryk University [Brno] (MUNI), Università degli studi di Torino = University of Turin (UNITO), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Imperial College London, University of Oxford, Din L., Sheikh M., Kosaraju N., Smedby K.E., Bernatsky S., Berndt S.I., Skibola C.F., Nieters A., Wang S., McKay J.D., Cocco P., Maynadie M., Foretova L., Staines A., Mack T.M., de Sanjose S., Vyse T.J., Padyukov L., Monnereau A., Arslan A.A., Moore A., Brooks-Wilson A.R., Novak A.J., Glimelius B., Birmann B.M., Link B.K., Stewart C., Vajdic C.M., Haioun C., Magnani C., Conti D.V., Cox D.G., Casabonne D., Albanes D., Kane E., Roman E., Muzi G., Salles G., Giles G.G., Adami H.-O., Ghesquieres H., De Vivo I., Clavel J., Cerhan J.R., Spinelli J.J., Hofmann J., Vijai J., Curtin K., Costenbader K.H., Onel K., Offit K., Teras L.R., Morton L., Conde L., Miligi L., Melbye M., Ennas M.G., Liebow M., Purdue M.P., Glenn M., Southey M.C., Din M., Rothman N., Camp N.J., Wong Doo N., Becker N., Pradhan N., Bracci P.M., Boffetta P., Vineis P., Brennan P., Kraft P., Lan Q., Severson R.K., Vermeulen R.C.H., Milne R.L., Kaaks R., Travis R.C., Weinstein S.J., Chanock S.J., Ansell S.M., Slager S.L., Zheng T., Zhang Y., Benavente Y., Taub Z., Madireddy L., Gourraud P.-A., Oksenberg J.R., Cozen W., Hjalgrim H., Khankhanian P., and Le Bihan, Sylvie
Subjects: Oncology, Male, Multifactorial Inheritance, Lymphoma, Epidemiology, Chronic lymphocytic leukemia, Follicular lymphoma, Genome-wide association study, Disease, Neurodegenerative, meta-analysi, immune system diseases, HLA Antigens, Risk Factors, hemic and lymphatic diseases, 2.1 Biological and endogenous factors, HLA Antigen, Aetiology, Genetics (clinical), Cancer, Allele, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Lymphoma, Non-Hodgkin, non-Hodgkin lymphoma, 030305 genetics & heredity, Single Nucleotide, Hematology, Middle Aged, 3. Good health, Public Health and Health Services, Female, Human, medicine.medical_specialty, autoimmune disease, genome-wide association study, meta-analysis, Alleles, Autoimmune Diseases, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Non-Hodgkin, Article, 03 medical and health sciences, Rare Diseases, Internal medicine, Genetic variation, medicine, Genetics, Polymorphism, 030304 developmental biology, Autoimmune disease, business.industry, Multiple sclerosis, Risk Factor, Arthritis, Inflammatory and immune system, Human Genome, medicine.disease, Brain Disorders, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.
Published: 2019
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37. Triton: an intermediate language and compiler for tiled neural network computations

Author: David G. Cox, Hsiang-Tsung Kung, and Philippe Tillet
Subjects: Artificial neural network, business.industry, Programming language, Computer science, Deep learning, computer.software_genre, Matrix multiplication, CUDA, Software portability, High-level programming language, Leverage (statistics), Compiler, Artificial intelligence, business, computer
Abstract: The validation and deployment of novel research ideas in the field of Deep Learning is often limited by the availability of efficient compute kernels for certain basic primitives. In particular, operations that cannot leverage existing vendor libraries (e.g., cuBLAS, cuDNN) are at risk of facing poor device utilization unless custom implementations are written by experts – usually at the expense of portability. For this reason, the development of new programming abstractions for specifying custom Deep Learning workloads at a minimal performance cost has become crucial. We present Triton, a language and compiler centered around the concept of tile, i.e., statically shaped multi-dimensional sub-arrays. Our approach revolves around (1) a C-based language and an LLVM-based intermediate representation (IR) for expressing tensor programs in terms of operations on parametric tile variables and (2) a set of novel tile-level optimization passes for compiling these programs into efficient GPU code. We demonstrate how Triton can be used to build portable implementations of matrix multiplication and convolution kernels on par with hand-tuned vendor libraries (cuBLAS / cuDNN), or for efficiently implementing recent research ideas such as shift convolutions.
Published: 2019
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38. Genome-wide association study of germline variants and breast cancer-specific mortality

Author: Wing-Yee Lo, Dhanya Ramachandran, Christos Petridis, Fernando Salvador Moreno, Tongguang Cheng, Bernardo Bonanni, Ann Smeets, Susan E. Hankinson, Caroline Seynaeve, Suet-Feung Chin, Vessela N. Kristensen, Christopher G. Scott, Javier Benitez, William T. Newman, Brigitte Rack, Marjanka K. Schmidt, Diether Lambrechts, Alfons Meindl, Maria Escala-Garcia, Hoda Anton-Culver, Veli-Matti Kosma, Nadege Presneau, Daniel F. Schmidt, Douglas F. Easton, Ans M.W. van den Ouweland, Emmanouil Saloustros, Antoinette Hollestelle, Darya Prokofieva, Elinor J. Sawyer, Louise A. Brinton, Manuela Gago-Dominguez, Minouk J. Schoemaker, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Eva Galle, Catriona McLean, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Per Hall, Jaana M. Hartikainen, Leslie Bernstein, Jose Ignacio Arias Perez, Flavio Lejbkowicz, Qi Guo, Brian D. Carter, Martha S. Linet, Fredrick R. Schumacher, Yan Zhang, Mikael Eriksson, Hiltrud Brauch, Janet A. Dunn, Gord Glendon, Bernd Holleczek, William J. Tapper, Marike Gabrielson, Keith Humphreys, Rodney J. Scott, Tabea Kühl, Lorraine Durcan, David J. Hunter, Pascal Guénel, Tom Maishman, Mary B. Daly, Rami Nassir, Andreas Schneeweiss, Kamila Czene, Jonine D. Figueroa, Grethe I. Grenaker Alnæs, Julia A. Knight, Angel Carracedo, Susan M. Gapstur, Manuel R. Teixeira, Guanmengqian Huang, Paul L. Auer, Sara Y. Brucker, Johanna I. Kiiski, Adam R. Brentnall, Simon S. Cross, Joe Dennis, Nicola Miller, Walter C. Willett, Melissa C. Southey, Christoph Engel, Niclas Håkansson, Diana Eccles, John L. Hopper, Elaine F. Harkness, Audrey Y. Jung, Trinidad Caldés, Steven N. Hart, Sara Lindström, Michael P. Lux, Julie Lecarpentier, Lian Li, Robert Winqvist, Peter Kraft, Stephen J. Chanock, Thilo Dörk, Melanie Maierthaler, Rudolf Kaaks, Angela Cox, Maartje J. Hooning, José A. García-Sáenz, Christi J. van Asperen, Mervi Grip, Enes Makalic, Mia M. Gaudet, David E. Goldgar, Ross L. Prentice, Carolina Ellberg, Sune F. Nielsen, Federico Canzian, Rebecca Roylance, Aline Talhouk, Vassilios Georgoulias, Eunjung Lee, Siranoush Manoukian, Sara Margolin, Paul D.P. Pharoah, Hedy S. Rennert, Mitul Shah, Matthias W. Beckmann, Anthony Howell, Anne Lise Børresen-Dale, Christopher A. Haiman, V. Shane Pankratz, Anna González-Neira, Kathrin Thöne, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Ute Krüger, Mehdi Manoochehri, Arja Jukkola-Vuorinen, Loic Le Marchand, Katri Pylkäs, Peter Hillemanns, Dieter Flesch-Janys, Volker Arndt, Peter A. Fasching, Christine L. Clarke, Louise Hiller, Eric Hahnen, Jan Lubinski, Jose E. Castelao, Roger L. Milne, Linetta B. Koppert, Peter Devilee, Rob A. E. M. Tollenaar, Ian W. Brock, Claire Mulot, Mila Pinchev, Carlos Caldas, Michael Untch, Gadi Rennert, Aaron D. Norman, Per Broberg, Anthony J. Swerdlow, Lothar Haeberle, Heli Nevanlinna, Arto Mannermaa, Irene L. Andrulis, Angela George, Montserrat Garcia-Closas, Jolanta Lissowska, Jonathan Beesley, Paolo Peterlongo, Cari M. Kitahara, Rulla M. Tamimi, Annika Lindblom, Sabine Behrens, Nick Orr, David G. Cox, D. Gareth Evans, Jacques Simard, Diana Torres, Constance Turman, Celine M. Vachon, Qin Wang, Hans-Ulrich Ulmer, Maria Kabisch, Maria Elena Martinez, Paolo Radice, Maria Tengström, Dimitrios Mavroudis, Jean Abraham, Helena M. Earl, Alice S. Whittemore, Hermann Brenner, Rita K. Schmutzler, Børge G. Nordestgaard, Barbara Burwinkel, Michael Jones, Esther M. John, Patricia Harrington, Daniele Campa, Elke M. van Veen, Clara Pérez-Barrios, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Elza Khusnutdinova, Michael J. Kerin, Miriam Dwek, Sibylle Loibl, Manjeet K. Bolla, Carl Blomqvist, Sander Canisius, Graham G. Giles, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Emilie Cordina-Duverger, Arif B. Ekici, Yon-Dschun Ko, Pooja Middha, Alison M. Dunning, Katarzyna Kaczmarek, Bram Boeckx, Mary Beth Terry, Jenny Chang-Claude, Karoliona Prajzendanc, Renske Keeman, Camilla Wendt, Atocha Romero, Stig E. Bojesen, Robert J. MacInnis, Clare Turnbull, Lukas Schwentner, Xiaohong R. Yang, Henrik Flyger, Håkan Olsson, Wolfgang Janni, Sofia Khan, Clinicum, Department of Oncology, University of Helsinki, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, HUS Comprehensive Cancer Center, Medical Oncology, Surgery, and Clinical Genetics
Subjects: Oncology, Cancer Research, PROGNOSIS, Genome-wide association study, PATHWAY, Prognostic markers, Breast cancer, 0302 clinical medicine, Epidemiology of cancer, Cancer genetics, RISK, Hazard ratio, SINGLE-NUCLEOTIDE POLYMORPHISMS, GENETIC-VARIATION, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, SURVIVAL, TUMOR SUBTYPES, Female, Chromosomes, Human, Pair 7, EXPRESSION, medicine.medical_specialty, CLINICAL-OUTCOMES, SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Article, White People, NBCS Collaborators, RC0254, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Proportional Hazards Models, business.industry, Proportional hazards model, Genetic Variation, Cancer, Bayes Theorem, medicine.disease, business, Genome-Wide Association Study
Abstract: Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
Published: 2019
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39. Biomarkers of folate and vitamin B12 and breast cancer risk: report from the EPIC cohort

Author: R. Tumino, Marco Matejcic, J. R. Quirós, Anne Zeleniuch-Jacquotte, Marc J. Gunter, Björn Gylling, Elisabete Weiderpass, Pagona Lagiou, Genevieve Buckland, Salvatore Panico, Flavie Perrier, C. Ricci, Renée T. Fortner, Fulvio Ricceri, Pilar Amiano, Inge Huybrechts, Veronique Chajes, Mathilde His, Claire Cadeau, Petra H.M. Peeters, Isabelle Romieu, M-D Chirlaque, Timothy J. Key, Vassiliki Benetou, Antonia Trichopoulou, David G. Cox, Elio Riboli, M. C. Boutron-Ruault, Rudolf Kaaks, Sabina Sieri, D. Palli, María José Sánchez, Aurelio Barricarte, Carine Biessy, H. Bas Bueno-de-Mesquita, J. D. De Batlle, H. Boeing, C. H. van Gils, and Guri Skeie
Subjects: 0301 basic medicine, Oncology, Gynecology, Cancer Research, medicine.medical_specialty, business.industry, Follow up studies, Case-control study, EPIC, medicine.disease, 03 medical and health sciences, B vitamins, 030104 developmental biology, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Internal medicine, Epidemiology, Cohort, medicine, Vitamin B12, business
Abstract: Epidemiological studies have reported inconsistent findings for the association between B vitamins and breast cancer (BC) risk. We investigated the relationship between biomarkers of folate and vit ...
Published: 2017
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40. Determinants of folate and vitamin B12 plasma levels in the French E3N-EPIC cohort

Author: Marco Matejcic, Amina Amadou, Isabelle Romieu, Veronique Chajes, Françoise Clavel-Chapelon, Guy Fagherazzi, David G. Cox, Hortensia Moreno-Macías, Jordi de Batlle, and Nadia Slimani
Subjects: 0301 basic medicine, medicine.medical_specialty, medicine.medical_treatment, Nutritional Status, Medicine (miscellaneous), Folic Acid Deficiency, Polymorphism, Single Nucleotide, Cohort Studies, 03 medical and health sciences, Folic Acid, 0302 clinical medicine, Internal medicine, Genotype, Humans, Medicine, Genetic Predisposition to Disease, Prospective Studies, 030212 general & internal medicine, Vitamin B12, Risk factor, Genetic Association Studies, Methylenetetrahydrofolate Reductase (NADPH2), 030109 nutrition & dietetics, Nutrition and Dietetics, biology, business.industry, Vitamin B 12 Deficiency, Hormone replacement therapy (menopause), Plasma levels, Middle Aged, Diet, Vitamin B 12, B vitamins, Endocrinology, Amino Acid Substitution, Biochemistry, Case-Control Studies, Methylenetetrahydrofolate reductase, Cohort, biology.protein, Patient Compliance, Female, France, Self Report, Diet, Healthy, business, Biomarkers
Abstract: Impaired B vitamin status has been identified as a risk factor for major chronic diseases. This study aims at examining the determinants of plasma folate and vitamin B12 concentrations, considering lifestyle factors and MTHFR polymorphisms. A total of 988 women aged 40–65 years from the French E3N cohort were investigated. Intakes of folate and vitamin B12 were assessed using food frequency questionnaires, and plasma concentrations were measured by microbiological assay. Dietary scores were computed to summarize folate and vitamin B12 dietary sources. MTHFR-C677T and MTHFR-A1298C were determined by Kaspar assay. Pearson’s partial correlation coefficients and multivariable linear regression models were used to assess correlations between main determinants and plasma folate and vitamin B12 levels. The partial correlation coefficient between dietary intakes and plasma folate was 0.19 (p value
Published: 2016
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41. Genotype transposer: automated genotype manipulation for linkage disequilibrium analysis.

Author: David G. Cox and Federico Canzian
Published: 2001
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42. Abstract P1-08-06: SToRM: A prospective clinical trial of 1502 metastatic breast cancer (mBC) patients with detail of clinical presentation, molecular subtype, treatment modalities, prognosis and GWAS genotyping

Author: Ellen Blanc, N Quenel-Tueux, Thierry Petit, Sophie Abadie-Lacourtoisie, Monica Arnedos, David G. Cox, J.P. Jacquin, Frédérique Penault-Llorca, Emilie Lavergne, Olivier Tredan, P-E Heudel, Isabelle Moullet, H. Orfeuvre, Thomas Bachelot, Gilles Romieu, Loic Chaigneau, Maria Rios, C. Roemer-Becuwe, Christelle Jouannaud, and J-M Ferrero
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Cancer, Bone metastasis, Retrospective cohort study, medicine.disease, Metastatic breast cancer, Surgery, Clinical trial, Breast cancer, Trastuzumab, Internal medicine, Epidemiology, medicine, business, medicine.drug
Abstract: Background: Due to better molecular classification and new treatment options, epidemiology and prognosis of mBC is rapidly changing. Clinical data extracted from randomized studies are only relevant to specific subpopulations and retrospective studies are prone to selection bias. SToRM is a prospective clinical trial that aims to create a cohort of 1500 mBC patients, with the ultimate goal of identifying germ line polymorphisms associated with prognosis of breast cancer (BC) and response to treatment in the metastatic phase. Material and methods: Any newly (within 1 year) diagnosed mBC patients were eligible. Whole blood samples were drawn and germline DNA extracted for genetic analysis. Extensive epidemiologic data, disease history from primary diagnosis to metastatic spread, pathological characteristics and ER, PR and HER2 status were collected. Patients are prospectively followed until death. Genotyping using the HumanCoreExome chipset from Illumina is currently underway and will be completed in early summer 2015. Results: 1502 patients were included from March 2012 to May 2014 from 71 French institutions. Median age at metastatic relapse was 60 years (range 26-93). Median time from primary diagnosis to metastatic relapse was 30 months (range 0-473) with 24% of patients already metastatic at initial diagnosis. 78% of patients were ER+, 18% were HER2+ and only 16% were triple negative. Molecular subtype classification derived from pathological data following St Gallen consensus recommendations is presented below: n (%)Luminal A like261 (22.2%)Luminal B like HER2 negative476 (40.5%)Luminal B like HER2 positive134 (11.4%)HER2 positive non Luminal (ER-)111 (9.5%)Triple negative193 (16.4%)Missing data327 64% of the patients had received previous adjuvant treatment, among which 81% received adjuvant chemotherapy and 9% trastuzumab. At metastatic relapse, loco-regional progression, liver, lung and bone metastasis were documented in 301 (20%), 494 (33%), 410 (27%) and 1017 (68%) patients respectively. 313 patients (21%) had bone only metastatic disease. First line treatment included: chemotherapy (71%), endocrine therapy (50%) and anti-HER2 treatments (17%). Survival data will be presented at the meeting. Conclusion: Despite a theoretically better prognosis and widespread use of adjuvant hormonal treatment, ER+/HER2- breast cancer still account for more than 60% of mBC. The proportion of patients with HER2+ disease (18%) and triple negative disease (16%) is consistent with percentages observed in early BC populations. In comparison with a cohort of "cured", localized cancer, such as the SIGNAL/PHARE study, GWAS analysis will allow for the identification of genetic polymorphisms correlated with treatment resistance. Fundamentally, such variants will provide insight into the molecular mechanisms responsible for host-genetic influence on BC progression. From a clinical perspective, genetic variants that predispose to metastatic disease can serve as stratification variables in future clinical trials, particularly as the development of new treatment options for resistant BC is needed. Citation Format: Bachelot T, Lavergne E, Romieu G, Rios M, Heudel P-E, Roemer-Becuwe C, Jouannaud C, Tredan O, Chaigneau L, Arnedos M, Orfeuvre H, Petit T, Quenel-Tueux N, Jacquin J-P, Ferrero J-M, Moullet I, Abadie-Lacourtoisie S, Penault-Llorca F, Blanc E, Cox D. SToRM: A prospective clinical trial of 1502 metastatic breast cancer (mBC) patients with detail of clinical presentation, molecular subtype, treatment modalities, prognosis and GWAS genotyping. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-08-06.
Published: 2016
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43. T.I.M.S: TaqMan Information Management System, tools to organize data flow in a genotyping laboratory.

Author: Stéphanie Monnier, David G. Cox, Tim Albion, and Federico Canzian
Published: 2005
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44. 'Half Bacchanalian, Half Devout': White Intellectuals, Black Folk Culture, and the 'Negro Problem'

Author: David G. Cox
Subjects: History, White (horse), Folklore, media_common.quotation_subject, Gender studies, Racial politics, Politics, White supremacy, Local color, Aesthetics, Sociology, Ideology, Folk culture, media_common
Abstract: In the wake of the Civil War, white Americans generated an unprecedented amount of writing about the songs, stories, and “superstitions” of black southerners. This interest was not purely esthetic. In the late nineteenth century, folk culture was commonly conceptualized as a gauge of racial character and potential; in consequence, discourse on black folklore was entangled with the debate on the social and political place of African Americans. A number of scholars have noted the ways in which white supremacy was bulwarked by the work of folklorists, ethnologists, local color writers, and other intellectuals. The variety and contingency of this discourse on race, however, has sometimes been obscured, giving the impression of a static and monolithic racial ideology. Ideas about black folk culture shifted over time, shaped by a range of racial attitudes encompassing a liberal emphasis on uplift, a conservative commitment to stasis, and a radical insistence on regression. Moreover, the racial politics of intel...
Published: 2015
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45. Impact of Body Mass Index, Age, Prostate Volume, and Genetic Polymorphisms on Prostate-specific Antigen Levels in a Control Population

Author: N. Koutlidis, Abdel-Rahmène Azzouzi, C. Gaffory, Geraldine Cancel-Tassin, Morgan Rouprêt, Luc Cormier, Olivier Cussenot, David G. Cox, Pierre Bigot, Antoine Valeri, Jean-Nicolas Cornu, Georges Fournier, V. Ondet, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'Urologie [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service de Chirurgie Urologique (BREST - Urologie), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre de Recherche pour les Pathologies Prostatiques [Paris] (CeRePP), Sorbonne Université (SU), Service d'urologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Universitaire de Cancérologie [Paris] (IUC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de chirurgie urologique [CHU de Reims], Centre Hospitalier Universitaire de Reims (CHU Reims), Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Universitaire de Cancérologie [Sorbonne Université] (IUC), and Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de recherche pour le développement [IRD] : UR206-Centre National de la Recherche Scientifique (CNRS)
Subjects: Male, Risk, 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, diagnosis, Urology, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Single-nucleotide polymorphism, Context (language use), urologic and male genital diseases, Polymorphism, Single Nucleotide, Body Mass Index, Mitochondrial Proteins, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, blood, Prostate, Internal medicine, medicine, Genetic predisposition, Humans, Receptor, Fibroblast Growth Factor, Type 2, Cation Transport Proteins, 2. Zero hunger, Gynecology, business.industry, Age Factors, Prostatic Secretory Proteins, Organ Size, Prostate-Specific Antigen, medicine.disease, 3. Good health, Prostate-specific antigen, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cohort, Kallikreins, pathology, France, T-Box Domain Proteins, business, Body mass index
Abstract: International audience; Prostate-specific antigen (PSA) is still the cornerstone of prostate cancer (PCa) screening and diagnosis in both research and current clinical practice. Inaccuracy of PSA is partly due to the influence of a number of genetic, clinical, and biological factors modifying PSA blood levels. In the present study, we detailed the respective influence of each factor among age, body mass index (BMI), prostate volume, and five single-nucleotide polymorphisms-rs10788160 (10q26), rs10993994 (10q11), rs11067228 (12q24), rs17632542 (19q13.33), and rs2928679 (8p21)-on PSA values in a cohort of 1374 men without PCa. Our results show that genetic factors, when risk variants are combined, influence PSA levels with an effect size similar to that of BMI. Taken together, the respective correlations of clinical parameters and genetic parameters would make it possible to correct and adjust PSA values more effectively in each individual. These results establish the basis to understand and implement a more personalised approach for the interpretation of PSA blood levels in the context of PCa screening and diagnosis. PATIENT SUMMARY: Prostate-specific antigen (PSA) values in an individual may vary according to genetic predisposition. The effect size of this variation can be significant, comparable with those resulting from clinical characteristics. Personalised PSA testing should take this into account
Published: 2016
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46. Treatment Patterns and Clinical Outcomes in Patients With Metastatic Gastroenteropancreatic Neuroendocrine Tumors Treated in the Community Practice Setting in the United States

Author: Beloo Mirakhur, Jennifer Frytak, A. Scott Paulson, Susan Pitman Lowenthal, Patricia S. Fox, Fadi Braiteh, Marley Boyd, Xiaolong Jiao, Sonia Pulgar, and David G. Cox
Subjects: Adult, Male, medicine.medical_specialty, Abdominal pain, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Octreotide, Neuroendocrine tumors, Overweight, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Stomach Neoplasms, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Intestinal Neoplasms, Internal Medicine, medicine, Humans, 030212 general & internal medicine, Longitudinal Studies, Neoplasm Metastasis, Aged, Retrospective Studies, Aged, 80 and over, Chemotherapy, Hepatology, business.industry, Retrospective cohort study, Middle Aged, medicine.disease, Primary tumor, Survival Analysis, United States, Pancreatic Neoplasms, Neuroendocrine Tumors, 030220 oncology & carcinogenesis, Female, medicine.symptom, business, Somatostatin, medicine.drug
Abstract: OBJECTIVE This study was conducted to understand treatment patterns and clinical outcomes in metastatic gastroenteropancreatic neuroendocrine tumor patients treated in a large community oncology network. METHODS This retrospective study used the McKesson Specialty Health/US Oncology Network iKnowMed electronic health record database with supplemental chart review. Eligibility criteria included a metastatic neuroendocrine tumor diagnosis between January 1, 2008, and to December 31, 2012; at least 2 US Oncology Network visits; and age at least 18 years. Follow-up was through October 31, 2014. RESULTS Among the 229 patients identified, median age was 64.0 years, 52.4% were male, 69.4% were white, and 62.9% were overweight/obese. Primary tumor sites included small bowel (47.6%), pancreas (31.4%), and stomach/colorectum (21.0%). There were 16.2% under observation without treatment, 52.4% received only somatostatin analogs (SSAs), and 31.4% received chemotherapy/targeted therapy during treatment. In the first-line setting (n = 192), 77% received SSAs, 12% received chemotherapy, and 10.9% received targeted therapy. Fifty percent of patients receiving octreotide had a relative dose intensity of less than 85%, and 16.7% received above-label dose. Toxicities of SSAs included diarrhea (18.2%), abdominal pain (16.9%), and fatigue (13.5%). Median overall survival from diagnosis was 68.0 months (95% confidence interval, 57.1 to not reached). CONCLUSIONS Most metastatic gastroenteropancreatic neuroendocrine tumor patients received systemic treatment with SSAs. Patient treatment used an individualized dosing approach. Overall survival and toxicity were consistent with the published literature.
Published: 2017

47. Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma

Author: Mariagrazia Zucca, Thomas M. Habermann, Lauren R. Teras, Joseph Vijai, Lenka Foretova, Simon Crouch, Anneclaire J. De Roos, Jacqueline Clavel, Lindsay M. Morton, Melissa C. Southey, W. Ryan Diver, Patrick M. Gaffney, James McKay, Eve Roman, Sophia S. Wang, Mark P. Purdue, Hans-Olov Adami, Gilles Salles, Jarmo Virtamo, Yan W. Asmann, Angela Brooks-Wilson, Thierry Jo Molina, Andrew D. Zelenetz, Ahmet Dogan, Kenneth Offit, Peter Kraft, Gianluca Severi, Zhaoming Wang, Tongzhang Zheng, Sonja I. Berndt, Brian K. Link, Sasha Bernatsky, Theodore R. Holford, Emanuele Angelucci, Paige M. Bracci, Martyn T. Smith, Stephen J. Chanock, Brenda M. Birmann, Hervé Ghesquières, Stephen M. Ansell, Paolo Vineis, Mads Melbye, Kari E. North, Jenny Turner, Jacques Riby, Charles E. Lawrence, Alain Monnereau, Nikolaus Becker, Lucia Conde, James R. Cerhan, Susan L. Slager, Demetrius Albanes, Henrik Hjalgrim, Hervé Tilly, Héctor A. Velásquez García, Rebecca D. Jackson, Ann E. Clarke, Elizabeth A. Holly, Robert J. Klein, Paolo Boffetta, Mark Liebow, Karin E. Smedby, Marco Rais, David G. Cox, Patricia Hartge, Rosalind Ramsey-Goldman, Rachel S. Kelly, Lesley F. Tinker, Christine F. Skibola, Wendy Cozen, Tracy Lightfoot, Anne J. Novak, Heiner Boeing, Roel Vermeulen, Claire M. Vajdic, Bengt Glimelius, Kimberly A. Bertrand, Marc Maynadie, Eleanor Kane, Nathaniel Rothman, Yolanda Benavente, Paul Brennan, Anne Tjønneland, John J. Spinelli, Qing Lan, Anne Kricker, Alex Smith, Anthony Staines, Graham G. Giles, Carrie A. Thompson, Thomas E. Witzig, Stephanie J. Weinstein, Karen H. Cotenbader, Corinne Haioun, Anne Zeleniuch-Jacquotte, Simonetta Di Lollo, Alexandra Nieters, Rudolph Kaaks, Silvia de Sanjosé, Richard K. Severson, Yawei Zhang, Research Institute of the McGill University Health Centre, 1650 Cedar Avenue, Oklahoma Medical Research Foundation, Registre des hémopathies malignes de Côte d'Or, Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Université Bourgogne Franche-Comté ( UBFC ), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), University of Calgary, Bernatsky, S. and García, H.A.V. and Spinelli, J.J. and Gaffney, P. and Smedby, K.E. and Ramsey-Goldman, R. and Wang, S.S. and Adami, H.-O. and Albanes, D. and Angelucci, E. and Ansell, S.M. and WAsmann, Y. and Becker, N. and Benavente, Y. and Berndt, S.I. and Bertrand, K.A. and Birmann, B.M. and Boeing, H. and Boffetta, P. and Bracci, P.M. and Brennan, P. and Brooks-Wilson, A.R. and Cerhan, J.R. and Chanock, S.J. and Clavel, J. and Conde, L. and Cotenbader, K.H. and Cox, D.G. and Cozen, W. and Crouch, S. and De Roos, A.J. and De Sanjose, S. and Di Lollo, S. and Diver, W.R. and Dogan, A. and Foretova, L. and Ghesquières, H. and Giles, G.G. and Glimelius, B. and Habermann, T.M. and Haioun, C. and Hartge, P. and Hjalgrim, H. and Holford, T.R. and Holly, E.A. and Jackson, R.D. and Kaaks, R. and Kane, E. and Kelly, R.S. and Klein, R.J. and Kraft, P. and Kricker, A. and Lan, Q. and Lawrence, C. and Liebow, M. and Lightfoot, T. and Link, B.K. and Maynadie, M. and McKay, J. and Melbye, M. and Molina, T.J. and Monnereau, A. and Morton, L.M. and Nieters, A. and North, K.E. and Novak, A.J. and Offit, K. and Purdue, M.P. and Rais, M. and Riby, J. and Roman, E. and Rothman, N. and Salles, G. and Severi, G. and Severson, R.K. and Skibola, C.F. and Slager, S.L. and Smith, A. and Smith, M.T. and Southey, M.C. and Staines, A. and Teras, L.R. and Thompson, C.A. and Tilly, H. and Tinker, L.F. and Tjonneland, A. and Turner, J. and Vajdic, C.M. and Vermeulen, R.C.H. and Vijai, J. and Vineis, P. and Virtamo, J. and Wang, Z. and Weinstein, S. and Witzig, T.E. and Zelenetz, A. and Zeleniuch-Jacquotte, A. and Zhang, Y. and Zheng, T. and Zucca, M. and Clarke, A.E., McGill University Health Center [Montreal] (MUHC), Oklahoma Medical Research Foundation (OMRF), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), LS IRAS EEPI GRA (Gezh.risico-analyse), dIRAS RA-2, and dIRAS RA-I&I RA
Subjects: Oncology, medicine.medical_specialty, Immunology, Single-nucleotide polymorphism, Genome-wide association study, [SDV.CAN]Life Sciences [q-bio]/Cancer, lymphoma, Human leukocyte antigen, Bioinformatics, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 0302 clinical medicine, immune system diseases, Internal medicine, medicine, SNP, 030203 arthritis & rheumatology, Systemic lupus erythematosus, business.industry, General Medicine, medicine.disease, Systemic lupus, Lupus Nephritis, Risk of diffuse large B-cell lymphoma, 3. Good health, Lymphoma, 030220 oncology & carcinogenesis, business, Diffuse large B-cell lymphoma, IRF5, malignancy
Abstract: Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genomewide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE. © 2017 BMJ Publishing Group. All rights reserved.
Published: 2017
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48. Input-aware auto-tuning of compute-bound HPC kernels

Author: David G. Cox and Philippe Tillet
Subjects: 020203 distributed computing, Computer science, business.industry, Parameterized complexity, 02 engineering and technology, Parallel computing, Pascal (programming language), Square matrix, Matrix multiplication, CUDA, Software, Template, 020204 information systems, 0202 electrical engineering, electronic engineering, information engineering, business, computer, computer.programming_language
Abstract: Efficient implementations of HPC applications for parallel architectures generally rely on external software packages (e.g., BLAS, LAPACK, CUDNN). While these libraries provide highly optimized routines for certain characteristics of inputs (e.g., square matrices), they generally do not retain optimal performance across the wide range of problems encountered in practice. In this paper, we present an input-aware auto-tuning framework for matrix multiplications and convolutions, ISAAC, which uses predictive modeling techniques to drive highly parameterized PTX code templates towards not only hardware-, but also application-specific kernels. Numerical experiments on the NVIDIA Maxwell and Pascal architectures show up to 3x performance gains over both cuBLAS and cuDNN after only a few hours of auto-tuning.
Published: 2017
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49. A new era for treatment development in HER2-positive breast cancer

Author: Xavier Pivot and David G. Cox
Subjects: Oncology, medicine.medical_specialty, Pyridines, medicine.medical_treatment, MEDLINE, Breast Neoplasms, Antibodies, Monoclonal, Humanized, Piperazines, 03 medical and health sciences, 0302 clinical medicine, Trastuzumab, HER2 Positive Breast Cancer, Internal medicine, medicine, Humans, 030212 general & internal medicine, Fulvestrant, Neoadjuvant therapy, biology, business.industry, Treatment development, Neoadjuvant Therapy, 030220 oncology & carcinogenesis, Monoclonal, biology.protein, Antibody, business, medicine.drug
Published: 2017

50. A stemness-related ZEB1–MSRB3 axis governs cellular pliancy and breast cancer genome stability

Author: David G. Cox, Daniel Birnbaum, Qing Wang, Pascal Finetti, Frédéric Hollande, Emmanuelle Despras, François Bertucci, Emmanuelle Ruiz, Joël Lachuer, Christelle Chassot, Frédérique Fauvet, Pierre Saintigny, Roxane M. Pommier, Julie Caramel, Arnaud M. Vigneron, Anne Wierinckx, Nina Radosevic-Robin, Frédérique Penault-Llorca, Emmanuelle Charafe-Jauffret, Julien Wicinski, Emilie Thomas, Mojgan Devouassoux-Shisheboran, Stéphane Ansieau, Christiane Pinatel, Olivier Cabaud, Alain Puisieux, Anne-Pierre Morel, Jean-Luc Jauffret, Valérie Combaret, Jérôme Guitton, Caroline Moyret-Lalle, Agnès Tissier, Christophe Ginestier, Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomo-Pathologie [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Synergie Lyon Cancer [Lyon], Laboratoire de Génétique de la Radiosensibilité (LGR), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), clinique Phenicia, Service d'Oncologie Médicale, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), ProfileXpert, Université de Lyon, Matériaux, ingénierie et science [Villeurbanne] (MATEIS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, University of Melbourne, Cancérologie expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire des Arts et Métiers ParisTech d'Angers - Procédés Matériaux Durabilité ( LAMPA - PMD ), Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes-Aix Marseille Université ( AMU ), Institut de biologie et chimie des protéines [Lyon] ( IBCP ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire d'Oncologie Moléculaire, Oncovirologie et Biothérapies, Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Laboratoire de Génétique de la Radiosensibilité ( LGR ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Laboratoire de Toxicologie ( ISPB ), Université de Lyon-Université de Lyon, Hunan Institute of Science and Technology, Equipe de recherche sur les traitements individualisés des cancers ( ERTICa ), Université d'Auvergne - Clermont-Ferrand I ( UdA ), Centre Jean Perrin, CRLCC Jean Perrin, Imagerie Moléculaire et Stratégies Théranostiques - Clermont Auvergne ( IMoST ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Clermont Auvergne ( UCA ), Equipe 6, Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Institut de Génomique Fonctionnelle ( IGF ), Centre National de la Recherche Scientifique ( CNRS ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Montpellier 1 ( UM1 ) -Université de Montpellier ( UM ), equipe 2, Institut de Génétique Moléculaire de Montpellier ( IGMM ), Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -labex DEVweCAN, Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ) -Ministère de l'Éducation nationale, de l’Enseignement supérieur et de la Recherche ( M.E.N.E.S.R. ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fondation Synergie Lyon Cancer [Lyon], Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Genome instability, Pathology, Cellular differentiation, [SDV]Life Sciences [q-bio], Fluorescent Antibody Technique, medicine.disease_cause, Malignant transformation, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Mice, Inbred NOD, Chromosome instability, Aged, 80 and over, Stem Cells, Cell Differentiation, General Medicine, Middle Aged, Flow Cytometry, 3. Good health, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, Female, Stem cell, Adult, Chromatin Immunoprecipitation, medicine.medical_specialty, Adolescent, DNA damage, Immunoblotting, Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Real-Time Polymerase Chain Reaction, Genomic Instability, General Biochemistry, Genetics and Molecular Biology, Young Adult, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Epithelial–mesenchymal transition, Mammary Glands, Human, Aged, Gene Expression Profiling, Carcinoma, Zinc Finger E-box-Binding Homeobox 1, Epithelial Cells, Sequence Analysis, DNA, 030104 developmental biology, Tissue Array Analysis, Methionine Sulfoxide Reductases, Cancer research, Tumor Suppressor Protein p53, Reactive Oxygen Species, Carcinogenesis, DNA Damage
Abstract: International audience; Chromosomal instability (CIN), a feature of most adult neoplasms from their early stages onward, is a driver of tumorigenesis. However, several malignancy subtypes, including some triple-negative breast cancers, display a paucity of genomic aberrations, thus suggesting that tumor development may occur in the absence of CIN. Here we show that the differentiation status of normal human mammary epithelial cells dictates cell behavior after an oncogenic event and predetermines the genetic routes toward malignancy. Whereas oncogene induction in differentiated cells induces massive DNA damage, mammary stem cells are resistant, owing to a preemptive program driven by the transcription factor ZEB1 and the methionine sulfoxide reductase MSRB3. The prevention of oncogene-induced DNA damage precludes induction of the oncosuppressive p53-dependent DNA-damage response, thereby increasing stem cells' intrinsic susceptibility to malignant transformation. In accord with this model, a subclass of breast neoplasms exhibit unique pathological features, including high ZEB1 expression, a low frequency of TP53 mutations and low CIN.
Published: 2017
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