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1. Germline specific genes increase DNA double-strand break repair and radioresistance in lung adenocarcinoma cells

Author

Wenqing Liu, Jan Willem Bruggeman, Qijing Lei, Ans M. M. van Pelt, Jan Koster, and Geert Hamer

Subjects
Cytology, QH573-671
Abstract

Abstract In principle, germline cells possess the capability to transmit a nearly unaltered set of genetic material to infinite future generations, whereas somatic cells are limited by strict growth constraints necessary to assure an organism’s physical structure and eventual mortality. As the potential to replicate indefinitely is a key feature of cancer, we hypothesized that the activation of a “germline program” in somatic cells can contribute to oncogenesis. Our group recently described over one thousand germline specific genes that can be ectopically expressed in cancer, yet how germline specific processes contribute to the malignant properties of cancer is poorly understood. We here show that the expression of germ cell/cancer (GC) genes correlates with malignancy in lung adenocarcinoma (LUAD). We found that LUAD cells expressing more GC genes can repair DNA double strand breaks more rapidly, show higher rates of proliferation and are more resistant to ionizing radiation, compared to LUAD cells that express fewer GC genes. In particular, we identified the HORMA domain protein regulator TRIP13 to be predominantly responsible for this malignant phenotype, and that TRIP13 inhibition or expression levels affect the response to ionizing radiation and subsequent DNA repair. Our results demonstrate that GC genes are viable targets in oncology, as they induce increased radiation resistance and increased propagation in cancer cells. Because their expression is normally restricted to germline cells, we anticipate that GC gene directed therapeutic options will effectively target cancer, with limited side effects besides (temporary) infertility.

Published
2024
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2. Favorable culture conditions for spermatogonial propagation in human and non-human primate primary testicular cell cultures: a systematic review and meta-analysis

Author

Jillis van Maaren, Luis F. Alves, Madelon van Wely, Ans M. M. van Pelt, and Callista L. Mulder

Subjects
spermatogonial stem cells, fertility restoration, childhood cancer, spermatogonial propagation, culture methods, Biology (General), QH301-705.5
Abstract

Introduction: Autologous transplantation of spermatogonial stem cells (SSCs) isolated from cryopreserved testicular biopsies obtained before oncological treatment could restore fertility in male childhood cancer survivors. There is a clear necessity for in vitro propagation of the limited SSCs from the testicular biopsy prior to transplantation due to limited numbers of spermatogonia in a cryopreserved testicular biopsy. Still, there is no consensus regarding their optimal culture method.Methods: We performed a systematic review and meta-analysis of studies reporting primary testicular cell cultures of human and non-human primate origin through use of Pubmed, EMBASE, and Web of Science core collection databases. Of 760 records, we included 42 articles for qualitative and quantitative analysis. To quantify in vitro spermatogonial propagation, spermatogonial colony doubling time (CDT) was calculated, which measures the increase in the number of spermatogonial colonies over time. A generalized linear mixed model analysis was used to assess the statistical effect of various culture conditions on CDT.Results: Our analysis indicates decreased CDTs, indicating faster spermatogonial propagation in cultures with a low culture temperature (32°C); with use of non-cellular matrices; use of StemPro-34 medium instead of DMEM; use of Knockout Serum Replacement; and when omitting additional growth factors in the culture medium.Discussion: The use of various methods and markers to detect the presence of spermatogonia within the reported cultures could result in detection bias, thereby potentially influencing comparability between studies. However, through use of CDT in the quantitative analysis this bias was reduced. Our results provide insight into critical culture conditions to further optimize human spermatogonial propagation in vitro, and effectively propagate and utilize these cells in a future fertility restoration therapy and restore hope of biological fatherhood for childhood cancer survivors.

Published
2024
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3. Sperm DNA methylation is predominantly stable in mice offspring born after transplantation of long-term cultured spermatogonial stem cells

Author

Joana B. Serrano, Nils C. Tabeling, Cindy M. de Winter-Korver, Saskia K. M. van Daalen, Ans M. M. van Pelt, and Callista L. Mulder

Subjects
Spermatogenesis, Spermatogonial stem cells, Spermatogonial stem cell transplantation, SSCT, Preclinical epigenetics, DNA methylation, Medicine, Genetics, QH426-470
Abstract

Abstract Background Spermatogonial stem cell transplantation (SSCT) is proposed as a fertility therapy for childhood cancer survivors. SSCT starts with cryopreserving a testicular biopsy prior to gonadotoxic treatments such as cancer treatments. When the childhood cancer survivor reaches adulthood and desires biological children, the biopsy is thawed and SSCs are propagated in vitro and subsequently auto-transplanted back into their testis. However, culturing stress during long-term propagation can result in epigenetic changes in the SSCs, such as DNA methylation alterations, and might be inherited by future generations born after SSCT. Therefore, SSCT requires a detailed preclinical epigenetic assessment of the derived offspring before this novel cell therapy is clinically implemented. With this aim, the DNA methylation status of sperm from SSCT-derived offspring, with in vitro propagated SSCs, was investigated in a multi-generational mouse model using reduced-representation bisulfite sequencing. Results Although there were some methylation differences, they represent less than 0.5% of the total CpGs and methylated regions, in all generations. Unsupervised clustering of all samples showed no distinct grouping based on their pattern of methylation differences. After selecting the few single genes that are significantly altered in multiple generations of SSCT offspring compared to control, we validated the results with quantitative Bisulfite Sanger sequencing and RT-qPCRin various organs. Differential methylation was confirmed only for Tal2, being hypomethylated in sperm of SSCT offspring and presenting higher gene expression in ovaries of SSCT F1 offspring compared to control F1. Conclusions We found no major differences in DNA methylation between SSCT-derived offspring and control, both in F1 and F2 sperm. The reassuring outcomes from our study are a prerequisite for promising translation of SSCT to the human situation.

Published
2023
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4. Spermatogonial Stem Cell-Based Therapies: Taking Preclinical Research to the Next Level

Author

Iris Sanou, Jillis van Maaren, Jitske Eliveld, Qijing Lei, Andreas Meißner, Annemieke A. de Melker, Geert Hamer, Ans M. M. van Pelt, and Callista L. Mulder

Subjects
spermatogonial stem cells, fertility preservation, fertility restoration, childhood cancer, preclinical research, spermatogonial stem cell transplantation, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Fertility preservation via biobanking of testicular tissue retrieved from testicular biopsies is now generally recommended for boys who need to undergo gonadotoxic treatment prior to the onset of puberty, as a source of spermatogonial stem cells (SSCs). SSCs have the potential of forming spermatids and may be used for therapeutic fertility approaches later in life. Although in the past 30 years many milestones have been reached to work towards SSC-based fertility restoration therapies, including transplantation of SSCs, grafting of testicular tissue and various in vitro and ex vivo spermatogenesis approaches, unfortunately, all these fertility therapies are still in a preclinical phase and not yet available for patients who have become infertile because of their treatment during childhood. Therefore, it is now time to take the preclinical research towards SSC-based therapy to the next level to resolve major issues that impede clinical implementation. This review gives an outline of the state of the art of the effectiveness and safety of fertility preservation and SSC-based therapies and addresses the hurdles that need to be taken for optimal progression towards actual clinical implementation of safe and effective SSC-based fertility treatments in the near future.

Published
2022
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5. Meiotic Chromosome Synapsis and XY-Body Formation In Vitro

Author

Qijing Lei, Eden Zhang, Ans M. M. van Pelt, and Geert Hamer

Subjects
in vitro spermatogenesis, in vitro meiosis, spermatogonial stem cells (SSCs), Sertoli cells, spermatocytes, fertility preservation, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

To achieve spermatogenesis in vitro, one of the most challenging processes to mimic is meiosis. Meiotic problems, like incomplete synapsis of the homologous chromosomes, or impaired homologous recombination, can cause failure of crossover formation and subsequent chromosome nondisjunction, eventually leading to aneuploid sperm. These meiotic events are therefore strictly monitored by meiotic checkpoints that initiate apoptosis of aberrant spermatocytes and lead to spermatogenic arrest. However, we recently found that, in vitro derived meiotic cells proceeded to the first meiotic division (MI) stage, despite displaying incomplete chromosome synapsis, no discernible XY-body and lack of crossover formation. We therefore optimized our in vitro culture system of meiosis from male germline stem cells (mGSCs) in order to achieve full chromosome synapsis, XY-body formation and meiotic crossovers. In comparison to previous culture system, the in vitro-generated spermatocytes were transferred after meiotic initiation to a second culture dish. This dish already contained a freshly plated monolayer of proliferatively inactivated immortalized Sertoli cells supporting undifferentiated mGSCs. In this way we aimed to simulate the multiple layers of germ cell types that support spermatogenesis in vivo in the testis. We found that in this optimized culture system, although independent of the undifferentiated mGSCs, meiotic chromosome synapsis was complete and XY body appeared normal. However, meiotic recombination still occurred insufficiently and only few meiotic crossovers were formed, leading to MI-spermatocytes displaying univalent chromosomes (paired sister chromatids). Therefore, considering that meiotic checkpoints are not necessarily fully functional in vitro, meiotic crossover formation should be closely monitored when mimicking gametogenesis in vitro to prevent generation of aneuploid gametes.

Published
2021
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6. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author

Manuel A. Ferreira, Eric R. Gamazon, Fares Al-Ejeh, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Adalgeir Arason, Volker Arndt, Kristan J. Aronson, Banu K. Arun, Ella Asseryanis, Jacopo Azzollini, Judith Balmaña, Daniel R. Barnes, Daniel Barrowdale, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Katarzyna Białkowska, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Ake Borg, Hiltrud Brauch, Hermann Brenner, Annegien Broeks, Barbara Burwinkel, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Ian Campbell, Federico Canzian, Jonathan Carter, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Hans Christiansen, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Miguel de la Hoya, Joe Dennis, Peter Devilee, Orland Diez, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Bent Ejlertsen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Eitan Friedman, Debra Frost, Marike Gabrielson, Manuela Gago-Dominguez, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Wei He, Jane Heyworth, Frans B. L. Hogervorst, Antoinette Hollestelle, Robert N. Hoover, John L. Hopper, Peter J. Hulick, Keith Humphreys, Evgeny N. Imyanitov, ABCTB Investigators, HEBON Investigators, BCFR Investigators, Claudine Isaacs, Milena Jakimovska, Anna Jakubowska, Paul A. James, Ramunas Janavicius, Rachel C. Jankowitz, Esther M. John, Nichola Johnson, Vijai Joseph, Beth Y. Karlan, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Michael E. Jones, Irene Konstantopoulou, Vessela N. Kristensen, Yael Laitman, Diether Lambrechts, Conxi Lazaro, Goska Leslie, Jenny Lester, Fabienne Lesueur, Sara Lindström, Jirong Long, Jennifer T. Loud, Jan Lubiński, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Tabea Maurer, Dimitrios Mavroudis, Lesley McGuffog, Alfons Meindl, Usha Menon, Kyriaki Michailidou, Austin Miller, Marco Montagna, Fernando Moreno, Lidia Moserle, Anna Marie Mulligan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Finn C. Nielsen, Liene Nikitina-Zake, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Håkan Olsson, Ana Osorio, Janos Papp, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Ana Peixoto, Paolo Peterlongo, Paul D. P. Pharoah, Dijana Plaseska-Karanfilska, Bruce Poppe, Nadege Presneau, Paolo Radice, Johanna Rantala, Gad Rennert, Harvey A. Risch, Emmanouil Saloustros, Kristin Sanden, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Priyanka Sharma, Xiao-Ou Shu, Jacques Simard, Christian F. Singer, Penny Soucy, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Jennifer Stone, Anthony J. Swerdlow, William J. Tapper, Jack A. Taylor, Manuel R. Teixeira, Mary Beth Terry, Alex Teulé, Mads Thomassen, Kathrin Thöne, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Thérèse Truong, Nadine Tung, Celine M. Vachon, Christi J. van Asperen, Ans M. W. van den Ouweland, Elizabeth J. van Rensburg, Ana Vega, Alessandra Viel, Qin Wang, Barbara Wappenschmidt, Jeffrey N. Weitzel, Camilla Wendt, Robert Winqvist, Xiaohong R. Yang, Drakoulis Yannoukakos, Argyrios Ziogas, Peter Kraft, Antonis C. Antoniou, Wei Zheng, Douglas F. Easton, Roger L. Milne, Jonathan Beesley, and Georgia Chenevix-Trench

Subjects
Science
Abstract

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

Published
2019
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8. Comparing genome-scale DNA methylation and CNV marks between adult human cultured ITGA6+ testicular cells and seminomas to assess in vitro genomic stability.

Author

Robert B Struijk, Lambert C J Dorssers, Peter Henneman, Martin A Rijlaarsdam, Andrea Venema, Aldo Jongejan, Marcel M A M Mannens, Leendert H J Looijenga, Sjoerd Repping, and Ans M M van Pelt

Subjects
Medicine, Science
Abstract

Autologous transplantation of spermatogonial stem cells is a promising new avenue to restore fertility in infertile recipients. Expansion of the initial spermatogonial stem cell pool through cell culturing is a necessary step to obtain enough cells for effective repopulation of the testis after transplantation. Since in vitro propagation can lead to (epi-)genetic mutations and possibly malignant transformation of the starting cell population, we set out to investigate genome-wide DNA methylation status in uncultured and cultured primary testicular ITGA6+ sorted cells and compare them with germ cell tumor samples of the seminoma subtype. Seminomas displayed a severely global hypomethylated profile, including loss of genomic imprinting, which we did not detect in cultured primary testicular ITGA6+ cells. Differential methylation analysis revealed altered regulation of gamete formation and meiotic processes in cultured primary testicular ITGA6+ cells but not in seminomas. The pivotal POU5F1 marker was hypomethylated in seminomas but not in uncultured or cultured primary testicular ITGA6+ cells, which is reflected in the POU5F1 mRNA expression levels. Lastly, seminomas displayed a number of characteristic copy number variations that were not detectable in primary testicular ITGA6+ cells, either before or after culture. Together, the data show a distinct DNA methylation patterns in cultured primary testicular ITGA6+ cells that does not resemble the pattern found in seminomas, but also highlight the need for more sensitive methods to fully exclude the presence of malignant cells after culture and to further study the epigenetic events that take place during in vitro culture.

Published
2020
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9. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus

Author

Kate Lawrenson, Siddhartha Kar, Karen McCue, Karoline Kuchenbaeker, Kyriaki Michailidou, Jonathan Tyrer, Jonathan Beesley, Susan J. Ramus, Qiyuan Li, Melissa K. Delgado, Janet M. Lee, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Banu K. Arun, Brita Arver, Elisa V. Bandera, Monica Barile, Rosa B. Barkardottir, Daniel Barrowdale, Matthias W. Beckmann, Javier Benitez, Andrew Berchuck, Maria Bisogna, Line Bjorge, Carl Blomqvist, William Blot, Natalia Bogdanova, Anders Bojesen, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Fiona Bruinsma, Joan Brunet, Shaik Ahmad Buhari, Barbara Burwinkel, Ralf Butzow, Saundra S. Buys, Qiuyin Cai, Trinidad Caldes, Ian Campbell, Rikki Canniotto, Jenny Chang-Claude, Jocelyne Chiquette, Ji-Yeob Choi, Kathleen B. M. Claes, GEMO Study Collaborators, Linda S. Cook, Angela Cox, Daniel W. Cramer, Simon S. Cross, Cezary Cybulski, Kamila Czene, Mary B. Daly, Francesca Damiola, Agnieszka Dansonka-Mieszkowska, Hatef Darabi, Joe Dennis, Peter Devilee, Orland Diez, Jennifer A. Doherty, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Martine Dumont, Hans Ehrencrona, Bent Ejlertsen, Steve Ellis, EMBRACE, Christoph Engel, Eunjung Lee, D. Gareth Evans, Peter A. Fasching, Lidia Feliubadalo, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lenka Foretova, Florentia Fostira, William D. Foulkes, Brooke L. Fridley, Eitan Friedman, Debra Frost, Gaetana Gambino, Patricia A. Ganz, Judy Garber, Montserrat García-Closas, Aleksandra Gentry-Maharaj, Maya Ghoussaini, Graham G. Giles, Rosalind Glasspool, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Ellen L. Goode, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Pascal Guénel, Christopher A. Haiman, Per Hall, Emily Hallberg, Ute Hamann, Thomas V. O. Hansen, Patricia A. Harrington, Mikael Hartman, Norhashimah Hassan, Sue Healey, The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Florian Heitz, Josef Herzog, Estrid Høgdall, Claus K. Høgdall, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Peter J. Hulick, Tomasz Huzarski, Evgeny N. Imyanitov, KConFab Investigators, Australian Ovarian Cancer Study Group, Claudine Isaacs, Hidemi Ito, Anna Jakubowska, Ramunas Janavicius, Allan Jensen, Esther M. John, Nichola Johnson, Maria Kabisch, Daehee Kang, Miroslav Kapuscinski, Beth Y. Karlan, Sofia Khan, Lambertus A. Kiemeney, Susanne Kruger Kjaer, Julia A. Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela Kristensen, Jolanta Kupryjanczyk, Ava Kwong, Miguel de la Hoya, Yael Laitman, Diether Lambrechts, Nhu Le, Kim De Leeneer, Jenny Lester, Douglas A. Levine, Jingmei Li, Annika Lindblom, Jirong Long, Artitaya Lophatananon, Jennifer T. Loud, Karen Lu, Jan Lubinski, Arto Mannermaa, Siranoush Manoukian, Loic Le Marchand, Sara Margolin, Frederik Marme, Leon F. A. G. Massuger, Keitaro Matsuo, Sylvie Mazoyer, Lesley McGuffog, Catriona McLean, Iain McNeish, Alfons Meindl, Usha Menon, Arjen R. Mensenkamp, Roger L. Milne, Marco Montagna, Kirsten B. Moysich, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, Roberta B. Ness, Susan L. Neuhausen, Heli Nevanlinna, Silje Nord, Robert L. Nussbaum, Kunle Odunsi, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Curtis Olswold, David O’Malley, Irene Orlow, Nick Orr, Ana Osorio, Sue Kyung Park, Celeste L. Pearce, Tanja Pejovic, Paolo Peterlongo, Georg Pfeiler, Catherine M. Phelan, Elizabeth M. Poole, Katri Pylkäs, Paolo Radice, Johanna Rantala, Muhammad Usman Rashid, Gad Rennert, Valerie Rhenius, Kerstin Rhiem, Harvey A. Risch, Gus Rodriguez, Mary Anne Rossing, Anja Rudolph, Helga B. Salvesen, Suleeporn Sangrajrang, Elinor J. Sawyer, Joellen M. Schildkraut, Marjanka K. Schmidt, Rita K. Schmutzler, Thomas A. Sellers, Caroline Seynaeve, Mitul Shah, Chen-Yang Shen, Xiao-Ou Shu, Weiva Sieh, Christian F. Singer, Olga M. Sinilnikova, Susan Slager, Honglin Song, Penny Soucy, Melissa C. Southey, Marie Stenmark-Askmalm, Dominique Stoppa-Lyonnet, Christian Sutter, Anthony Swerdlow, Sandrine Tchatchou, Manuel R. Teixeira, Soo H. Teo, Kathryn L. Terry, Mary Beth Terry, Mads Thomassen, Maria Grazia Tibiletti, Laima Tihomirova, Silvia Tognazzo, Amanda Ewart Toland, Ian Tomlinson, Diana Torres, Thérèse Truong, Chiu-chen Tseng, Nadine Tung, Shelley S. Tworoger, Celine Vachon, Ans M. W. van den Ouweland, Helena C. van Doorn, Elizabeth J. van Rensburg, Laura J. Van't Veer, Adriaan Vanderstichele, Ignace Vergote, Joseph Vijai, Qin Wang, Shan Wang-Gohrke, Jeffrey N. Weitzel, Nicolas Wentzensen, Alice S. Whittemore, Hans Wildiers, Robert Winqvist, Anna H. Wu, Drakoulis Yannoukakos, Sook-Yee Yoon, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Kum Kum Khanna, Jacques Simard, Alvaro N. Monteiro, Juliet D. French, Fergus J. Couch, Matthew L. Freedman, Douglas F. Easton, Alison M. Dunning, Paul D. Pharoah, Stacey L. Edwards, Georgia Chenevix-Trench, Antonis C. Antoniou, and Simon A. Gayther

Subjects
Science
Abstract

A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.

Published
2016
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10. Characterization of Human Mesenchymal Stem Cells Isolated from the Testis

Author

Letizia De Chiara, Elvira Smeralda Famulari, Sharmila Fagoonee, Saskia K. M. van Daalen, Stefano Buttiglieri, Alberto Revelli, Emanuela Tolosano, Lorenzo Silengo, Ans M. M. van Pelt, and Fiorella Altruda

Subjects
Internal medicine, RC31-1245
Abstract

Mesenchymal stem cells hold great promise for regenerative medicine as they can be easily isolated from different sources such as adipose tissue, bone marrow, and umbilical cord blood. Spontaneously arising pluripotent stem cells can be obtained in culture from murine spermatogonial stem cells (SSCs), while the pluripotency of the human counterpart remains a matter of debate. Recent gene expression profiling studies have demonstrated that embryonic stem cell- (ESC-) like cells obtained from the human testis are indeed closer to mesenchymal stem cells (MSCs) than to pluripotent stem cells. Here, we confirm that colonies derived from human testicular cultures, with our isolation protocol, are of mesenchymal origin and do not arise from spermatogonial stem cells (SSCs). The testis, thus, provides an important and accessible source of MSCs (tMSCs) that can be potentially used for nephrotoxicity testing in vitro. We further demonstrate, for the first time, that tMSCs are able to secrete microvesicles that could possibly be applied to the treatment of various chronic diseases, such as those affecting the kidney.

Published
2018
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11. Novel Histopathological Patterns in Cortical Tubers of Epilepsy Surgery Patients with Tuberous Sclerosis Complex.

Author

Angelika Mühlebner, Jackelien van Scheppingen, Hanna M Hulshof, Theresa Scholl, Anand M Iyer, Jasper J Anink, Ans M W van den Ouweland, Mark D Nellist, Floor E Jansen, Wim G M Spliet, Pavel Krsek, Barbora Benova, Josef Zamecnik, Peter B Crino, Daniela Prayer, Thomas Czech, Adelheid Wöhrer, Jasmin Rahimi, Romana Höftberger, Johannes A Hainfellner, Martha Feucht, and Eleonora Aronica

Subjects
Medicine, Science
Abstract

Tuberous Sclerosis Complex (TSC) is a genetic hamartoma syndrome frequently associated with severe intractable epilepsy. In some TSC patients epilepsy surgery is a promising treatment option provided that the epileptogenic zone can be precisely delineated. TSC brain lesions (cortical tubers) contain dysmorphic neurons, brightly eosinophilic giant cells and white matter alterations in various proportions. However, a histological classification system has not been established for tubers. Therefore, the aim of this study was to define distinct histological patterns within tubers based on semi-automated histological quantification and to find clinically significant correlations. In total, we studied 28 cortical tubers and seven samples of perituberal cortex from 28 TSC patients who had undergone epilepsy surgery. We assessed mammalian target of rapamycin complex 1 (mTORC1) activation, the numbers of giant cells, dysmorphic neurons, neurons, and oligodendrocytes, and calcification, gliosis, angiogenesis, inflammation, and myelin content. Three distinct histological profiles emerged based on the proportion of calcifications, dysmorphic neurons and giant cells designated types A, B, and C. In the latter two types we were able to subsequently associate them with specific features on presurgical MRI. Therefore, these histopathological patterns provide consistent criteria for improved definition of the clinico-pathological features of cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC.

Published
2016
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12. Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

Author

Ignacio Blanco, Karoline Kuchenbaecker, Daniel Cuadras, Xianshu Wang, Daniel Barrowdale, Gorka Ruiz de Garibay, Pablo Librado, Alejandro Sánchez-Gracia, Julio Rozas, Núria Bonifaci, Lesley McGuffog, Vernon S Pankratz, Abul Islam, Francesca Mateo, Antoni Berenguer, Anna Petit, Isabel Català, Joan Brunet, Lidia Feliubadaló, Eva Tornero, Javier Benítez, Ana Osorio, Teresa Ramón y Cajal, Heli Nevanlinna, Kristiina Aittomäki, Banu K Arun, Amanda E Toland, Beth Y Karlan, Christine Walsh, Jenny Lester, Mark H Greene, Phuong L Mai, Robert L Nussbaum, Irene L Andrulis, Susan M Domchek, Katherine L Nathanson, Timothy R Rebbeck, Rosa B Barkardottir, Anna Jakubowska, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Kathleen Claes, Tom Van Maerken, Orland Díez, Thomas V Hansen, Lars Jønson, Anne-Marie Gerdes, Bent Ejlertsen, Miguel de la Hoya, Trinidad Caldés, Alison M Dunning, Clare Oliver, Elena Fineberg, Margaret Cook, Susan Peock, Emma McCann, Alex Murray, Chris Jacobs, Gabriella Pichert, Fiona Lalloo, Carol Chu, Huw Dorkins, Joan Paterson, Kai-Ren Ong, Manuel R Teixeira, Teixeira, Frans B L Hogervorst, Annemarie H van der Hout, Caroline Seynaeve, Rob B van der Luijt, Marjolijn J L Ligtenberg, Peter Devilee, Juul T Wijnen, Matti A Rookus, Hanne E J Meijers-Heijboer, Marinus J Blok, Ans M W van den Ouweland, Cora M Aalfs, Gustavo C Rodriguez, Kelly-Anne A Phillips, Marion Piedmonte, Stacy R Nerenstone, Victoria L Bae-Jump, David M O'Malley, Elena S Ratner, Rita K Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg J Plendl, Dieter Niederacher, Christian Sutter, Shan Wang-Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Andrea Gehrig, Anders Bojesen, Inge Sokilde Pedersen, Lone Sunde, Uffe Birk Jensen, Mads Thomassen, Torben A Kruse, Lenka Foretova, Paolo Peterlongo, Loris Bernard, Bernard Peissel, Giulietta Scuvera, Siranoush Manoukian, Paolo Radice, Laura Ottini, Marco Montagna, Simona Agata, Christine Maugard, Jacques Simard, Penny Soucy, Andreas Berger, Anneliese Fink-Retter, Christian F Singer, Christine Rappaport, Daphne Geschwantler-Kaulich, Muy-Kheng Tea, Georg Pfeiler, BCFR, Esther M John, Alex Miron, Susan L Neuhausen, Mary Beth Terry, Wendy K Chung, Mary B Daly, David E Goldgar, Ramunas Janavicius, Cecilia M Dorfling, Elisabeth J van Rensburg, Florentia Fostira, Irene Konstantopoulou, Judy Garber, Andrew K Godwin, Edith Olah, Steven A Narod, Gad Rennert, Shani Shimon Paluch, Yael Laitman, Eitan Friedman, SWE-BRCA, Annelie Liljegren, Johanna Rantala, Marie Stenmark-Askmalm, Niklas Loman, Evgeny N Imyanitov, Ute Hamann, kConFab Investigators, Amanda B Spurdle, Sue Healey, Jeffrey N Weitzel, Josef Herzog, David Margileth, Chiara Gorrini, Manel Esteller, Antonio Gómez, Sergi Sayols, Enrique Vidal, Holger Heyn, GEMO, Dominique Stoppa-Lyonnet, Melanie Léoné, Laure Barjhoux, Marion Fassy-Colcombet, Antoine de Pauw, Christine Lasset, Sandra Fert Ferrer, Laurent Castera, Pascaline Berthet, François Cornelis, Yves-Jean Bignon, Francesca Damiola, Sylvie Mazoyer, Olga M Sinilnikova, Christopher A Maxwell, Joseph Vijai, Mark Robson, Noah Kauff, Marina J Corines, Danylko Villano, Julie Cunningham, Adam Lee, Noralane Lindor, Conxi Lázaro, Douglas F Easton, Kenneth Offit, Georgia Chenevix-Trench, Fergus J Couch, Antonis C Antoniou, and Miguel Angel Pujana

Subjects
Medicine, Science
Abstract

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.

Published
2015
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13. Descriptive Analysis of LAP1 Distribution and That of Associated Proteins throughout Spermatogenesis

Author

Joana B. Serrano, Filipa Martins, João C. Sousa, Cátia D. Pereira, Ans M. M. van Pelt, Sandra Rebelo, and Odete A. B. da Cruz e Silva

Subjects
nuclear envelope, lamina-associated polypeptide 1, lamins, protein phosphatase 1, manchette, spermatids, Chemical technology, TP1-1185, Chemical engineering, TP155-156
Abstract

Spermatogenesis comprises highly complex differentiation processes. Nuclear envelope (NE) proteins have been associated with these processes, including lamins, lamina-associated polypeptide (LAP) 2 and the lamin B-receptor. LAP1 is an important NE protein whose function has not been fully elucidated, but several binding partners allow predicting putative LAP1 functions. To date, LAP1 had not been associated with spermatogenesis. In this study, LAP1 expression and cellular/subcellular localization during spermatogenesis in human and mouse testes is established for the first time. The fact that LAP1 is expressed during nuclear elongation in spermiogenesis and is located at the spermatids’ centriolar pole is singularly important. LAP1 binds to members of the protein phosphatase 1 (PP1) family. Similar localization of LAP1 and PP1γ2, a testis-specific PP1 isoform, suggests a shared function for both proteins during spermiogenesis. Furthermore, this study suggests an involvement of LAP1 in manchette development and chromatin regulation possibly via interaction with acetylated α-tubulin and lamins, respectively. Taken together, the present results indicate that, by moving to the posterior pole in spermatids, LAP1 can contribute to the achievement of non-random, sperm-specific chromatin distribution, as well as modulate cellular remodeling during spermiogenesis. In addition, LAP1 seems to be associated with dynamic microtubule changes related to manchette formation and flagella development.

Published
2017
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14. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Author

Elinor Sawyer, Rebecca Roylance, Christos Petridis, Mark N Brook, Salpie Nowinski, Efterpi Papouli, Olivia Fletcher, Sarah Pinder, Andrew Hanby, Kelly Kohut, Patricia Gorman, Michele Caneppele, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Ruth Swann, Miriam Dwek, Katherine-Anne Perkins, Cheryl Gillett, Richard Houlston, Gillian Ross, Paolo De Ieso, Melissa C Southey, John L Hopper, Elena Provenzano, Carmel Apicella, Jelle Wesseling, Sten Cornelissen, Renske Keeman, Peter A Fasching, Sebastian M Jud, Arif B Ekici, Matthias W Beckmann, Michael J Kerin, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Therese Truong, Pierre Laurent-Puig, Pierre Kerbrat, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Javier Benitez, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Magdalena Lochmann, Hiltrud Brauch, Hans-Peter Fischer, Yon-Dschun Ko, GENICA Network, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Georgia Chenevix-Trench, KConFab Investigators, Diether Lambrechts, Caroline Weltens, Erik Van Limbergen, Sigrid Hatse, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Graham G Giles, Gianluca Severi, Laura Baglietto, Catriona A McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Vessela Kristensen, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Rob A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Jonine Figueroa, Stephen J Chanock, Mark E Sherman, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Carolien H M van Deurzen, Jingmei Li, Kamila Czene, Keith Humphreys, Angela Cox, Simon S Cross, Malcolm W R Reed, Mitul Shah, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Anthony Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Fergus J Couch, Emily Hallberg, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel C Tessier, Daniel Vincent, Francois Bacot, Manjeet K Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Alison M Dunning, Per Hall, Doug Easton, Paul Pharoah, Marjanka K Schmidt, Ian Tomlinson, and Montserrat Garcia-Closas

Subjects
Genetics, QH426-470
Abstract

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P

Published
2014
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15. Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Author

Mia M Gaudet, Karoline B Kuchenbaecker, Joseph Vijai, Robert J Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M Dunning, Andrew Lee, Joe Dennis, Sue Healey, Ed Dicks, Penny Soucy, Olga M Sinilnikova, Vernon S Pankratz, Xianshu Wang, Ronald C Eldridge, Daniel C Tessier, Daniel Vincent, Francois Bacot, Frans B L Hogervorst, Susan Peock, Dominique Stoppa-Lyonnet, KConFab Investigators, Paolo Peterlongo, Rita K Schmutzler, Katherine L Nathanson, Marion Piedmonte, Christian F Singer, Mads Thomassen, Ontario Cancer Genetics Network, Thomas v O Hansen, Susan L Neuhausen, Ignacio Blanco, Mark H Greene, Judith Garber, Jeffrey N Weitzel, Irene L Andrulis, David E Goldgar, Emma D'Andrea, Trinidad Caldes, Heli Nevanlinna, Ana Osorio, Elizabeth J van Rensburg, Adalgeir Arason, Gad Rennert, Ans M W van den Ouweland, Annemarie H van der Hout, Carolien M Kets, Cora M Aalfs, Juul T Wijnen, Margreet G E M Ausems, HEBON, EMBRACE, Debra Frost, Steve Ellis, Elena Fineberg, Radka Platte, D Gareth Evans, Chris Jacobs, Julian Adlard, Marc Tischkowitz, Mary E Porteous, Francesca Damiola, GEMO Study Collaborators, Lisa Golmard, Laure Barjhoux, Michel Longy, Muriel Belotti, Sandra Fert Ferrer, Sylvie Mazoyer, Amanda B Spurdle, Siranoush Manoukian, Monica Barile, Maurizio Genuardi, Norbert Arnold, Alfons Meindl, Christian Sutter, Barbara Wappenschmidt, Susan M Domchek, Georg Pfeiler, Eitan Friedman, Uffe Birk Jensen, Mark Robson, Sohela Shah, Conxi Lazaro, Phuong L Mai, Javier Benitez, Melissa C Southey, Marjanka K Schmidt, Peter A Fasching, Julian Peto, Manjeet K Humphreys, Qin Wang, Kyriaki Michailidou, Elinor J Sawyer, Barbara Burwinkel, Pascal Guénel, Stig E Bojesen, Roger L Milne, Hermann Brenner, Magdalena Lochmann, GENICA Network, Kristiina Aittomäki, Thilo Dörk, Sara Margolin, Arto Mannermaa, Diether Lambrechts, Jenny Chang-Claude, Paolo Radice, Graham G Giles, Christopher A Haiman, Robert Winqvist, Peter Devillee, Montserrat García-Closas, Nils Schoof, Maartje J Hooning, Angela Cox, Paul D P Pharoah, Anna Jakubowska, Nick Orr, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Per Hall, Fergus J Couch, Jacques Simard, David Altshuler, Douglas F Easton, Georgia Chenevix-Trench, Antonis C Antoniou, and Kenneth Offit

Subjects
Genetics, QH426-470
Abstract

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Published
2013
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16. A distinct expression pattern in mammalian testes indicates a conserved role for NANOG in spermatogenesis.

Author

Ewart W Kuijk, Jeffrey de Gier, Susana M Chuva de Sousa Lopes, Ian Chambers, Ans M M van Pelt, Ben Colenbrander, and Bernard A J Roelen

Subjects
Medicine, Science
Abstract

NANOG is a key player in pluripotency and its expression is restricted to pluripotent cells of the inner cell mass, the epiblast and to primordial germ cells. Spermatogenesis is closely associated with pluripotency, because through this process highly specialized sperm cells are produced that contribute to the formation of totipotent zygotes. Nevertheless, it is unknown if NANOG plays a role in this process.In the current study, NANOG expression was examined in testes of various mammals, including mouse and human. Nanog mRNA and NANOG protein were detected by RT-PCR, immunohistochemistry, and western blotting. Furthermore, eGFP expression was detected in the testis of a transgenic Nanog eGFP-reporter mouse. Surprisingly, although NANOG expression has previously been associated with undifferentiated cells with stem cell potential, expression in the testis was observed in pachytene spermatocytes and in the first steps of haploid germ cell maturation (spermiogenesis). Weak expression in type A spermatogonia was also observed.The findings of the current study strongly suggest a conserved role for NANOG in meiotic and post-meiotic stages of male germ cell development.

Published
2010
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19. Nonlocal multicontinua with Representative Volume Elements. Bridging separable and non-separable scales

Author

Chung, Eric T., Efendiev, Y., Leung, Wing T., and Vasilyeva, ans M.

Subjects
Mathematics - Numerical Analysis
Abstract

Recently, several approaches for multiscale simulations for problems with high contrast and no scale separation are introduced. Among them is the nonlocal multicontinua (NLMC) method, which introduces multiple macroscopic variables in each computational grid. These approaches explore the entire coarse block resolution and one can obtain optimal convergence results independent of contrast and scales. However, these approaches are not amenable to many multiscale simulations, where the subgrid effects are much smaller than the coarse-mesh resolution. For example, the molecular dynamics of shale gas occurs in much smaller length scales compared to the coarse-mesh size, which is of orders of meters. In this case, one can not explore the entire coarse-grid resolution in evaluating effective properties. In this paper, we merge the concepts of nonlocal multicontinua methods and Representative Volume Element (RVE) concepts to explore problems with extreme scale separation. The first step of this approach is to use sub-grid scale (sub to RVE) to write a large-scale macroscopic system. We call it intermediate scale macroscale system. In the next step, we couple this intermediate macroscale system to the simulation grid model, which are used in simulations. This is done using RVE concepts, where we relate intermediate macroscale variables to the macroscale variables defined on our simulation coarse grid. Our intermediate coarse model allows formulating macroscale variables correctly and coupling them to the simulation grid. We present the general concept of our approach and present details of single-phase flow. Some numerical results are presented. For nonlinear examples, we use machine learning techniques to compute macroscale parameters.

Published
2020

20. Stimulating Language Awareness in the Foreign Language Classroom: Exploring EFL Teaching Practices

Author

van den Broek, Ellen W. R., Oolbekkink-Marchand, Helma W., van Kemenade, Ans M. C., Meijer, Paulien C., and Unsworth, Sharon

Abstract

This study reports on EFL teachers' self-reported teaching practices aimed at stimulating students' language awareness. It investigates whether, and to what extent, awareness-raising practices are currently implemented in EFL secondary education in the Netherlands, how these practices can be characterised, and how awareness-raising practices can be developed and further integrated into foreign language education. In a semi-structured interview, 10 teachers were asked to provide examples which they believed stimulated students' awareness of language. A total of 41 teaching practices were collected. Analysis of teaching practices revealed that approximately half of all self-reported practices could be characterised as awareness-raising. These practices often integrated multiple topics, included authentic contexts, back-and-forth interaction and provided students with the opportunity to reflect on their own and other students' language difficulties. At the same time, numerous practices which were reported as awareness-raising could not yet be characterised as such, indicating that teachers' notion of what constitutes an awareness-raising practice may be incomplete. Nevertheless, these practices provide interesting leads for awareness-raising opportunities. In sum, the analysis of practices presents a valuable opportunity for teachers to discuss their notion of awareness-raising practices. In addition, such an analysis could support teachers in adjusting their own teaching practices.

Published
2022
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23. Communication and ethical considerations for fertility preservation for patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group

Author

Anderson, Richard A, Barnbrock, Anke, Beck, Joern D, Bos, Annelies M E, Calaminus, Gabriele, Constine, Louis S, Demeestere, Isabelle, Denzer, Christian, Grabow, Desiree, di Iorgi, Natascia, Hoefgen, Holly R, Jahnukainen, Kirsi, Kaatsch, Peter, Kebudi, Rejin, Lambalk, Cornelis, Langer, Thorsten, Loonen, Jacqueline, Lorenzo, Armando, Meacham, Lillian R, Meissner, Andreas, Mitchell, Rod T, Nahata, Leena, Ranft, Andreas, Dinkelman-Smit, Marij, Stern, Catharyn, Stutz-Grunder, Eveline, Tournaye, Herman, van Dorp, Wendy, van Pelt, Ans M M, de Vries, Andrica, Yu, Richard, Mulder, Renée L, Font-Gonzalez, Anna, van Dulmen-den Broeder, Eline, Quinn, Gwendolyn P, Ginsberg, Jill P, Loeffen, Erik A H, Hudson, Melissa M, Burns, Karen C, van Santen, Hanneke M, Berger, Claire, Diesch, Tamara, Dirksen, Uta, Giwercman, Aleksander, Gracia, Clarisa, Hunter, Sarah E, Kelvin, Joanne F, Klosky, James L, Laven, Joop S E, Lockart, Barbara A, Neggers, Sebastian J C M M, Peate, Michelle, Phillips, Bob, Reed, Damon R, Tinner, Eva Maria E, Byrne, Julianne, Veening, Margreet, van de Berg, Marleen, Verhaak, Chris M, Anazodo, Antoinette, Rodriguez-Wallberg, Kenny, van den Heuvel-Eibrink, Marry M, Asogwa, Ogechukwu A, Brownsdon, Alexandra, Wallace, W Hamish, Green, Daniel M, Skinner, Roderick, Haupt, Riccardo, Kenney, Lisa B, Levine, Jennifer, van de Wetering, Marianne D, Tissing, Wim J E, Paul, Norbert W, Kremer, Leontien C M, and Inthorn, Julia

Published
2021
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24. Fertility preservation for male patients with childhood, adolescent, and young adult cancer: recommendations from the PanCareLIFE Consortium and the International Late Effects of Childhood Cancer Guideline Harmonization Group

Author

Berger, Claire, Diesch, Tamara, Giwercman, Aleksander, Grabow, Desiree, Gracia, Clarisa, Hunter, Sarah E, Inthorn, Julia, Kaatsch, Peter, Kelvin, Joanne F, Klosky, James L, Laven, Joop S E, Lockart, Barbara A, Neggers, Sebastian JCMM, Paul, Norbert W, Peate, Michelle, Phillips, Bob, Quinn, Gwendolyn P, Reed, Damon R, Tinner, Eva Maria E, van den Berg, Marleen, Verhaak, Chris, Mulder, Renée L, Font-Gonzalez, Anna, Green, Daniel M, Loeffen, Erik A H, Hudson, Melissa M, Loonen, Jacqueline, Yu, Richard, Ginsberg, Jill P, Mitchell, Rod T, Byrne, Julianne, Skinner, Roderick, Anazodo, Antoinette, Constine, Louis S, de Vries, Andrica, Jahnukainen, Kirsi, Lorenzo, Armando, Meissner, Andreas, Nahata, Leena, Dinkelman-Smit, Marij, Tournaye, Herman, Haupt, Riccardo, van den Heuvel-Eibrink, Marry M, van Santen, Hanneke M, van Pelt, Ans M M, Dirksen, Uta, den Hartogh, Jaap, van Dulmen-den Broeder, Eline, Wallace, W Hamish, Levine, Jennifer, Tissing, Wim J E, Kremer, Leontien C M, Kenney, Lisa B, and van de Wetering, Marianne D

Published
2021
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25. Disruption of TUFT1, a Desmosome-Associated Protein, Causes Skin Fragility, Woolly Hair, and Palmoplantar Keratoderma

Author

Verkerk, Annemieke J M H, Andrei, Daniela, Vermeer, Mathilde C S C, Kramer, Duco, Schouten, Marloes, Arp, Pascal, Verlouw, Joost A M, Pas, Hendri H, Meijer, Hillegonda J, van der Molen, Marije, Oberdorf-Maass, Silke, Nijenhuis, Miranda, Romero-Herrera, Pedro H, Hoes, Martijn F, Bremer, Jeroen, Slotman, Johan A, van den Akker, Peter C, Diercks, Gilles F H, Giepmans, Ben N G, Stoop, Hans, Saris, Jasper, van den Ouweland, Ans M W, Willemsen, Rob, Hublin, Jean-Jacques, Dean, M Christopher, Hoogeboom, A Jeannette M, Silljé, Herman H W, Uitterlinden, André G, van der Meer, Peter, Bolling, Maria C, Verkerk, Annemieke J M H, Andrei, Daniela, Vermeer, Mathilde C S C, Kramer, Duco, Schouten, Marloes, Arp, Pascal, Verlouw, Joost A M, Pas, Hendri H, Meijer, Hillegonda J, van der Molen, Marije, Oberdorf-Maass, Silke, Nijenhuis, Miranda, Romero-Herrera, Pedro H, Hoes, Martijn F, Bremer, Jeroen, Slotman, Johan A, van den Akker, Peter C, Diercks, Gilles F H, Giepmans, Ben N G, Stoop, Hans, Saris, Jasper, van den Ouweland, Ans M W, Willemsen, Rob, Hublin, Jean-Jacques, Dean, M Christopher, Hoogeboom, A Jeannette M, Silljé, Herman H W, Uitterlinden, André G, van der Meer, Peter, and Bolling, Maria C

Abstract

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients’ skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients’ phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma.

Published
2024

27. A 20-year overview of fertility preservation in boys: new insights gained through a comprehensive international survey

Author

Duffin, Kathleen, primary, Neuhaus, Nina, additional, Andersen, Claus Yding, additional, Barraud-Lange, Virginie, additional, Braye, Aude, additional, Eguizabal, Cristina, additional, Feraille, Aurélie, additional, Ginsberg, Jill P, additional, Gook, Debra, additional, Goossens, Ellen, additional, Jahnukainen, Kirsi, additional, Jayasinghe, Yasmin, additional, Keros, Victoria, additional, Kliesch, Sabine, additional, Lane, Sheila, additional, Mulder, Callista L, additional, Orwig, Kyle E, additional, van Pelt, Ans M M, additional, Poirot, Catherine, additional, Rimmer, Michael P, additional, Rives, Nathalie, additional, Sadri-Ardekani, Hooman, additional, Safrai, Myriam, additional, Schlatt, Stefan, additional, Stukenborg, Jan-Bernd, additional, van de Wetering, Marianne D, additional, Wyns, Christine, additional, and Mitchell, Rod T, additional

Published
2024
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28. An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression

Author

Wyszynski, Asaf, Hong, Chi-Chen, Lam, Kristin, Michailidou, Kyriaki, Lytle, Christian, Yao, Song, Zhang, Yali, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Hopper, John L, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Peto, Julian, dos-Santos-Silva, Isabel, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Nordestgaard, Børge G, Gonzalez-Neira, Anna, Benitez, Javier, Neuhausen, Susan L, Brenner, Hermann, Dieffenbach, Aida Karina, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Nevanlinna, Heli, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, Dörk, Thilo, Bogdanova, Natalia V, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Wu, Anna H, Van Den Berg, David, Lambrechts, Diether, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Peterlongo, Paolo, Couch, Fergus J, Olson, Janet E, Giles, Graham G, Milne, Roger L, Haiman, Christopher A, Henderson, Brian E, Dumont, Martine, Teo, Soo Hwang, Wong, Tien Y, Kristensen, Vessela, Zheng, Wei, Long, Jirong, Winqvist, Robert, Pylkäs, Katri, Andrulis, Irene L, Knight, Julia A, Devilee, Peter, Seynaeve, Caroline, García-Closas, Montserrat, Figueroa, Jonine, Klevebring, Daniel, Czene, Kamila, Hooning, Maartje J, van den Ouweland, Ans M. W., Darabi, Hatef, Shu, Xiao-Ou, Gao, Yu-Tang, Cox, Angela, Blot, William, Signorello, Lisa B, Shah, Mitul, Kang, Daehee, Choi, Ji-Yeob, Hartman, Mikael, Miao, Hui, Hamann, Ute, Jakubowska, Anna, Lubinski, Jan, Sangrajrang, Suleeporn, McKay, James, Toland, Amanda E, Yannoukakos, Drakoulis, Shen, Chen-Yang, Wu, Pei-Ei, Swerdlow, Anthony, and Orr, Nick

Published
2016

29. Off to a good start after a cancer diagnosis: implementation of a time out consultation in primary care before cancer treatment decision

Author

Noteboom, Eveline A., de Wit, Niek J., van Asseldonk, Ingrid J. E. M., Janssen, Monique C. A. M., Lam-Wong, Wai Yee, Linssen, Rob H. P. J., Pepels, Manon J. A. E., Schrama, Natascha A. W. P., Trompper, Mariëlle E. H., Veldhuizen, L. Maaike, Wijtvliet, Anne P., Zeldenrust, Ed G. F., Hendrikx, Ans M., van de Boomen, Wil A., Elbersen, Dorothé M., Jacobs, Esther M. G., van der Wall, Elsken, and Helsper, Charles W.

Published
2020
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30. Unravelling Upper-Secondary School Teachers' Beliefs about Language Awareness: From Conflicts to Challenges in the EFL Context

Author

van den Broek, Ellen W. R., Oolbekkink-Marchand, Helma W., Unsworth, Sharon, van Kemenade, Ans M. C., and Meijer, Paulien C.

Abstract

This study presents an in-depth inquiry into teachers' beliefs about a language awareness approach to secondary school foreign language education. The study aims to deepen our insight into (the differences in) teachers' beliefs about language awareness and facilitate the discussion about including language awareness in foreign language curricula. Ten EFL teachers were interviewed about their beliefs about language awareness. Analysis of the interviews revealed that teachers do not have a shared understanding of the concept of language awareness as related to the five domains of language awareness set out. Furthermore, several beliefs could be characterised as conflicting. These conflicts were found in the context of student learning, teacher collaboration, the curriculum and the link with other languages. The results suggest a number of challenges that need to be addressed when including language awareness in foreign language education. These challenges could serve as a point of departure for a dialogue with and between teachers. Furthermore, they could support teachers to find out how language awareness fits best within the existing EFL curricula.

Published
2018
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31. Effects of many-electron jumps in relaxation and conductivity of Coulomb glasses

Author

Bergli, J., Somoza, A. M., and Ortuno, ans M.

Subjects
Condensed Matter - Disordered Systems and Neural Networks
Abstract

A numerical study of the energy relaxation and conductivity of the Coulomb glass is presented. The role of many-electron transitions is studied by two complementary methods: a kinetic Monte Carlo algorithm and a master equation in configuration space method. A calculation of the transition rate for two-electron transitions is presented, and the proper extension of this to multi-electron transitions is discussed. It is shown that two-electron transitions are important in bypassing energy barriers which effectively block sequential one-electron transitions. The effect of two-electron transitions is also discussed., Comment: 8 pages, 6 figures

Published
2011
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32. Genome-wide association study of germline variants and breast cancer-specific mortality

Author

Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K., Wang, Qin, Abraham, Jean, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L., Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E., Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W., Brucker, Sara Y., Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D., Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Chin, Suet-Feung, Clarke, Christine L., NBCS Collaborators, Cordina-Duverger, Emilie, Couch, Fergus J., Cox, David G., Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., Devilee, Peter, Dunn, Janet A., Dunning, Alison M., Durcan, Lorraine, Dwek, Miriam, Earl, Helena M., Ekici, Arif B., Eliassen, A. Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D. Gareth, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Galle, Eva, Gapstur, Susan M., García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., George, Angela, Georgoulias, Vassilios, Giles, Graham G., Glendon, Gord, Goldgar, David E., González-Neira, Anna, Alnæs, Grethe I. Grenaker, Grip, Mervi, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan, Harkness, Elaine F., Harrington, Patricia A., Hart, Steven N., Hartikainen, Jaana M., Hein, Alexander, Hillemanns, Peter, Hiller, Louise, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J., Hoover, Robert N., Hopper, John L., Howell, Anthony, Huang, Guanmengqian, Humphreys, Keith, Hunter, David J., Janni, Wolfgang, John, Esther M., Jones, Michael E., Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kabisch, Maria, Kaczmarek, Katarzyna, Kerin, Michael J., Khan, Sofia, Khusnutdinova, Elza, Kiiski, Johanna I., Kitahara, Cari M., Knight, Julia A., Ko, Yon-Dschun, Koppert, Linetta B., Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N., Krüger, Ute, Kühl, Tabea, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Li, Lian, Lindblom, Annika, Lindström, Sara, Linet, Martha, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Lubiński, Jan, Lux, Michael P., MacInnis, Robert J., Maierthaler, Melanie, Maishman, Tom, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, McLean, Catriona, Meindl, Alfons, Middha, Pooja, Miller, Nicola, Milne, Roger L., Moreno, Fernando, Mulligan, Anna Marie, Mulot, Claire, Nassir, Rami, Neuhausen, Susan L., Newman, William T., Nielsen, Sune F., Nordestgaard, Børge G., Norman, Aaron, Olsson, Håkan, Orr, Nick, Pankratz, V. Shane, Park-Simon, Tjoung-Won, Perez, Jose I. A., Pérez-Barrios, Clara, Peterlongo, Paolo, Petridis, Christos, Pinchev, Mila, Prajzendanc, Karoliona, Prentice, Ross, Presneau, Nadege, Prokofieva, Darya, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Ramachandran, Dhanya, Rennert, Gadi, Rennert, Hedy S., Rhenius, Valerie, Romero, Atocha, Roylance, Rebecca, Saloustros, Emmanouil, Sawyer, Elinor J., Schmidt, Daniel F., Schmutzler, Rita K., Schneeweiss, Andreas, Schoemaker, Minouk J., Schumacher, Fredrick, Schwentner, Lukas, Scott, Rodney J., Scott, Christopher, Seynaeve, Caroline, Shah, Mitul, Simard, Jacques, Smeets, Ann, Sohn, Christof, Southey, Melissa C., Swerdlow, Anthony J., Talhouk, Aline, Tamimi, Rulla M., Tapper, William J., Teixeira, Manuel R., Tengström, Maria, Terry, Mary Beth, Thöne, Kathrin, Tollenaar, Rob A. E. M., Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Turman, Constance, Turnbull, Clare, Ulmer, Hans-Ulrich, Untch, Michael, Vachon, Celine, van Asperen, Christi J., van den Ouweland, Ans M. W., van Veen, Elke M., Wendt, Camilla, Whittemore, Alice S., Willett, Walter, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R., Zhang, Yan, Easton, Douglas F., Fasching, Peter A., Nevanlinna, Heli, Eccles, Diana M., Pharoah, Paul D. P., and Schmidt, Marjanka K.

Published
2019
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33. Transcriptional comparison of testicular adrenal rest tumors with fetal and adult tissues

Author

Mariska A M Schröder, Fred C G J Sweep, Antonius E van Herwaarden, Rod T Mitchell, Jitske Eliveld, Ans M M van Pelt, Alan E Rowan, Darren Korbie, Nike M M L Stikkelbroeck, Hedi L Claahsen-van der Grinten, Paul N Span, Reproductive Biology Laboratory, Center for Reproductive Medicine, and Amsterdam Reproduction & Development (AR&D)

Subjects
Adult, Male, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Adrenal Hyperplasia, Congenital, Endocrinology, Diabetes and Metabolism, Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], General Medicine, Cyclic AMP-Dependent Protein Kinases, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Fetus, Endocrinology, Adrenocorticotropic Hormone, Testicular Neoplasms, Adrenal Rest Tumor, Humans, Steroid 11-beta-Hydroxylase, Receptors, Platelet-Derived Growth Factor
Abstract

Background Testicular adrenal rest tumors (TART) are a common complication of unknown cellular origin in patients with congenital adrenal hyperplasia (CAH). These benign tumors have both adrenal and testicular characteristics and are hypothesized to either derive from cells of adrenal origin from the fetal adrenogonadal primordium or by atypical differentiation of adult Leydig-progenitor cells. Objective This study aims to unravel the identity and etiology of TART. Methods Co-expression of adrenal-specific CYP11B1 and Leydig cell-specific HSD17B3 in TART was studied using immunohistochemistry. We studied the possibility of TART being derived from atypical differentiation of adult Leydig-progenitor cells by the quantification of adrenal-specific enzyme expression upon adrenocorticotrophic hormone (ACTH)-like stimulation of ex vivo cultured platelet-derived growth factor receptor alpha-positive cells. By comparing the transcriptome of TART (n = 16) with the transcriptome of fetal adrenal (n = 13), fetal testis (n = 5), adult adrenal (n = 11), and adult testis (n = 10) tissues, we explored the identity of TART. Results We demonstrate co-expression of adrenal-specific CYP11B1 and testis-specific HSD17B3 in TART cells, indicating the existence of a distinct TART cell exhibiting both adrenal and testicular characteristics. Ex vivo cultured adult Leydig-progenitor cells did not express the ACTH-receptor MC2R but did express CYP11B1 upon stimulation. Unsupervised clustering of transcriptome data showed that TART was most similar to adult adrenal tissue, followed by adult testis tissue, and least similar to either fetal tissue. Conclusion Our data suggest that TART is induced — most likely via activation of a cAMP/protein kinase A-dependent receptor — from a progenitor cell into a unique mature adrenal-like cell type, sometimes exhibiting both adrenal and testicular features.

Published
2022

35. Childhood cancer and hematological disorders negatively affect spermatogonial quantity at diagnosis : a retrospective study of a male fertility preservation cohort

Author

Ieva Masliukaite, Elissavet Ntemou, Elizabeth A M Feijen, Marianne van de Wetering, Andreas Meissner, Alexandre T Soufan, Sjoerd Repping, Leontien M C Kremer, Kirsi Jahnukainen, Ellen Goossens, Ans M M van Pelt, HUS Children and Adolescents, Children's Hospital, University of Helsinki, Internal medicine, Brussels Heritage Lab, Basic (bio-) Medical Sciences, Biology of the Testis, Graduate School, Amsterdam Reproduction & Development (AR&D), Center for Reproductive Medicine, Urology, APH - Personalized Medicine, APH - Quality of Care, Cancer Center Amsterdam, Other Research, and Reproductive Biology Laboratory

Subjects
Testicular tissue cryopreservation, 3123 Gynaecology and paediatrics, Hematological disorders, Male fertility, Rehabilitation, oncology, Obstetrics and Gynecology, Pediatric oncology, Pediatrics, Perinatology, and Child Health, Fertility preservation, Prepubertal boys, Spermatogonia, reproductive medicine
Abstract

STUDY QUESTIONWhat is the impact of cancer or hematological disorders on germ cells in pediatric male patients?SUMMARY ANSWERSpermatogonial quantity is reduced in testes of prepubertal boys diagnosed with cancer or severe hematological disorder compared to healthy controls and this reduction is disease and age dependent: patients with central nervous system cancer (CNS tumors) and hematological disorders, as well as boys WHAT IS KNOWN ALREADYFertility preservation in pediatric male patients is considered based on the gonadotoxicity of selected treatments. Although treatment effects on germ cells have been extensively investigated, limited data are available on the effect of the disease on the prepubertal male gonad. Of the few studies investigating the effects of cancer or hematologic disorders on testicular function and germ cell quantity in prepuberty, the results are inconsistent. However, recent studies suggested impairments before the initiation of known gonadotoxic therapy. Understanding which diseases and at what age affect the germ cell pool in pediatric patients before treatment is critical to optimize strategies and counseling for fertility preservation.STUDY DESIGN, SIZE, DURATIONThis multicenter retrospective cohort study included 101 boys aged PARTICIPANTS/MATERIALS, SETTING, METHODSIn addition to clinical data, we analyzed measurements of testicular volume and performed histological staining on testicular biopsies obtained before treatment, at cryopreservation, to evaluate number of spermatogonia per tubular cross-section, tubular fertility index, and the most advanced germ cell type prior to chemo-/radiotherapy. The controls were data simulations with summary statistics from original studies reporting healthy prepubertal boys’ testes characteristics.MAIN RESULTS AND THE ROLE OF CHANCEPrepubertal patients with childhood cancer or hematological disorders were more likely to have significantly reduced spermatogonial quantity compared to healthy controls (48.5% versus 31.0% prevalence, respectively). The prevalence of patients with reduced spermatogonial quantity was highest in the CNS tumor (56.7%) and the hematological disorder (55.6%) groups, including patients with hydroxyurea pre-treated sickle cell disease (58.3%) and patients not exposed to hydroxyurea (50%). Disease also adversely impacted spermatogonial distribution and differentiation. Irrespective of disease, we observed the highest spermatogonial quantity reduction in patients LIMITATIONS, REASONS FOR CAUTIONFor ethical reasons, we could not collect spermatogonial quantity data in healthy prepubertal boys as controls and thus deployed statistical simulation on data from literature. Also, our results should be interpreted considering low patient numbers per (sub)group.WIDER IMPLICATIONS OF THE FINDINGSCancers, especially CNS tumors, and severe hematological disorders can affect spermatogonial quantity in prepubertal boys before treatment. Consequently, these patients may have a higher risk of depleted spermatogonia following therapies, resulting in persistent infertility. Therefore, patient counseling prior to disease treatment and timing of fertility preservation should not only be based on treatment regimes, but also on diagnoses and age.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by Marie Curie Initial Training Network (ITN) (EU-FP7-PEOPLE-2013-ITN) funded by European Commision grant no. 603568; ZonMW Translational Adult stem cell research (TAS) grant no. 116003002. No competing interests.TRIAL REGISTRATION NUMBERN/A.

Published
2023

36. Two truncating variants in FANCC and breast cancer risk

Author

Dörk, Thilo, Peterlongo, Paolo, Mannermaa, Arto, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahearn, Thomas, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J., Augustinsson, Annelie, Freeman, Laura E. Beane, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Stig E., Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Canzian, Federico, Chan, Tsun L., Chang-Claude, Jenny, Chanock, Stephen J., Choi, Ji-Yeob, Christiansen, Hans, Clarke, Christine L., Couch, Fergus J., Czene, Kamila, Daly, Mary B., dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M., García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Giles, Graham G., Goldberg, Mark S., Goldgar, David E., Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hein, Alexander, Hillemanns, Peter, Hogervorst, Frans B. L., Hooning, Maartje J., Hopper, John L., Howell, Tony, Huo, Dezheng, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M., Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Khusnutdinova, Elza, Kim, Sung-Won, Kitahara, Cari M., Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Kwong, Ava, Lambrechts, Diether, Marchand, Loic Le, Li, Jingmei, Lindström, Sara, Linet, Martha, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Lubiński, Jan, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Elena, Matsuo, Keitaro, Mavroudis, Dimitris, Meindl, Alfons, Menon, Usha, Milne, Roger L., Mohd Taib, Nur Aishah, Muir, Kenneth, Mulligan, Anna Marie, Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Newman, William G., Offit, Kenneth, Olopade, Olufunmilayo I., Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Park, Sue K., Park-Simon, Tjoung-Won, Peto, Julian, Plaseska-Karanfilska, Dijana, Pohl-Rescigno, Esther, Presneau, Nadege, Rack, Brigitte, Radice, Paolo, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Romero, Atocha, Ruebner, Matthias, Saloustros, Emmanouil, Schmidt, Marjanka K., Schmutzler, Rita K., Schneider, Michael O., Schoemaker, Minouk J., Scott, Christopher, Shen, Chen-Yang, Shu, Xiao-Ou, Simard, Jacques, Slager, Susan, Smichkoska, Snezhana, Southey, Melissa C., Spinelli, John J., Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Teo, Soo H., Terry, Mary Beth, Toland, Amanda E., Tollenaar, Rob A. E. M., Torres, Diana, Torres-Mejía, Gabriela, Troester, Melissa A., Truong, Thérèse, Tsugane, Shoichiro, Untch, Michael, Vachon, Celine M., Ouweland, Ans M. W. van den, Veen, Elke M. van, Vijai, Joseph, Wendt, Camilla, Wolk, Alicja, Yu, Jyh-Cherng, Zheng, Wei, Ziogas, Argyrios, Ziv, Elad, ABCTB Investigators, NBCS Collaborators, Dunning, Alison M., Pharoah, Paul D. P., Schindler, Detlev, Devilee, Peter, and Easton, Douglas F.

Published
2019
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37. Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Author

Ferreira, Manuel A., Gamazon, Eric R., Al-Ejeh, Fares, Aittomäki, Kristiina, Andrulis, Irene L., Anton-Culver, Hoda, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J., Arun, Banu K., Asseryanis, Ella, Azzollini, Jacopo, Balmaña, Judith, Barnes, Daniel R., Barrowdale, Daniel, Beckmann, Matthias W., Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Stig E., Bolla, Manjeet K., Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Broeks, Annegien, Burwinkel, Barbara, Caldés, Trinidad, Caligo, Maria A., Campa, Daniele, Campbell, Ian, Canzian, Federico, Carter, Jonathan, Carter, Brian D., Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Christiansen, Hans, Chung, Wendy K., Claes, Kathleen B. M., Clarke, Christine L., EMBRACE Collaborators, GC-HBOC Study Collaborators, GEMO Study Collaborators, Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., de la Hoya, Miguel, Dennis, Joe, Devilee, Peter, Diez, Orland, Dörk, Thilo, Dunning, Alison M., Dwek, Miriam, Eccles, Diana M., Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A., Fletcher, Olivia, Flyger, Henrik, Friedman, Eitan, Frost, Debra, Gabrielson, Marike, Gago-Dominguez, Manuela, Ganz, Patricia A., Gapstur, Susan M., Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Giles, Graham G., Glendon, Gord, Godwin, Andrew K., Goldberg, Mark S., Goldgar, David E., González-Neira, Anna, Greene, Mark H., Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A., Hall, Per, Hamann, Ute, He, Wei, Heyworth, Jane, Hogervorst, Frans B. L., Hollestelle, Antoinette, Hoover, Robert N., Hopper, John L., Hulick, Peter J., Humphreys, Keith, Imyanitov, Evgeny N., ABCTB Investigators, HEBON Investigators, BCFR Investigators, Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul A., Janavicius, Ramunas, Jankowitz, Rachel C., John, Esther M., Johnson, Nichola, Joseph, Vijai, Karlan, Beth Y., Khusnutdinova, Elza, Kiiski, Johanna I., Ko, Yon-Dschun, Jones, Michael E., Konstantopoulou, Irene, Kristensen, Vessela N., Laitman, Yael, Lambrechts, Diether, Lazaro, Conxi, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindström, Sara, Long, Jirong, Loud, Jennifer T., Lubiński, Jan, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Maurer, Tabea, Mavroudis, Dimitrios, McGuffog, Lesley, Meindl, Alfons, Menon, Usha, Michailidou, Kyriaki, Miller, Austin, Montagna, Marco, Moreno, Fernando, Moserle, Lidia, Mulligan, Anna Marie, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Nevelsteen, Ines, Nielsen, Finn C., Nikitina-Zake, Liene, Nussbaum, Robert L., Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Olsson, Håkan, Osorio, Ana, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T., Pedersen, Inge Sokilde, Peixoto, Ana, Peterlongo, Paolo, Pharoah, Paul D. P., Plaseska-Karanfilska, Dijana, Poppe, Bruce, Presneau, Nadege, Radice, Paolo, Rantala, Johanna, Rennert, Gad, Risch, Harvey A., Saloustros, Emmanouil, Sanden, Kristin, Sawyer, Elinor J., Schmidt, Marjanka K., Schmutzler, Rita K., Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F., Soucy, Penny, Southey, Melissa C., Spinelli, John J., Spurdle, Amanda B., Stone, Jennifer, Swerdlow, Anthony J., Tapper, William J., Taylor, Jack A., Teixeira, Manuel R., Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thöne, Kathrin, Thull, Darcy L., Tischkowitz, Marc, Toland, Amanda E., Torres, Diana, Truong, Thérèse, Tung, Nadine, Vachon, Celine M., van Asperen, Christi J., van den Ouweland, Ans M. W., van Rensburg, Elizabeth J., Vega, Ana, Viel, Alessandra, Wang, Qin, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Wendt, Camilla, Winqvist, Robert, Yang, Xiaohong R., Yannoukakos, Drakoulis, Ziogas, Argyrios, Kraft, Peter, Antoniou, Antonis C., Zheng, Wei, Easton, Douglas F., Milne, Roger L., Beesley, Jonathan, and Chenevix-Trench, Georgia

Published
2019
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38. Childhood cancer and hematological disorders negatively affect spermatogonial quantity at diagnosis: a retrospective study of a male fertility preservation cohort

Author

Masliukaite, Ieva, primary, Ntemou, Elissavet, additional, Feijen, Elizabeth A M, additional, van de Wetering, Marianne, additional, Meissner, Andreas, additional, Soufan, Alexandre T, additional, Repping, Sjoerd, additional, Kremer, Leontien M C, additional, Jahnukainen, Kirsi, additional, Goossens, Ellen, additional, and van Pelt, Ans M M, additional

Published
2023
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39. Fathering a child after childhood cancer treatments

Author

Joana B. Serrano, Andreas Meißner, Ans M. M. van Pelt, and Callista L. Mulder

Subjects
Urology
Abstract

Among many deleterious ramifications of oncological treatments, there is permanent male infertility due to the damage to spermatogonial stem cells (SSC) in the testes after chemotherapy or irradiation. For those patients that cannot produce sperm before cancer treatment, because of prepubertal age, there are no clinical options available to father a child. To preserve fertility in childhood cancer patients, freezing of a testis biopsy is already offered before cancer treatment, while fertility treatment options using this biopsy are still under development, including spermatogonial stem cell transplantation (SSCT). SSCT requires isolation and in vitro propagation of spermatogonial stem cells from the cryopreserved biopsy, followed by autologous transplantation back to the adult cancer survivor. Given the implications of this potential stem cell therapy to recipients, their partners, and future offspring, we here aim to thoroughly appraise the state-of-the-art of SSCT focussing on safety for both patient and his future children.

Published
2022

42. Association of breast cancer risk in BRCA1 and BRCA2 mutation carriers with genetic variants showing differential allelic expression: identification of a modifier of breast cancer risk at locus 11q22.3

Author

Hamdi, Yosr, Soucy, Penny, Kuchenbaeker, Karoline B., Pastinen, Tomi, Droit, Arnaud, Lemaçon, Audrey, Adlard, Julian, Aittomäki, Kristiina, Andrulis, Irene L., Arason, Adalgeir, Arnold, Norbert, Arun, Banu K., Azzollini, Jacopo, Bane, Anita, Barjhoux, Laure, Barrowdale, Daniel, Benitez, Javier, Berthet, Pascaline, Blok, Marinus J., Bobolis, Kristie, Bonadona, Valérie, Bonanni, Bernardo, Bradbury, Angela R., Brewer, Carole, Buecher, Bruno, Buys, Saundra S., Caligo, Maria A., Chiquette, Jocelyne, Chung, Wendy K., Claes, Kathleen B. M., Daly, Mary B., Damiola, Francesca, Davidson, Rosemarie, De la Hoya, Miguel, De Leeneer, Kim, Diez, Orland, Ding, Yuan Chun, Dolcetti, Riccardo, Domchek, Susan M., Dorfling, Cecilia M., Eccles, Diana, Eeles, Ros, Einbeigi, Zakaria, Ejlertsen, Bent, Engel, Christoph, Gareth Evans, D., Feliubadalo, Lidia, Foretova, Lenka, Fostira, Florentia, Foulkes, William D., Fountzilas, George, Friedman, Eitan, Frost, Debra, Ganschow, Pamela, Ganz, Patricia A., Garber, Judy, Gayther, Simon A., Gerdes, Anne-Marie, Glendon, Gord, Godwin, Andrew K., Goldgar, David E., Greene, Mark H., Gronwald, Jacek, Hahnen, Eric, Hamann, Ute, Hansen, Thomas V. O., Hart, Steven, Hays, John L., Hogervorst, Frans B. L., Hulick, Peter J., Imyanitov, Evgeny N., Isaacs, Claudine, Izatt, Louise, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M., Joseph, Vijai, Just, Walter, Kaczmarek, Katarzyna, Karlan, Beth Y., Kets, Carolien M., Kirk, Judy, Kriege, Mieke, Laitman, Yael, Laurent, Maïté, Lazaro, Conxi, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Loman, Niklas, Loud, Jennifer T., Manoukian, Siranoush, Mariani, Milena, Mazoyer, Sylvie, McGuffog, Lesley, Meijers-Heijboer, Hanne E. J., Meindl, Alfons, Miller, Austin, Montagna, Marco, Mulligan, Anna Marie, Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Nussbaum, Robert L., Olah, Edith, Olopade, Olufunmilayo I., Ong, Kai-ren, Oosterwijk, Jan C., Osorio, Ana, Papi, Laura, Park, Sue Kyung, Pedersen, Inge Sokilde, Peissel, Bernard, Segura, Pedro Perez, Peterlongo, Paolo, Phelan, Catherine M., Radice, Paolo, Rantala, Johanna, Rappaport-Fuerhauser, Christine, Rennert, Gad, Richardson, Andrea, Robson, Mark, Rodriguez, Gustavo C., Rookus, Matti A., Schmutzler, Rita Katharina, Sevenet, Nicolas, Shah, Payal D., Singer, Christian F., Slavin, Thomas P., Snape, Katie, Sokolowska, Johanna, Sønderstrup, Ida Marie Heeholm, Southey, Melissa, Spurdle, Amanda B., Stadler, Zsofia, Stoppa-Lyonnet, Dominique, Sukiennicki, Grzegorz, Sutter, Christian, Tan, Yen, Tea, Muy-Kheng, Teixeira, Manuel R., Teulé, Alex, Teo, Soo-Hwang, Terry, Mary Beth, Thomassen, Mads, Tihomirova, Laima, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda Ewart, Tung, Nadine, van den Ouweland, Ans M. W., van der Luijt, Rob B., van Engelen, Klaartje, van Rensburg, Elizabeth J., Varon-Mateeva, Raymonda, Wappenschmidt, Barbara, Wijnen, Juul T., Rebbeck, Timothy, Chenevix-Trench, Georgia, Offit, Kenneth, Couch, Fergus J., Nord, Silje, Easton, Douglas F., Antoniou, Antonis C., Simard, Jacques, EMBRACE, GEMO Study Collaborators, HEBON, and KConFab Investigators

Published
2017
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44. A Spatially Explicit Migration Model for Pike

Author

Van Nieuland, Steffie, Baetens, Jan M., Pauwels, Ine S., De Baets, Bernard, Mouton, Ans M., Goethals, Peter L. M., Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Doug, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Sirakoulis, Georgios Ch., editor, and Bandini, Stefania, editor

Published
2012
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45. The predictive ability of the 313 variant–based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant

Author

Lakeman, Inge M. M., Van Den Broek, Alexandra J., Vos, Juliën A. M., Barnes, Daniel R., Adlard, Julian, Andrulis, Irene L., Arason, Adalgeir, Arnold, Norbert, Arun, Banu K., Balmaña, Judith, Barrowdale, Daniel, Giraud, Sophie, Golmard, Lisa, Hake, Christopher R., Houdayer, Claude, Risch, Harvey A., Lasset, Christine, Laurent, Maïté, Spurdle, Amanda B., Hooning, Maartje J., Hopper, John L., Kets, Carolien M., Leroux, Dominique, Longy, Michel, Mari, Véronique, Mazoyer, Sylvie, Mebirouk, Noura, Mortemousque, Isabelle, Blok, Marinus J., Prieur, Fabienne, Hamann, Ute, Pujol, Pascal, Konstantopoulou, Irene, Heemskerk Gerritsen, Bernadette A. M., Isaacs, Claudine, Saule, Claire, Piedmonte, Marion, Schuster, Helene, Sevenet, Nicolas, Sobol, Hagay, Sokolowska, Johanna, Gómez Garcia, Encarna B., Venat Bouvet, Laurence, Claes, Kathleen B. M., Ahmed, Munaza, Teixeira, Manuel R., Barwell, Julian, Brady, Angela, Izatt, Louise, Hogervorst, Frans B. L., Brennan, Paul, Harrington, Patricia A., Henderson, Alex, Hodgson, Shirley, Kwong, Ava, Borg, Ake, Kennedy, M. John, Porteous, Mary E., Rogers, Mark T., Side, Lucy E., Snape, Katie, Walker, Lisa, Collée, J. Margriet, Jakubowska, Anna, Couch, Fergus J., Hahnen, Eric, Daly, Mary B., Dennis, Joe, Teo, Soo Hwang, Jensen, Uffe Birk, Rantala, Johanna, Dhawan, Mallika, Benitez, Javier, Domchek, Susan M., Eeles, Ros, Engel, Christoph, Legrand, Clémentine, Evans, D. Gareth, James, Paul A., Feliubadaló i Elorza, Maria Lídia, Teulé-Vega, Àlex, Foretova, Lenka, Castera, Laurent, Friedman, Eitan, Frost, Debra, Rennert, Gad, Ganz, Patricia A., Leslie, Goska, Garber, Judy, Hulick, Peter J., Imyanitov, Evgeny N., Glendon, Gord, Thomassen, Mads, Janavicius, Ramunas, Mulligan, Anna Marie, Hollestelle, Antoinette, Jager, Agnes, Koppert, Linetta B., Cook, Jackie, Koudijs, Marco, Kriege, Mieke, Meijers Heijboer, Hanne E. J., Schmutzler, Rita K., Mensenkamp, Arjen R., Dunning, Alison M., Mooij, Thea M., Oosterwijk, Jan C., Caux Moncoutier, Virginie, Singer, Christian F., Berthet, Pascaline, Caldés, Trinidad, Van den Ouweland, Ans M. W., Van der Baan, Frederieke H., Van der Hout, Annemieke H., Van der Kolk, Lizet E., Van der Luijt, Rob B., Thull, Darcy L., Van Deurzen, Carolien H. M., Sharma, Priyanka, Van Doorn, Helena C., Bignon, Yves Jean, Colas, Chrystelle, Van Engelen, Klaartje, Brewer, Carole, Van Hest, Liselotte P., Van Os, Theo A. M., Caligo, Maria A., Verhoef, Senno, Tischkowitz, Marc, Vogel, Maartje J., Wijnen, Juul T., Lalloo, Fiona, Beesley, Jonathan, Fox, Stephen, Collonge Rame, Marie Agnès, Simard, Jacques, Holland, Helene, Jiao, Yue, John, Esther M., Joseph, Vijai, Gerdes, Anne Marie, Karlan, Beth Y., Lesueur, Fabienne, Loud, Jennifer T., Lubiński, Jan, Manoukian, Siranoush, Mcguffog, Lesley, Miller, Austin, Coupier, Isabelle, Gomes, Denise Molina, Barouk Simonet, Emmanuelle, Montagna, Marco, Miller, Clare, Elan, Camille, Davidson, Rosemarie, Mouret Fourme, Emmanuelle, Gayther, Simon A., Nathanson, Katherine L., Neuhausen, Susan L., Nevanlinna, Heli, Yie, Joanne Ngeow Yuen, Pauw, Antoine de, Olah, Edith, Morrison, Patrick J., Olopade, Olufunmilayo I., Van Asperen, Christi J., Park, Sue K., Parsons, Michael T., Donaldson, Alan, Belotti, Muriel, Peterlongo, Paolo, Stadler, Zsofia, Stoppa Lyonnet, Dominique, Sutter, Christian, Ong, Kai Ren, Delnatte, Capucine, Tan, Yen Yen, Toland, Amanda E., Tung, Nadine, Van Rensburg, Elizabeth J., Vega, Ana, Wappenschmidt, Barbara, Devilee, Peter, Eason, Jacqueline, Chung, Wendy K., Bernstein, Jonine L., Offit, Kenneth, Aalfs, Cora M., Hanson, Helen, Godwin, Andrew K., Easton, Douglas F., Bonadona, Valérie, Rookus, Matti A., Chenevix-Trench, Georgia, Antoniou, Antonis C., O’shaughnessy Kirwan, Aoife, Robson, Mark, Eccles, Diana M., Schmidt, Marjanka K., Adank, Muriel A., Gemo Study Collaborators, Phillips, Kelly Anne, Embrace Collaborators, Ocgn Investigators, Goldgar, David E., Hebon Investigators, Perkins, Jo, Kconfab Investigators, Bressac de Paillerets, Brigitte, Buecher, Bruno, Caputo, Sandrine, Ausems, Margreet G. E. M., Gregory, Helen, Caron, Olivier, Faivre, Laurence, Fert Ferrer, Sandra, Gauthier Villars, Marion, Radice, Paolo, Gesta, Paul, Clinical Genetics, Medical Oncology, Surgery, Pathology, Gynecological Oncology, Schmidt, Marjanka K. [0000-0002-2228-429X], Apollo - University of Cambridge Repository, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Schmidt, Marjanka K [0000-0002-2228-429X], HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Institut Català de la Salut, [Lakeman IMM] Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. [van den Broek AJ, Vos JAM] Division of Molecular Pathology, The Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. [Barnes DR] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. [Adlard J] Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK. [Andrulis IL] Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. [Balmaña J] Hereditary cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, Pediatric surgery, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, CCA - Cancer biology and immunology, Epidemiology and Data Science, Human Genetics, ARD - Amsterdam Reproduction and Development, APH - Personalized Medicine, APH - Quality of Care, Chapel Allerton Hospital, University of Leeds, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto-Cancer Care Ontario, Reykjavík University, Division of Oncology, Department of Gynaecology and Obstetrics, University Hospital Schleswig–Holstein, The University of Texas M.D. Anderson Cancer Center [Houston], Unitat d'Alt Risc i Prevenció del Càncer, Vall d'Hebron University Hospital [Barcelona], University of Cambridge [UK] (CAM), Group of Human Genetics, Human Cancer Genetics Programme, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Department of Oncology, Clinical Sciences, Lund University [Lund]-Skåne University Hospital, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Section of Genetic Oncology, University of Pisa - Università di Pisa, Columbia University [New York], Ghent University Hospital, Department of Clinical Genetics, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Department of Laboratory Medicine and Pathology, Mayo Clinic, Division of Population Science, Fox Chase Cancer Center, Institut Curie [Paris], Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL), CHU Grenoble, CHI Poissy-Saint-Germain, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA KG Polikliniek (9), and Klinische Genetica

Subjects
0301 basic medicine, Percentile, Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Susceptibility::Genetic Predisposition to Disease [DISEASES], Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], SUSCEPTIBILITY ALLELES, Diàtesi, FAMILIES, Tumours of the digestive tract Radboud Institute for Health Sciences [Radboudumc 14], MESH: BRCA2 Protein, Breast cancer, 0302 clinical medicine, MESH: Risk Factors, Risk Factors, Other subheadings::/diagnosis [Other subheadings], Medicine and Health Sciences, Medicine, Mama - Càncer - Diagnòstic, Family history, skin and connective tissue diseases, Genetics (clinical), MESH: Heterozygote, neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Factors de risc en les malalties, BRCA1 Protein, Hazard ratio, MESH: Genetic Predisposition to Disease, 1184 Genetics, developmental biology, physiology, article, OVARIAN, BRCA2 Protein/genetics, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, 030220 oncology & carcinogenesis, Female, Malalties congènites, Adult, Heterozygote, medicine.medical_specialty, MESH: Mutation, Risk factors in diseases, Otros calificadores::/diagnóstico [Otros calificadores], Breast Neoplasms, Context (language use), MUTATION CARRIERS, Càncer de mama, afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::susceptibilidad a enfermedades::predisposición genética a la enfermedad [ENFERMEDADES], 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Humans, Genetic Predisposition to Disease, MESH: BRCA1 Protein, Retrospective Studies, BRCA2 Protein, MESH: Humans, business.industry, Proportional hazards model, CONSORTIUM, Breast Neoplasms/diagnosis, MESH: Adult, MESH: Retrospective Studies, Retrospective cohort study, medicine.disease, Confidence interval, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, BRCA1 Protein/genetics, 3111 Biomedicine, business, MESH: Female, MESH: Breast Neoplasms
Abstract

Predicció de risc de càncer de mama; Dones europees; Variant patògena heterozigota Predicción del riesgo de cáncer de mama; Mujeres europeas; Variante patógena heterocigota Breast cancer risk prediction; European women; Heterozygous pathogenic variant Purpose To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC

Published
2021

49. Transcriptional comparison of testicular adrenal rest tumors with fetal and adult tissues

Author

Schröder, Mariska A M, primary, Sweep, Fred C G J, additional, van Herwaarden, Antonius E, additional, Mitchell, Rod T, additional, Eliveld, Jitske, additional, van Pelt, Ans M M, additional, Rowan, Alan E, additional, Korbie, Darren, additional, Stikkelbroeck, Nike M M L, additional, Claahsen-van der Grinten, Hedi L, additional, and Span, Paul N, additional

Published
2022
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