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2. Physical activity and Mediterranean diet as potential modulators of osteoprotegerin and soluble RANKL in gBRCA1/2 mutation carriers: results of the lifestyle intervention pilot study LIBRE-1

Author

Neirich, Leonie, Yahiaoui-Doktor, Maryam, Lammert, Jacqueline, Basrai, Maryam, Seethaler, Benjamin, Berling-Ernst, Anika, Ramser, Juliane, Quante, Anne S., Schmidt, Thorsten, Niederberger, Uwe, Rhiem, Kerstin, Schmutzler, Rita, Engel, Christoph, Bischoff, Stephan C., Halle, Martin, Kiechle, Marion, and Grill, Sabine

Published
2021
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9. Data from Epidemiologic Risk Factors in a Comparison of a Barrett Esophagus Registry (BarrettNET) and a Case–Control Population in Germany

Author

Schmidt, Melissa, primary, Ankerst, Donna P., primary, Chen, Yiyao, primary, Wiethaler, Maria, primary, Slotta-Huspenina, Julia, primary, Becker, Karl-Friedrich, primary, Horstmann, Julia, primary, Kohlmayer, Florian, primary, Lehmann, Andreas, primary, Linkohr, Birgit, primary, Strauch, Konstantin, primary, Schmid, Roland M., primary, Quante, Anne S., primary, and Quante, Michael, primary

Published
2023
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14. Supplemental Table 1 from Epidemiologic Risk Factors in a Comparison of a Barrett Esophagus Registry (BarrettNET) and a Case–Control Population in Germany

Author

Schmidt, Melissa, primary, Ankerst, Donna P., primary, Chen, Yiyao, primary, Wiethaler, Maria, primary, Slotta-Huspenina, Julia, primary, Becker, Karl-Friedrich, primary, Horstmann, Julia, primary, Kohlmayer, Florian, primary, Lehmann, Andreas, primary, Linkohr, Birgit, primary, Strauch, Konstantin, primary, Schmid, Roland M., primary, Quante, Anne S., primary, and Quante, Michael, primary

Published
2023
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15. Umstrukturierung der Risikoberechnung für die intensivierte Früherkennung im Deutschen Konsortium für Brust- und Eierstockkrebs

Author

Quante, Anne S., Engel, Christoph, Kiechle, Marion, Schmutzler, Rita K., and Fischer, Christine

Abstract

Brustkrebs ist die häufigste Krebserkrankung bei Frauen. Bei etwa 30 % der Betroffenen liegt eine familiäre Belastung entsprechend der Einschlusskriterien des Deutschen Konsortiums (DK) Familiärer Brust- und Eierstockkrebs vor. Frauen aus diesen Familien, bei denen eine Mutation in einem der bekannten Krebsgene nachgewiesen wird, erhalten u. a. das Angebot der Teilnahme am intensivierten Nachsorge- bzw. Früherkennungsprogramm (INFP). Wird in einer Familie allerdings keine Veränderung gefunden, basiert das Angebot auf einer Risikoberechnung. Erste Ergebnisse des DK legen es nahe, das INFP effizienter zu gestalten und diese Strategie weiter wissenschaftlich auszuwerten. Bisher wurde im DK das Risikoberechnungsprogramm Cyrillic verwendet. Da Cyrillic inhaltlich und technisch jedoch überholt ist, wird das DK die Risikoberechnung auf das Programm BOADICEA umstellen. BOADICEA wurde aus folgenden Gründen ausgewählt: (i) Es ist wissenschaftlich auf dem aktuellsten Stand, (ii) es liefert genauere Risikoberechnungen unter Einbezug neuer Risikogene und (iii) es wurde anhand von Daten des DK und weiterer Populationen entwickelt und validiert. Die Veränderung des Risikoberechnungsverfahrens beinhaltet, dass für die betroffenen Frauen abweichende Brustkrebsrisiken errechnet werden. Daher müssen neue Regeln zur Risikoklassifikation definiert werden, um die Effizienz des bisherigen INFP zu prüfen und ggf. weiter zu steigern.

Published
2024
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16. NCALD as a potential predictive biomarker for the efficacy of platinum-based chemotherapy in ovarian cancer

Author

Konrad, Sarah M, primary, Schwamborn, Kristina, additional, Krüger, Achim, additional, Honert, Katja, additional, Schmitt, Manfred, additional, Hellmann, Daniela, additional, Schmalfeldt, Barbara, additional, Meindl, Alfons, additional, Kiechle, Marion, additional, Quante, Anne S, additional, Brambs, Christine, additional, Grill, Sabine, additional, and Ramser, Juliane, additional

Published
2022
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19. Effects of Metformin on Metabolite Profiles and LDL Cholesterol in Patients With Type 2 Diabetes

Author

Xu, Tao, Brandmaier, Stefan, Messias, Ana C., Herder, Christian, Draisma, Harmen H.M., Demirkan, Ayse, Yu, Zhonghao, Ried, Janina S., Haller, Toomas, Heier, Margit, Campillos, Monica, Fobo, Gisela, Stark, Renee, Holzapfel, Christina, Adam, Jonathan, Chi, Shen, Rotter, Markus, Panni, Tommaso, Quante, Anne S., He, Ying, Prehn, Cornelia, Roemisch-Margl, Werner, Kastenmüller, Gabi, Willemsen, Gonneke, Pool, René, Kasa, Katarina, van Dijk, Ko Willems, Hankemeier, Thomas, Meisinger, Christa, Thorand, Barbara, Ruepp, Andreas, Hrabé de Angelis, Martin, Li, Yixue, Wichmann, H.-Erich, Stratmann, Bernd, Strauch, Konstantin, Metspalu, Andres, Gieger, Christian, Suhre, Karsten, Adamski, Jerzy, Illig, Thomas, Rathmann, Wolfgang, Roden, Michael, Peters, Annette, van Duijn, Cornelia M., Boomsma, Dorret I., Meitinger, Thomas, and Wang-Sattler, Rui

Published
2015
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21. Breast cancer risk inBRCA1/2mutation carriers and noncarriers under prospective intensified surveillance

Author

Engel, Christoph, Fischer, Christine, Zachariae, Silke, Bucksch, Karolin, Rhiem, Kerstin, Giesecke, Jutta, Herold, Natalie, Wappenschmidt, Barbara, Huebbel, Verena, Maringa, Monika, Reichstein-Gnielinski, Simone, Hahnen, Eric, Bartram, Claus R., Dikow, Nicola, Schott, Sarah, Speiser, Dorothee, Horn, Denise, Fallenberg, Eva M., Kiechle, Marion, Quante, Anne S., Vesper, Anne-Sophie, Fehm, Tanja, Mundhenke, Christoph, Arnold, Norbert, Leinert, Elena, Just, Walter, Siebers-Renelt, Ulrike, Weigel, Stefanie, Gehrig, Andrea, Woeckel, Achim, Schlegelberger, Brigitte, Pertschy, Stefanie, Kast, Karin, Wimberger, Pauline, Briest, Susanne, Loeffler, Markus, Bick, Ulrich, Schmutzler, Rita K., Engel, Christoph, Fischer, Christine, Zachariae, Silke, Bucksch, Karolin, Rhiem, Kerstin, Giesecke, Jutta, Herold, Natalie, Wappenschmidt, Barbara, Huebbel, Verena, Maringa, Monika, Reichstein-Gnielinski, Simone, Hahnen, Eric, Bartram, Claus R., Dikow, Nicola, Schott, Sarah, Speiser, Dorothee, Horn, Denise, Fallenberg, Eva M., Kiechle, Marion, Quante, Anne S., Vesper, Anne-Sophie, Fehm, Tanja, Mundhenke, Christoph, Arnold, Norbert, Leinert, Elena, Just, Walter, Siebers-Renelt, Ulrike, Weigel, Stefanie, Gehrig, Andrea, Woeckel, Achim, Schlegelberger, Brigitte, Pertschy, Stefanie, Kast, Karin, Wimberger, Pauline, Briest, Susanne, Loeffler, Markus, Bick, Ulrich, and Schmutzler, Rita K.

Abstract

Comparably little is known about breast cancer (BC) risks in women from families tested negative forBRCA1/2mutations despite an indicative family history, as opposed toBRCA1/2mutation carriers. We determined the age-dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers ofBRCA1/2mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n= 4,380; 16,398 person-years [PY], median baseline age: 39 years) and CBC (n= 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8-70.9%) forBRCA1mutation carriers, 43.2% (95% CI 32.1-56.3%) forBRCA2mutation carriers and 15.7% (95% CI 11.9-20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9-29.8) forBRCA1mutation carriers, 13.5 (95% CI 9.2-19.1) forBRCA2mutation carriers and 4.9 (95% CI 3.8-6.3) forBRCA1/2noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6-31.9%) forBRCA1mutation carriers, 6.6% (95% CI 3.4-12.5%) forBRCA2mutation carriers and 3.6% (95% CI 2.2-5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women fromBRCA1/2negative families with elevated risk.

Published
2020

22. Changes in risk calculation for the intensified surveillance programme of the German Consortium for Breast and Ovarian Cancer

Author

Quante, Anne S., Engel, Christoph, Kiechle, Marion, Schmutzler, Rita K., Fischer, Christine, Quante, Anne S., Engel, Christoph, Kiechle, Marion, Schmutzler, Rita K., and Fischer, Christine

Abstract

Breast cancer is the most common cancer in women. About 30% of breast cancer patients have a family history of breast cancer and fulfil the inclusion criteria of the German Consortium (DK) Familial Breast and Ovarian Cancer. Women from these families in whom a mutation in one of the known cancer genes is detected are offered, among other things, the opportunity to participate in the intensified surveillance programme (INFP). However, if no mutation is found in a family, the decision to recommend intensified surveillance is based on the calculated risk. Preliminary results of the DK suggest that there is a need to improve the efficiency of the INFP and to continue the evaluation. So far, the risk calculation program Cyrillic has been used by the DK. However, as Cyrillic is outdated in terms of content and technology, DK will use the BOADICEA program in the future. BOADICEA was chosen for the following reasons: (i) it is scientifically up to date, (ii) it provides more accurate risk calculations taking into account new risk genes and (iii) it has been developed and validated using data from the DK and other populations. The change in the risk calculation procedure implies that different breast cancer risks are calculated for the women concerned. Therefore, new rules for risk classification have to be defined in order to improve the efficiency of the current INFP.

Published
2020

23. Mammography Screening 2.0 – How Can Risk-Adapted Screening be Implemented in Clinical Practice?

Author

Fürst, Nicole, Kiechle, Marion, Strahwald, Brigitte, and Quante, Anne S.

Subjects
participatory decision-making, breast cancer risk, mammography screening, Mammografie-Screening, partizipative Entscheidungsfindung, focus group, Original Article/Originalarbeit, GebFra Science, Fokusgruppe, risikoadaptiertes Screening, Brustkrebsrisiko, risk-adapted screening
Abstract

Introduction The mammography screening programme has been the subject of criticism for some time. Invitation to take part is currently based only on the risk factors of age and female sex, whereby women with an above-average risk are screened too seldom and women with a low risk are possibly screened too often. In future, an individualised risk assessment could make a risk-adapted procedure possible in breast cancer screening. In the RISIKOLOTSE.DE project, schemes are devised to calculate the individual breast cancer risk and evaluate the results. The aim is to assist doctors and screening participants in participatory decision-making. To gauge the baseline situation in the target groups, qualitative and quantitative surveys were conducted. Method At the start of the project, a guideline-based focus group discussion was held with 15 doctors and representatives of the public health service. The transcript of this discussion was evaluated by means of a qualitative content analysis. Results The participants assessed the concept of risk-adapted screening positively overall. At the same time, the majority of them were of the opinion that the results of individualised risk calculation can be understood and evaluated adequately only by doctors. The great communication requirement and lack of remuneration were given as practical obstacles to implementation. Discussion The suggestions and new ideas from the focus group ranged from administrative and regulatory changes to new forms of counselling and adaptable practice aids. An important indicator for the RISIKOLOTSE.DE conception and for planning future surveys was that risk calculation for mammography screening 2.0 was regarded as a purely medical function and that the concept of participatory decision-making played hardly any part in the discussion.

Published
2018

24. PALLD mutation in a European family conveys a stromal predisposition for familial pancreatic cancer

Author

Liotta, Lucia, primary, Lange, Sebastian, additional, Maurer, H. Carlo, additional, Olive, Kenneth P., additional, Braren, Rickmer, additional, Pfarr, Nicole, additional, Burger, Sebastian, additional, Muckenhuber, Alexander, additional, Jesinghaus, Moritz, additional, Steiger, Katja, additional, Weichert, Wilko, additional, Friess, Helmut, additional, Schmid, Roland, additional, Algül, Hana, additional, Jost, Philipp J., additional, Ramser, Juliane, additional, Fischer, Christine, additional, Quante, Anne S., additional, Reichert, Maximilian, additional, and Quante, Michael, additional

Published
2021
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26. Performance of Breast Cancer Polygenic Risk Scores in 760 FemaleCHEK2Germline Mutation Carriers

Author

Borde, Julika, primary, Ernst, Corinna, additional, Wappenschmidt, Barbara, additional, Niederacher, Dieter, additional, Weber-Lassalle, Konstantin, additional, Schmidt, Gunnar, additional, Hauke, Jan, additional, Quante, Anne S, additional, Weber-Lassalle, Nana, additional, Horváth, Judit, additional, Pohl-Rescigno, Esther, additional, Arnold, Norbert, additional, Rump, Andreas, additional, Gehrig, Andrea, additional, Hentschel, Julia, additional, Faust, Ulrike, additional, Dutrannoy, Véronique, additional, Meindl, Alfons, additional, Kuzyakova, Maria, additional, Wang-Gohrke, Shan, additional, Weber, Bernhard H. F, additional, Sutter, Christian, additional, Volk, Alexander E, additional, Giannakopoulou, Olga, additional, Lee, Andrew, additional, Engel, Christoph, additional, Schmidt, Marjanka K, additional, Antoniou, Antonis C, additional, Schmutzler, Rita K, additional, Kuchenbaecker, Karoline, additional, and Hahnen, Eric, additional

Published
2020
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27. TP53 germline mutations in the context of families with hereditary breast and ovarian cancer: a clinical challenge

Author

Grill, Sabine, primary, Ramser, Juliane, additional, Hellebrand, Heide, additional, Pfarr, Nicole, additional, Boxberg, Melanie, additional, Brambs, Christine, additional, Ditsch, Nina, additional, Meindl, Alfons, additional, Groß, Eva, additional, Meitinger, Thomas, additional, Kiechle, Marion, additional, and Quante, Anne S., additional

Published
2020
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28. Epidemiologic Risk Factors in a Comparison of a Barrett Esophagus Registry (BarrettNET) and a Case–Control Population in Germany

Author

Schmidt, Melissa, primary, Ankerst, Donna P., additional, Chen, Yiyao, additional, Wiethaler, Maria, additional, Slotta-Huspenina, Julia, additional, Becker, Karl-Friedrich, additional, Horstmann, Julia, additional, Kohlmayer, Florian, additional, Lehmann, Andreas, additional, Linkohr, Birgit, additional, Strauch, Konstantin, additional, Schmid, Roland M., additional, Quante, Anne S., additional, and Quante, Michael, additional

Published
2020
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30. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Parsons, Michael T., Tudini, Emma, Li, Hongyan, Hahnen, Eric, Wappenschmidt, Barbara, Feliubadalo, Lidia, Aalfs, Cora M., Agata, Simona, Aittomaki, Kristiina, Alducci, Elisa, Concepcion Alonso-Cerezo, Maria, Arnold, Norbert, Auber, Bernd, Austin, Rachel, Azzollini, Jacopo, Balmana, Judith, Barbieri, Elena, Bartram, Claus R., Blanco, Ana, Bluemcke, Britta, Bonache, Sandra, Bonanni, Bernardo, Borg, Ake, Bortesi, Beatrice, Brunet, Joan, Bruzzone, Carla, Bucksch, Karolin, Cagnoli, Giulia, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Calvello, Mariarosaria, Capone, Gabriele L., Caputo, Sandrine M., Carnevali, Ileana, Carrasco, Estela, Caux-Moncoutier, Virginie, Cavalli, Pietro, Cini, Giulia, Clarke, Edward M., Concolino, Paola, Cops, Elisa J., Cortesi, Laura, Couch, Fergus J., Darder, Esther, de la Hoya, Miguel, Dean, Michael, Debatin, Irmgard, Del Valle, Jesus, Delnatte, Capucine, Derive, Nicolas, Diez, Orland, Ditsch, Nina, Domchek, Susan M., Dutrannoy, Veronique, Eccles, Diana M., Ehrencrona, Hans, Enders, Ute, Evans, D. Gareth, Farra, Chantal, Faust, Ulrike, Felbor, Ute, Feroce, Irene, Fine, Miriam, Foulkes, William D., Galvao, Henrique Cr, Gambino, Gaetana, Gehrig, Andrea, Gensini, Francesca, Gerdes, Anne-Marie, Germani, Aldo, Giesecke, Jutta, Gismondi, Viviana, Gomez, Carolina, Garcia, Encarna B. Gomez, Gonzalez, Sara, Grau, Elia, Grill, Sabine, Gross, Eva, Guerrieri-Gonzaga, Aliana, Guillaud-Bataille, Marine, Gutierrez-Enriquez, Sara, Haaf, Thomas, Hackmann, Karl, Hansen, Thomas Vo, Harris, Marion, Hauke, Jan, Heinrich, Tilman, Hellebrand, Heide, Herold, Karen N., Honisch, Ellen, Horvath, Judit, Houdayer, Claude, Huebbel, Verena, Iglesias, Silvia, Izquierdo, Angel, James, Paul A., Janssen, Linda Am, Jeschke, Udo, Kaulfuss, Silke, Keupp, Katharina, Kiechle, Marion, Koelbl, Alexandra, Krieger, Sophie, Kruse, Torben A., Kvist, Anders, Lalloo, Fiona, Larsen, Mirjam, Lattimore, Vanessa L., Lautrup, Charlotte, Ledig, Susanne, Leinert, Elena, Lewis, Alexandra L., Lim, Joanna, Loeffler, Markus, Lopez-Fernandez, Adria, Lucci-Cordisco, Emanuela, Maass, Nicolai, Manoukian, Siranoush, Marabelli, Monica, Matricardi, Laura, Meindl, Alfons, Michelli, Rodrigo D., Moghadasi, Setareh, Moles-Fernandez, Alejandro, Montagna, Marco, Montalban, Gemma, Monteiro, Alvaro N., Montes, Eva, Mori, Luigi, Moserle, Lidia, Mueller, Clemens R., Mundhenke, Christoph, Naldi, Nadia, Nathanson, Katherine L., Navarro, Matilde, Nevanlinna, Heli, Nichols, Cassandra B., Niederacher, Dieter, Nielsen, Henriette R., Ong, Kai-ren, Pachter, Nicholas, Palmero, Edenir, I, Papi, Laura, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Pfeifer, Katharina, Pineda, Marta, Pohl-Rescigno, Esther, Poplawski, Nicola K., Porfirio, Berardino, Quante, Anne S., Ramser, Juliane, Reis, Rui M., Revillion, Francoise, Rhiem, Kerstin, Riboli, Barbara, Ritter, Julia, Rivera, Daniela, Rofes, Paula, Rump, Andreas, Salinas, Monica, Sanchez de Abajo, Ana Maria, Schmidt, Gunnar, Schoenwiese, Ulrike, Seggewiss, Jochen, Solanes, Ares, Steinemann, Doris, Stiller, Mathias, Stoppa-Lyonnet, Dominique, Sullivan, Kelly J., Susman, Rachel, Sutter, Christian, Tavtigian, Sean, V, Teo, Soo H., Teule, Alex, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Tornero, Eva, Torngren, Therese, Torres-Esquius, Sara, Toss, Angela, Trainer, Alison H., Tucker, Katherine M., van Asperen, Christi J., van Mackelenbergh, Marion T., Varesco, Liliana, Vargas-Parra, Gardenia, Varon, Raymonda, Vega, Ana, Velasco, Angela, Vesper, Anne-Sophie, Viel, Alessandra, Vreeswijk, Maaike P. G., Wagner, Sebastian A., Waha, Anke, Walker, Logan C., Walters, Rhiannon J., Wang-Gohrke, Shan, Weber, Bernhard H. F., Weichert, Wilko, Wieland, Kerstin, Wiesmueller, Lisa, Witzel, Isabell, Woeckel, Achim, Woodward, Emma R., Zachariae, Silke, Zampiga, Valentina, Zeder-Goss, Christine, Lazaro, Conxi, De Nicolo, Arcangela, Radice, Paolo, Engel, Christoph, Schmutzler, Rita K., Goldgar, David E., Spurdle, Amanda B., Parsons, Michael T., Tudini, Emma, Li, Hongyan, Hahnen, Eric, Wappenschmidt, Barbara, Feliubadalo, Lidia, Aalfs, Cora M., Agata, Simona, Aittomaki, Kristiina, Alducci, Elisa, Concepcion Alonso-Cerezo, Maria, Arnold, Norbert, Auber, Bernd, Austin, Rachel, Azzollini, Jacopo, Balmana, Judith, Barbieri, Elena, Bartram, Claus R., Blanco, Ana, Bluemcke, Britta, Bonache, Sandra, Bonanni, Bernardo, Borg, Ake, Bortesi, Beatrice, Brunet, Joan, Bruzzone, Carla, Bucksch, Karolin, Cagnoli, Giulia, Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Calvello, Mariarosaria, Capone, Gabriele L., Caputo, Sandrine M., Carnevali, Ileana, Carrasco, Estela, Caux-Moncoutier, Virginie, Cavalli, Pietro, Cini, Giulia, Clarke, Edward M., Concolino, Paola, Cops, Elisa J., Cortesi, Laura, Couch, Fergus J., Darder, Esther, de la Hoya, Miguel, Dean, Michael, Debatin, Irmgard, Del Valle, Jesus, Delnatte, Capucine, Derive, Nicolas, Diez, Orland, Ditsch, Nina, Domchek, Susan M., Dutrannoy, Veronique, Eccles, Diana M., Ehrencrona, Hans, Enders, Ute, Evans, D. Gareth, Farra, Chantal, Faust, Ulrike, Felbor, Ute, Feroce, Irene, Fine, Miriam, Foulkes, William D., Galvao, Henrique Cr, Gambino, Gaetana, Gehrig, Andrea, Gensini, Francesca, Gerdes, Anne-Marie, Germani, Aldo, Giesecke, Jutta, Gismondi, Viviana, Gomez, Carolina, Garcia, Encarna B. Gomez, Gonzalez, Sara, Grau, Elia, Grill, Sabine, Gross, Eva, Guerrieri-Gonzaga, Aliana, Guillaud-Bataille, Marine, Gutierrez-Enriquez, Sara, Haaf, Thomas, Hackmann, Karl, Hansen, Thomas Vo, Harris, Marion, Hauke, Jan, Heinrich, Tilman, Hellebrand, Heide, Herold, Karen N., Honisch, Ellen, Horvath, Judit, Houdayer, Claude, Huebbel, Verena, Iglesias, Silvia, Izquierdo, Angel, James, Paul A., Janssen, Linda Am, Jeschke, Udo, Kaulfuss, Silke, Keupp, Katharina, Kiechle, Marion, Koelbl, Alexandra, Krieger, Sophie, Kruse, Torben A., Kvist, Anders, Lalloo, Fiona, Larsen, Mirjam, Lattimore, Vanessa L., Lautrup, Charlotte, Ledig, Susanne, Leinert, Elena, Lewis, Alexandra L., Lim, Joanna, Loeffler, Markus, Lopez-Fernandez, Adria, Lucci-Cordisco, Emanuela, Maass, Nicolai, Manoukian, Siranoush, Marabelli, Monica, Matricardi, Laura, Meindl, Alfons, Michelli, Rodrigo D., Moghadasi, Setareh, Moles-Fernandez, Alejandro, Montagna, Marco, Montalban, Gemma, Monteiro, Alvaro N., Montes, Eva, Mori, Luigi, Moserle, Lidia, Mueller, Clemens R., Mundhenke, Christoph, Naldi, Nadia, Nathanson, Katherine L., Navarro, Matilde, Nevanlinna, Heli, Nichols, Cassandra B., Niederacher, Dieter, Nielsen, Henriette R., Ong, Kai-ren, Pachter, Nicholas, Palmero, Edenir, I, Papi, Laura, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Pfeifer, Katharina, Pineda, Marta, Pohl-Rescigno, Esther, Poplawski, Nicola K., Porfirio, Berardino, Quante, Anne S., Ramser, Juliane, Reis, Rui M., Revillion, Francoise, Rhiem, Kerstin, Riboli, Barbara, Ritter, Julia, Rivera, Daniela, Rofes, Paula, Rump, Andreas, Salinas, Monica, Sanchez de Abajo, Ana Maria, Schmidt, Gunnar, Schoenwiese, Ulrike, Seggewiss, Jochen, Solanes, Ares, Steinemann, Doris, Stiller, Mathias, Stoppa-Lyonnet, Dominique, Sullivan, Kelly J., Susman, Rachel, Sutter, Christian, Tavtigian, Sean, V, Teo, Soo H., Teule, Alex, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E., Tornero, Eva, Torngren, Therese, Torres-Esquius, Sara, Toss, Angela, Trainer, Alison H., Tucker, Katherine M., van Asperen, Christi J., van Mackelenbergh, Marion T., Varesco, Liliana, Vargas-Parra, Gardenia, Varon, Raymonda, Vega, Ana, Velasco, Angela, Vesper, Anne-Sophie, Viel, Alessandra, Vreeswijk, Maaike P. G., Wagner, Sebastian A., Waha, Anke, Walker, Logan C., Walters, Rhiannon J., Wang-Gohrke, Shan, Weber, Bernhard H. F., Weichert, Wilko, Wieland, Kerstin, Wiesmueller, Lisa, Witzel, Isabell, Woeckel, Achim, Woodward, Emma R., Zachariae, Silke, Zampiga, Valentina, Zeder-Goss, Christine, Lazaro, Conxi, De Nicolo, Arcangela, Radice, Paolo, Engel, Christoph, Schmutzler, Rita K., Goldgar, David E., and Spurdle, Amanda B.

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Published
2019

31. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., Lucci Cordisco E. (ORCID:0000-0002-6279-7604), Parsons, M. T., Tudini, E., Li, H., Hahnen, E., Wappenschmidt, B., Feliubadalo, L., Aalfs, C. M., Agata, S., Aittomaki, K., Alducci, E., Alonso-Cerezo, M. C., Arnold, N., Auber, B., Austin, R., Azzollini, J., Balmana, J., Barbieri, E., Bartram, C. R., Blanco, A., Blumcke, B., Bonache, S., Bonanni, B., Borg, A., Bortesi, B., Brunet, J., Bruzzone, C., Bucksch, K., Cagnoli, G., Caldes, T., Caliebe, A., Caligo, M. A., Calvello, M., Capone, G. L., Caputo, S. M., Carnevali, I., Carrasco, E., Caux-Moncoutier, V., Cavalli, P., Cini, G., Clarke, E. M., Concolino, Paola, Cops, E. J., Cortesi, L., Couch, F. J., Darder, E., de la Hoya, M., Dean, M., Debatin, I., Del Valle, J., Delnatte, C., Derive, N., Diez, O., Ditsch, N., Domchek, S. M., Dutrannoy, V., Eccles, D. M., Ehrencrona, H., Enders, U., Evans, D. G., Farra, C., Faust, U., Felbor, U., Feroce, I., Fine, M., Foulkes, W. D., Galvao, H. C. R., Gambino, G., Gehrig, A., Gensini, F., Gerdes, A. -M., Germani, A., Giesecke, J., Gismondi, V., Gomez, C., Gomez Garcia, E. B., Gonzalez, S., Grau, E., Grill, S., Gross, E., Guerrieri-Gonzaga, A., Guillaud-Bataille, M., Gutierrez-Enriquez, S., Haaf, T., Hackmann, K., Hansen, T. V. O., Harris, M., Hauke, J., Heinrich, T., Hellebrand, H., Herold, K. N., Honisch, E., Horvath, J., Houdayer, C., Hubbel, V., Iglesias, S., Izquierdo, A., James, P. A., Janssen, L. A. M., Jeschke, U., Kaulfuss, S., Keupp, K., Kiechle, M., Kolbl, A., Krieger, S., Kruse, T. A., Kvist, A., Lalloo, F., Larsen, M., Lattimore, V. L., Lautrup, C., Ledig, S., Leinert, E., Lewis, A. L., Lim, J., Loeffler, M., Lopez-Fernandez, A., Lucci Cordisco, Emanuela, Maass, N., Manoukian, S., Marabelli, M., Matricardi, L., Meindl, A., Michelli, R. D., Moghadasi, S., Moles-Fernandez, A., Montagna, M., Montalban, G., Monteiro, A. N., Montes, E., Mori, L., Moserle, L., Muller, C. R., Mundhenke, C., Naldi, N., Nathanson, K. L., Navarro, M., Nevanlinna, H., Nichols, C. B., Niederacher, D., Nielsen, H. R., Ong, K. -R., Pachter, N., Palmero, E. I., Papi, L., Pedersen, I. S., Peissel, B., Perez-Segura, P., Pfeifer, K., Pineda, M., Pohl-Rescigno, E., Poplawski, N. K., Porfirio, B., Quante, A. S., Ramser, J., Reis, R. M., Revillion, F., Rhiem, K., Riboli, B., Ritter, J., Rivera, D., Rofes, P., Rump, A., Salinas, M., Sanchez de Abajo, A. M., Schmidt, G., Schoenwiese, U., Seggewiss, J., Solanes, A., Steinemann, D., Stiller, M., Stoppa-Lyonnet, D., Sullivan, K. J., Susman, R., Sutter, C., Tavtigian, S. V., Teo, S. H., Teule, A., Thomassen, M., Tibiletti, M. G., Tischkowitz, M., Tognazzo, S., Toland, A. E., Tornero, E., Torngren, T., Torres-Esquius, S., Toss, A., Trainer, A. H., Tucker, K. M., van Asperen, C. J., van Mackelenbergh, M. T., Varesco, L., Vargas-Parra, G., Varon, R., Vega, A., Velasco, A., Vesper, A. -S., Viel, A., Vreeswijk, M. P. G., Wagner, S. A., Waha, A., Walker, L. C., Walters, R. J., Wang-Gohrke, S., Weber, B. H. F., Weichert, W., Wieland, K., Wiesmuller, L., Witzel, I., Wockel, A., Woodward, E. R., Zachariae, S., Zampiga, V., Zeder-Goss, C., Investigators, K., Lazaro, C., De Nicolo, A., Radice, P., Engel, C., Schmutzler, R. K., Goldgar, D. E., Spurdle, A. B., Concolino P., and Lucci Cordisco E. (ORCID:0000-0002-6279-7604)

Abstract

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Published
2019

32. Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers.

Author

Borde, Julika, Ernst, Corinna, Wappenschmidt, Barbara, Niederacher, Dieter, Weber-Lassalle, Konstantin, Schmidt, Gunnar, Hauke, Jan, Quante, Anne S, Weber-Lassalle, Nana, Horváth, Judit, Pohl-Rescigno, Esther, Arnold, Norbert, Rump, Andreas, Gehrig, Andrea, Hentschel, Julia, Faust, Ulrike, Dutrannoy, Véronique, Meindl, Alfons, Kuzyakova, Maria, and Wang-Gohrke, Shan

Subjects
DISEASE risk factors, GENOME-wide association studies, SINGLE nucleotide polymorphisms, BREAST cancer, GERM cells, PROTEIN kinases, GENETIC mutation, SEQUENCE analysis, DISEASE susceptibility, RESEARCH funding, BREAST tumors
Abstract

Background: Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2.Methods: A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided.Results: Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26).Conclusions: PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition. [ABSTRACT FROM AUTHOR]

Published
2021
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33. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Author

Parsons, Michael T., primary, Tudini, Emma, additional, Li, Hongyan, additional, Hahnen, Eric, additional, Wappenschmidt, Barbara, additional, Feliubadaló, Lidia, additional, Aalfs, Cora M., additional, Agata, Simona, additional, Aittomäki, Kristiina, additional, Alducci, Elisa, additional, Alonso‐Cerezo, María Concepción, additional, Arnold, Norbert, additional, Auber, Bernd, additional, Austin, Rachel, additional, Azzollini, Jacopo, additional, Balmaña, Judith, additional, Barbieri, Elena, additional, Bartram, Claus R., additional, Blanco, Ana, additional, Blümcke, Britta, additional, Bonache, Sandra, additional, Bonanni, Bernardo, additional, Borg, Åke, additional, Bortesi, Beatrice, additional, Brunet, Joan, additional, Bruzzone, Carla, additional, Bucksch, Karolin, additional, Cagnoli, Giulia, additional, Caldés, Trinidad, additional, Caliebe, Almuth, additional, Caligo, Maria A., additional, Calvello, Mariarosaria, additional, Capone, Gabriele L., additional, Caputo, Sandrine M., additional, Carnevali, Ileana, additional, Carrasco, Estela, additional, Caux‐Moncoutier, Virginie, additional, Cavalli, Pietro, additional, Cini, Giulia, additional, Clarke, Edward M., additional, Concolino, Paola, additional, Cops, Elisa J., additional, Cortesi, Laura, additional, Couch, Fergus J., additional, Darder, Esther, additional, Hoya, Miguel, additional, Dean, Michael, additional, Debatin, Irmgard, additional, Del Valle, Jesús, additional, Delnatte, Capucine, additional, Derive, Nicolas, additional, Diez, Orland, additional, Ditsch, Nina, additional, Domchek, Susan M., additional, Dutrannoy, Véronique, additional, Eccles, Diana M., additional, Ehrencrona, Hans, additional, Enders, Ute, additional, Evans, D. Gareth, additional, Farra, Chantal, additional, Faust, Ulrike, additional, Felbor, Ute, additional, Feroce, Irene, additional, Fine, Miriam, additional, Foulkes, William D., additional, Galvao, Henrique C.R., additional, Gambino, Gaetana, additional, Gehrig, Andrea, additional, Gensini, Francesca, additional, Gerdes, Anne‐Marie, additional, Germani, Aldo, additional, Giesecke, Jutta, additional, Gismondi, Viviana, additional, Gómez, Carolina, additional, Garcia, Encarna B., additional, González, Sara, additional, Grau, Elia, additional, Grill, Sabine, additional, Gross, Eva, additional, Guerrieri‐Gonzaga, Aliana, additional, Guillaud‐Bataille, Marine, additional, Gutiérrez‐Enríquez, Sara, additional, Haaf, Thomas, additional, Hackmann, Karl, additional, Hansen, Thomas V.O., additional, Harris, Marion, additional, Hauke, Jan, additional, Heinrich, Tilman, additional, Hellebrand, Heide, additional, Herold, Karen N., additional, Honisch, Ellen, additional, Horvath, Judit, additional, Houdayer, Claude, additional, Hübbel, Verena, additional, Iglesias, Silvia, additional, Izquierdo, Angel, additional, James, Paul A., additional, Janssen, Linda A.M., additional, Jeschke, Udo, additional, Kaulfuß, Silke, additional, Keupp, Katharina, additional, Kiechle, Marion, additional, Kölbl, Alexandra, additional, Krieger, Sophie, additional, Kruse, Torben A., additional, Kvist, Anders, additional, Lalloo, Fiona, additional, Larsen, Mirjam, additional, Lattimore, Vanessa L., additional, Lautrup, Charlotte, additional, Ledig, Susanne, additional, Leinert, Elena, additional, Lewis, Alexandra L., additional, Lim, Joanna, additional, Loeffler, Markus, additional, López‐Fernández, Adrià, additional, Lucci‐Cordisco, Emanuela, additional, Maass, Nicolai, additional, Manoukian, Siranoush, additional, Marabelli, Monica, additional, Matricardi, Laura, additional, Meindl, Alfons, additional, Michelli, Rodrigo D., additional, Moghadasi, Setareh, additional, Moles‐Fernández, Alejandro, additional, Montagna, Marco, additional, Montalban, Gemma, additional, Monteiro, Alvaro N., additional, Montes, Eva, additional, Mori, Luigi, additional, Moserle, Lidia, additional, Müller, Clemens R., additional, Mundhenke, Christoph, additional, Naldi, Nadia, additional, Nathanson, Katherine L., additional, Navarro, Matilde, additional, Nevanlinna, Heli, additional, Nichols, Cassandra B., additional, Niederacher, Dieter, additional, Nielsen, Henriette R., additional, Ong, Kai‐ren, additional, Pachter, Nicholas, additional, Palmero, Edenir I., additional, Papi, Laura, additional, Pedersen, Inge Sokilde, additional, Peissel, Bernard, additional, Perez‐Segura, Pedro, additional, Pfeifer, Katharina, additional, Pineda, Marta, additional, Pohl‐Rescigno, Esther, additional, Poplawski, Nicola K., additional, Porfirio, Berardino, additional, Quante, Anne S., additional, Ramser, Juliane, additional, Reis, Rui M., additional, Revillion, Françoise, additional, Rhiem, Kerstin, additional, Riboli, Barbara, additional, Ritter, Julia, additional, Rivera, Daniela, additional, Rofes, Paula, additional, Rump, Andreas, additional, Salinas, Monica, additional, Sánchez de Abajo, Ana María, additional, Schmidt, Gunnar, additional, Schoenwiese, Ulrike, additional, Seggewiß, Jochen, additional, Solanes, Ares, additional, Steinemann, Doris, additional, Stiller, Mathias, additional, Stoppa‐Lyonnet, Dominique, additional, Sullivan, Kelly J., additional, Susman, Rachel, additional, Sutter, Christian, additional, Tavtigian, Sean V., additional, Teo, Soo H., additional, Teulé, Alex, additional, Thomassen, Mads, additional, Tibiletti, Maria Grazia, additional, Tischkowitz, Marc, additional, Tognazzo, Silvia, additional, Toland, Amanda E., additional, Tornero, Eva, additional, Törngren, Therese, additional, Torres‐Esquius, Sara, additional, Toss, Angela, additional, Trainer, Alison H., additional, Tucker, Katherine M., additional, Asperen, Christi J., additional, Mackelenbergh, Marion T., additional, Varesco, Liliana, additional, Vargas‐Parra, Gardenia, additional, Varon, Raymonda, additional, Vega, Ana, additional, Velasco, Ángela, additional, Vesper, Anne‐Sophie, additional, Viel, Alessandra, additional, Vreeswijk, Maaike P. G., additional, Wagner, Sebastian A., additional, Waha, Anke, additional, Walker, Logan C., additional, Walters, Rhiannon J., additional, Wang‐Gohrke, Shan, additional, Weber, Bernhard H. F., additional, Weichert, Wilko, additional, Wieland, Kerstin, additional, Wiesmüller, Lisa, additional, Witzel, Isabell, additional, Wöckel, Achim, additional, Woodward, Emma R., additional, Zachariae, Silke, additional, Zampiga, Valentina, additional, Zeder‐Göß, Christine, additional, Investigators, KConFab, additional, Lázaro, Conxi, additional, Nicolo, Arcangela, additional, Radice, Paolo, additional, Engel, Christoph, additional, Schmutzler, Rita K., additional, Goldgar, David E., additional, and Spurdle, Amanda B., additional

Published
2019
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35. Modifying effect of metabotype on diet–diabetes associations

Author

Riedl, Anna, primary, Wawro, Nina, additional, Gieger, Christian, additional, Meisinger, Christa, additional, Peters, Annette, additional, Rathmann, Wolfgang, additional, Koenig, Wolfgang, additional, Strauch, Konstantin, additional, Quante, Anne S., additional, Thorand, Barbara, additional, Huth, Cornelia, additional, Daniel, Hannelore, additional, Hauner, Hans, additional, and Linseisen, Jakob, additional

Published
2019
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36. BarrettNET—a prospective registry for risk estimation of patients with Barrett's esophagus to progress to adenocarcinoma

Author

Wiethaler, Maria, primary, Slotta-Huspenina, Julia, additional, Brandtner, Anna, additional, Horstmann, Julia, additional, Wein, Frederik, additional, Baumeister, Theresa, additional, Radani, Nikole, additional, Gerland, Sophie, additional, Anand, Akanksha, additional, Lange, Sebastian, additional, Schmidt, Melissa, additional, Janssen, Klaus-Peter, additional, Conrad, Anja, additional, Johannes, Widya, additional, Strauch, Konstantin, additional, Quante, Anne S, additional, Linkohr, Birgit, additional, Kuhn, Klaus A, additional, Blaser, Rainer, additional, Lehmann, Andreas, additional, Kohlmayer, Florian, additional, Weichert, Wilko, additional, Schmid, Roland M, additional, Becker, Karl-Friedrich, additional, and Quante, Michael, additional

Published
2019
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37. Breast cancer risk in BRCA1/2 mutation carriers and noncarriers under prospective intensified surveillance.

Author

Engel, Christoph, Fischer, Christine, Zachariae, Silke, Bucksch, Karolin, Rhiem, Kerstin, Giesecke, Jutta, Herold, Natalie, Wappenschmidt, Barbara, Hübbel, Verena, Maringa, Monika, Reichstein‐Gnielinski, Simone, Hahnen, Eric, Bartram, Claus R., Dikow, Nicola, Schott, Sarah, Speiser, Dorothee, Horn, Denise, Fallenberg, Eva M., Kiechle, Marion, and Quante, Anne S.

Subjects
BREAST cancer, BREAST imaging, OVARIAN cancer, HORMONE receptor positive breast cancer, FILAGGRIN
Abstract

Comparably little is known about breast cancer (BC) risks in women from families tested negative for BRCA1/2 mutations despite an indicative family history, as opposed to BRCA1/2 mutation carriers. We determined the age‐dependent risks of first and contralateral breast cancer (FBC, CBC) both in noncarriers and carriers of BRCA1/2 mutations, who participated in an intensified breast imaging surveillance program. The study was conducted between January 1, 2005, and September 30, 2017, at 12 university centers of the German Consortium for Hereditary Breast and Ovarian Cancer. Two cohorts were prospectively followed up for incident FBC (n = 4,380; 16,398 person‐years [PY], median baseline age: 39 years) and CBC (n = 2,993; 10,090 PY, median baseline age: 42 years). Cumulative FBC risk at age 60 was 61.8% (95% CI 52.8–70.9%) for BRCA1 mutation carriers, 43.2% (95% CI 32.1–56.3%) for BRCA2 mutation carriers and 15.7% (95% CI 11.9–20.4%) for noncarriers. FBC risks were significantly higher than in the general population, with incidence rate ratios of 23.9 (95% CI 18.9–29.8) for BRCA1 mutation carriers, 13.5 (95% CI 9.2–19.1) for BRCA2 mutation carriers and 4.9 (95% CI 3.8–6.3) for BRCA1/2 noncarriers. Cumulative CBC risk 10 years after FBC was 25.1% (95% CI 19.6–31.9%) for BRCA1 mutation carriers, 6.6% (95% CI 3.4–12.5%) for BRCA2 mutation carriers and 3.6% (95% CI 2.2–5.7%) for noncarriers. CBC risk in noncarriers was similar to women with unilateral BC from the general population. Further studies are needed to confirm whether less intensified surveillance is justified in women from BRCA1/2 negative families with elevated risk. What's new? Women with a family history of breast cancer often have relatives who test negative for pathogenic BRCA1/2 mutations. Compared to BRCA1/2‐positive women, however, little is known about breast cancer risk among women from BRCA1/2‐negative families. In this study of women with and without BRCA1/2 mutations who participated in a German breast imaging surveillance program between 2005 and 2017, risk of first breast cancer was markedly lower in BRCA1/2‐negative women compared to BRCA1/2 mutation carriers. Relative to the general population, unilateral breast cancer risk was elevated in BRCA1/2‐negative women, while contralateral breast cancer risk was similar between the two groups. [ABSTRACT FROM AUTHOR]

Published
2020
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44. Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes.

Author

Tao Xu, Brandmaier, Stefan, Messias, Ana C., Herder, Christian, Draisma, Harmen H. M., Demirkan, Ayse, Zhonghao Yu, Ried, Janina S., Haller, Toomas, Heier, Margit, Campillos, Monica, Fobo, Gisela, Stark, Renee, Holzapfel, Christina, Adam, Jonathan, Shen Chi, Rotter, Markus, Panni, Tommaso, Quante, Anne S., and Ying He

Abstract

Objective: Metformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin.Research Design and Methods: We analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metformin-associated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways.Results: We found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years' follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target.Conclusions: Our results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Published
2015
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45. Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations

Author

Zenker, M., primary, Lehmann, K., additional, Schulz, A. L., additional, Barth, H., additional, Hansmann, D., additional, Koenig, R., additional, Korinthenberg, R., additional, Kreiss-Nachtsheim, M., additional, Meinecke, P., additional, Morlot, S., additional, Mundlos, S., additional, Quante, A. S, additional, Raskin, S., additional, Schnabel, D., additional, Wehner, L.-E., additional, Kratz, C. P, additional, Horn, D., additional, and Kutsche, K., additional

Published
2006
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46. Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers

Author

Borde, Julika, Ernst, Corinna, Wappenschmidt, Barbara, Niederacher, Dieter, Weber-Lassalle, Konstantin, Schmidt, Gunnar, Hauke, Jan, Quante, Anne S, Weber-Lassalle, Nana, Horváth, Judit, Pohl-Rescigno, Esther, Arnold, Norbert, Rump, Andreas, Gehrig, Andrea, Hentschel, Julia, Faust, Ulrike, Dutrannoy, Véronique, Meindl, Alfons, Kuzyakova, Maria, Wang-Gohrke, Shan, Weber, Bernhard HF, Sutter, Christian, Volk, Alexander E, Giannakopoulou, Olga, Lee, Andrew, Engel, Christoph, Schmidt, Marjanka K, Antoniou, Antonis C, Schmutzler, Rita K, Kuchenbaecker, Karoline, and Hahnen, Eric

Subjects
Checkpoint Kinase 2, Risk Factors, Mutation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Germ-Line Mutation, 3. Good health, Genome-Wide Association Study
Abstract

BACKGROUND: Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2. METHODS: A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided. RESULTS: Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26). CONCLUSIONS: PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.

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