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Cost-effectiveness of different strategies to prevent breast and ovarian cancer in German women with a BRCA 1 or 2 mutation
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Women with a BRCA1 or BRCA2 mutation are at increased risk of developing breast and/or ovarian cancer. This economic modeling study evaluated different preventive interventions for 30-year-old …d women with a confirmed BRCA (1 or 2) mutation. METHODS A Markov model was developed to estimate the costs and benefits [i.e., quality-adjusted life years (QALYs), and life years gained (LYG)] associated with prophylactic bilateral mastectomy (BM), prophylactic bilateral salpingo-oophorectomy (BSO), BM plus BSO, BM plus BSO at age 40, and intensified surveillance. Relevant input data was obtained from a large German database including 5902 women with BRCA 1 or 2, and from the literature. The analysis was performed from the German Statutory Health Insurance (SHI) perspective. In order to assess the robustness of the results, deterministic and probabilistic sensitivity analyses were performed. RESULTS With costs of \text€29,434 and a gain in QALYs of 17.7 (LYG 19.9), BM plus BSO at age 30 was less expensive and more effective than the other strategies, followed by BM plus BSO at age 40. Women who were offered the surveillance strategy had the highest costs at the lowest gain in QALYs/LYS. In the probabilistic sensitivity analysis, the probability of cost-saving was 57% for BM plus BSO. At a WTP of 10,000 \text€ per QALY, the probability of the intervention being cost-effective was 80%. CONCLUSIONS From the SHI perspective, undergoing BM plus immediate BSO should be recommended to BRCA 1 or 2 mutation carriers due to its favorable comparative cost-effectiveness.

Authors: Dirk Müller, Marion Danner, Kerstin Rhiem, Björn Stollenwerk, Christoph Engel, Linda Rasche, Lisa Borsi, Rita Schmutzler, Stephanie Stock

Date Published: 1st Apr 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. … In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67-4.94), CDH1 (OR: 17.04, 95%CI: 3.54-82), CHEK2 (OR: 2.93, 95%CI: 2.29-3.75), PALB2 (OR: 9.53, 95%CI: 6.25-14.51), and TP53 (OR: 7.30, 95%CI: 1.22-43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73-2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors.

Authors: Jan Hauke, Judit Horvath, Eva Groß, Andrea Gehrig, Ellen Honisch, Karl Hackmann, Gunnar Schmidt, Norbert Arnold, Ulrike Faust, Christian Sutter, Julia Hentschel, Shan Wang-Gohrke, Mateja Smogavec, Bernhard H. F. Weber, Nana Weber-Lassalle, Konstantin Weber-Lassalle, Julika Borde, Corinna Ernst, Janine Altmüller, Alexander E. Volk, Holger Thiele, Verena Hübbel, Peter Nürnberg, Katharina Keupp, Beatrix Versmold, Esther Pohl, Christian Kubisch, Sabine Grill, Victoria Paul, Natalie Herold, Nadine Lichey, Kerstin Rhiem, Nina Ditsch, Christian Ruckert, Barbara Wappenschmidt, Bernd Auber, Andreas Rump, Dieter Niederacher, Thomas Haaf, Juliane Ramser, Bernd Dworniczak, Christoph Engel, Alfons Meindl, Rita K. Schmutzler, Eric Hahnen

Date Published: 1st Apr 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using … 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P \textless 5 \times 10-8 with ten variants at nine new loci. At P \textless 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Authors: Roger L. Milne, Karoline B. Kuchenbaecker, Kyriaki Michailidou, Jonathan Beesley, Siddhartha Kar, Sara Lindström, Shirley Hui, Audrey Lemaçon, Penny Soucy, Joe Dennis, Xia Jiang, Asha Rostamianfar, Hilary Finucane, Manjeet K. Bolla, Lesley McGuffog, Qin Wang, Cora M. Aalfs, Marcia Adams, Julian Adlard, Simona Agata, Shahana Ahmed, Habibul Ahsan, Kristiina Aittomäki, Fares Al-Ejeh, Jamie Allen, Christine B. Ambrosone, Christopher I. Amos, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Bernd Auber, Paul L. Auer, Margreet G. E. M. Ausems, Jacopo Azzollini, François Bacot, Judith Balmaña, Monica Barile, Laure Barjhoux, Rosa B. Barkardottir, Myrto Barrdahl, Daniel Barnes, Daniel Barrowdale, Caroline Baynes, Matthias W. Beckmann, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Yves-Jean Bignon, Kathleen R. Blazer, Marinus J. Blok, Carl Blomqvist, William Blot, Kristie Bobolis, Bram Boeckx, Natalia V. Bogdanova, Anders Bojesen, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Aniko Bozsik, Angela R. Bradbury, Judith S. Brand, Hiltrud Brauch, Hermann Brenner, Brigitte Bressac-de Paillerets, Carole Brewer, Louise Brinton, Per Broberg, Angela Brooks-Wilson, Joan Brunet, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Jinyoung Byun, Qiuyin Cai, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Federico Canzian, Olivier Caron, Angel Carracedo, Brian D. Carter, J. Esteban Castelao, Laurent Castera, Virginie Caux-Moncoutier, Salina B. Chan, Jenny Chang-Claude, Stephen J. Chanock, Xiaoqing Chen, Ting-Yuan David Cheng, Jocelyne Chiquette, Hans Christiansen, Kathleen B. M. Claes, Christine L. Clarke, Thomas Conner, Don M. Conroy, Jackie Cook, Emilie Cordina-Duverger, Sten Cornelissen, Isabelle Coupier, Angela Cox, David G. Cox, Simon S. Cross, Katarina Cuk, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Francesca Damiola, Hatef Darabi, Rosemarie Davidson, Kim de Leeneer, Peter Devilee, Ed Dicks, Orland Diez, Yuan Chun Ding, Nina Ditsch, Kimberly F. Doheny, Susan M. Domchek, Cecilia M. Dorfling, Thilo Dörk, Isabel Dos-Santos-Silva, Stéphane Dubois, Pierre-Antoine Dugué, Martine Dumont, Alison M. Dunning, Lorraine Durcan, Miriam Dwek, Bernd Dworniczak, Diana Eccles, Ros Eeles, Hans Ehrencrona, Ursula Eilber, Bent Ejlertsen, Arif B. Ekici, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, Laura Fachal, Laurence Faivre, Peter A. Fasching, Ulrike Faust, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, William D. Foulkes, Eitan Friedman, Lin Fritschi, Debra Frost, Marike Gabrielson, Pragna Gaddam, Marilie D. Gammon, Patricia A. Ganz, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, José A. García-Sáenz, Mia M. Gaudet, Marion Gauthier-Villars, Andrea Gehrig, Vassilios Georgoulias, Anne-Marie Gerdes, Graham G. Giles, Gord Glendon, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Paul Goodfellow, Mark H. Greene, Grethe I. Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Daphne Gschwantler-Kaulich, Pascal Guénel, Qi Guo, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Emily Hallberg, Ute Hamann, Nathalie Hamel, Susan Hankinson, Thomas v. O. Hansen, Patricia Harrington, Steven N. Hart, Jaana M. Hartikainen, Catherine S. Healey, Alexander Hein, Sonja Helbig, Alex Henderson, Jane Heyworth, Belynda Hicks, Peter Hillemanns, Shirley Hodgson, Frans B. Hogervorst, Antoinette Hollestelle, Maartje J. Hooning, Bob Hoover, John L. Hopper, Chunling Hu, Guanmengqian Huang, Peter J. Hulick, Keith Humphreys, David J. Hunter, Evgeny N. Imyanitov, Claudine Isaacs, Motoki Iwasaki, Louise Izatt, Anna Jakubowska, Paul James, Ramunas Janavicius, Wolfgang Janni, Uffe Birk Jensen, Esther M. John, Nichola Johnson, Kristine Jones, Michael Jones, Arja Jukkola-Vuorinen, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Daehee Kang, Karin Kast, Renske Keeman, Michael J. Kerin, Carolien M. Kets, Machteld Keupers, Sofia Khan, Elza Khusnutdinova, Johanna I. Kiiski, Sung-Won Kim, Julia A. Knight, Irene Konstantopoulou, Veli-Matti Kosma, Vessela N. Kristensen, Torben A. Kruse, Ava Kwong, Anne-Vibeke Lænkholm, Yael Laitman, Fiona Lalloo, Diether Lambrechts, Keren Landsman, Christine Lasset, Conxi Lazaro, Loic Le Marchand, Julie Lecarpentier, Andrew Lee, Eunjung Lee, Jong Won Lee, Min Hyuk Lee, Flavio Lejbkowicz, Fabienne Lesueur, Jingmei Li, Jenna Lilyquist, Anne Lincoln, Annika Lindblom, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Jennifer T. Loud, Jan Lubinski, Craig Luccarini, Michael Lush, Robert J. MacInnis, Tom Maishman, Enes Makalic, Ivana Maleva Kostovska, Kathleen E. Malone, Siranoush Manoukian, JoAnn E. Manson, Sara Margolin, John W. M. Martens, Maria Elena Martinez, Keitaro Matsuo, Dimitrios Mavroudis, Sylvie Mazoyer, Catriona McLean, Hanne Meijers-Heijboer, Primitiva Menéndez, Jeffery Meyer, Hui Miao, Austin Miller, Nicola Miller, Gillian Mitchell, Marco Montagna, Kenneth Muir, Anna Marie Mulligan, Claire Mulot, Sue Nadesan, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Ines Nevelsteen, Dieter Niederacher, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Robert L. Nussbaum, Edith Olah, Olufunmilayo I. Olopade, Janet E. Olson, Curtis Olswold, Kai-Ren Ong, Jan C. Oosterwijk, Nick Orr, Ana Osorio, V. Shane Pankratz, Laura Papi, Tjoung-Won Park-Simon, Ylva Paulsson-Karlsson, Rachel Lloyd, Inge Søkilde Pedersen, Bernard Peissel, Ana Peixoto, Jose I. A. Perez, Paolo Peterlongo, Julian Peto, Georg Pfeiler, Catherine M. Phelan, Mila Pinchev, Dijana Plaseska-Karanfilska, Bruce Poppe, Mary E. Porteous, Ross Prentice, Nadege Presneau, Darya Prokofieva, Elizabeth Pugh, Miquel Angel Pujana, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Johanna Rantala, Christine Rappaport-Fuerhauser, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Kerstin Rhiem, Andrea Richardson, Gustavo C. Rodriguez, Atocha Romero, Jane Romm, Matti A. Rookus, Anja Rudolph, Thomas Ruediger, Emmanouil Saloustros, Joyce Sanders, Dale P. Sandler, Suleeporn Sangrajrang, Elinor J. Sawyer, Daniel F. Schmidt, Minouk J. Schoemaker, Fredrick Schumacher, Peter Schürmann, Lukas Schwentner, Christopher Scott, Rodney J. Scott, Sheila Seal, Leigha Senter, Caroline Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xin Sheng, Hermela Shimelis, Martha J. Shrubsole, Xiao-Ou Shu, Lucy E. Side, Christian F. Singer, Christof Sohn, Melissa C. Southey, John J. Spinelli, Amanda B. Spurdle, Christa Stegmaier, Dominique Stoppa-Lyonnet, Grzegorz Sukiennicki, Harald Surowy, Christian Sutter, Anthony Swerdlow, Csilla I. Szabo, Rulla M. Tamimi, Yen Y. Tan, Jack A. Taylor, Maria-Isabel Tejada, Maria Tengström, Soo H. Teo, Mary B. Terry, Daniel C. Tessier, Alex Teulé, Kathrin Thöne, Darcy L. Thull, Maria Grazia Tibiletti, Laima Tihomirova, Marc Tischkowitz, Amanda E. Toland, Rob A. E. M. Tollenaar, Ian Tomlinson, Ling Tong, Diana Torres, Martine Tranchant, Thérèse Truong, Kathy Tucker, Nadine Tung, Jonathan Tyrer, Hans-Ulrich Ulmer, Celine Vachon, Christi J. van Asperen, David van den Berg, Ans M. W. van den Ouweland, Elizabeth J. van Rensburg, Liliana Varesco, Raymonda Varon-Mateeva, Ana Vega, Alessandra Viel, Joseph Vijai, Daniel Vincent, Jason Vollenweider, Lisa Walker, Zhaoming Wang, Shan Wang-Gohrke, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Jelle Wesseling, Alice S. Whittemore, Juul T. Wijnen, Walter Willett, Robert Winqvist, Alicja Wolk, Anna H. Wu, Lucy Xia, Xiaohong R. Yang, Drakoulis Yannoukakos, Daniela Zaffaroni, Wei Zheng, Bin Zhu, Argyrios Ziogas, Elad Ziv, Kristin K. Zorn, Manuela Gago-Dominguez, Arto Mannermaa, Håkan Olsson, Manuel R. Teixeira, Jennifer Stone, Kenneth Offit, Laura Ottini, Sue K. Park, Mads Thomassen, Per Hall, Alfons Meindl, Rita K. Schmutzler, Arnaud Droit, Gary D. Bader, Paul D. P. Pharoah, Fergus J. Couch, Douglas F. Easton, Peter Kraft, Georgia Chenevix-Trench, Montserrat García-Closas, Marjanka K. Schmidt, Antonis C. Antoniou, Jacques Simard

Date Published: 1st Dec 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Smoking and physical inactivity increase cancer prevalence in BRCA-1 and BRCA-2 mutation carriers: results from a retrospective observational analysis
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The aim of this analysis in a pilot study population was to investigate whether we can verify seemingly harmful lifestyle factors such as nicotine and alcohol indulgence, obesity, and physical …l inactivity, as well as a low socioeconomic status for increased cancer prevalence in a cohort of BRCA 1 and 2 mutation carriers. METHODS The analysis data are derived from 68 participants of the lifestyle intervention study LIBRE-1, a randomized, prospective trial that aimed to test the feasibility of a lifestyle modification in BRCA 1 and 2 mutation carriers. At study entry, factors such as medical history, lifestyle behavior, and socioeconomic status were retrospectively documented by interview and the current BMI was determined by clinical examination. The baseline measurements were compared within the cohort, and presented alongside reference values for the German population. RESULTS Study participants indicating a higher physical activity during their adolescence showed a significantly lower cancer prevalence (p = 0.019). A significant difference in cancer occurrence was observed in those who smoked prior to the disease, and those who did not smoke (p \textless 0.001). Diseased mutation carriers tended to have a lower BMI compared to non-diseased mutation carriers (p = 0.079), whereas non-diseased revealed a significantly higher physical activity level than diseased mutation carriers (p = 0.046). DISCUSSION The present data in this small cohort of 68 mutation carriers suggest that smoking and low physical activity during adolescence are risk factors for developing breast cancer in women with BRCA1 or BRCA2 mutation. Further data of the ongoing LIBRE 2 study are necessary to confirm these findings in a larger cohort of 600 mutation carriers.

Authors: Sabine Grill, Maryam Yahiaoui-Doktor, Ricarda Dukatz, Jacqueline Lammert, Mirjam Ullrich, Christoph Engel, Katharina Pfeifer, Maryam Basrai, Michael Siniatchkin, Thorsten Schmidt, Burkhard Weisser, Kerstin Rhiem, Nina Ditsch, Rita Schmutzler, Stephan C. Bischoff, Martin Halle, Marion Kiechle

Date Published: 1st Dec 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Feasibility of structured endurance training and Mediterranean diet in BRCA1 and BRCA2 mutation carriers - an interventional randomized controlled multicenter trial (LIBRE-1).
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND: Women with pathogenic BRCA germline mutations have an increased risk for breast and ovarian cancer that seems to be modified by life-style factors. Though, randomized trials investigating … the impact of lifestyle interventions on cancer prevention and prognosis in BRCA carriers are still missing. METHODS: We implemented a multicenter, prospective randomized controlled trial in BRCA1/2 patients, comparing a lifestyle intervention group (IG) with a control group (CG) with the primary aim to prove feasibility. Intervention comprised a structured, individualized endurance training alongside nutrition education based on the Mediterranean diet (MD) for 3 months, plus monthly group training and regular telephone contact during the subsequent 9 months. The CG attended one session on healthy nutrition and the benefits of physical activity. Primary endpoints were feasibility, acceptance and satisfaction over 12 months. Furthermore, effects on physical fitness, diet profile, body mass index (BMI), quality of life and perceived stress were investigated. RESULTS: Sixty-eight participants (mean age 41, mean BMI 23.2 kg/m(2)) were enrolled, of whom 55 (81%, 26 IG, 29 CG) completed 12 months. 73% (n = 26) participated in at least 70% of all intervention sessions. Predictors for drop-outs (19%; n = 13) or non-adherence (27%; n = 7) were not found. 73% rated the program highly and 80% would participate again. Severe adverse events did not occur. Positive effects in the IG compared to the CG were observed for secondary endpoints: BMI, MD eating pattern and stress levels. CONCLUSIONS: This lifestyle intervention was feasible, safe and well accepted. Positive results on eating habits, physical fitness and stress levels warrant a larger randomized trial. TRIAL REGISTRATION: The study has been retrospectively registered at ClinicalTrials.gov (reference: NCT02087592 ) on March 12, 2014. The first patient was included on February 24, 2014.

Authors: M. Kiechle, R. Dukatz, M. Yahiaoui-Doktor, A. Berling, M. Basrai, V. Staiger, U. Niederberger, N. Marter, J. Lammert, S. Grill, K. Pfeifer, K. Rhiem, R. K. Schmutzler, M. Laudes, M. Siniatchkin, M. Halle, S. C. Bischoff, C. Engel

Date Published: 10th Nov 2017

Publication Type: Not specified

Human Diseases: hereditary breast ovarian cancer syndrome

Association analysis identifies 65 new breast cancer risk loci
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer … risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P \textless 5 \times 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Authors: Kyriaki Michailidou, Sara Lindström, Joe Dennis, Jonathan Beesley, Shirley Hui, Siddhartha Kar, Audrey Lemaçon, Penny Soucy, Dylan Glubb, Asha Rostamianfar, Manjeet K. Bolla, Qin Wang, Jonathan Tyrer, Ed Dicks, Andrew Lee, Zhaoming Wang, Jamie Allen, Renske Keeman, Ursula Eilber, Juliet D. French, Xiao Qing Chen, Laura Fachal, Karen McCue, Amy E. McCart Reed, Maya Ghoussaini, Jason S. Carroll, Xia Jiang, Hilary Finucane, Marcia Adams, Muriel A. Adank, Habibul Ahsan, Kristiina Aittomäki, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Banu Arun, Paul L. Auer, François Bacot, Myrto Barrdahl, Caroline Baynes, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Judith S. Brand, Hiltrud Brauch, Paul Brennan, Hermann Brenner, Louise Brinton, Per Broberg, Ian W. Brock, Annegien Broeks, Angela Brooks-Wilson, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Katja Butterbach, Qiuyin Cai, Hui Cai, Trinidad Caldés, Federico Canzian, Angel Carracedo, Brian D. Carter, Jose E. Castelao, Tsun L. Chan, Ting-Yuan David Cheng, Kee Seng Chia, Ji-Yeob Choi, Hans Christiansen, Christine L. Clarke, Margriet Collée, Don M. Conroy, Emilie Cordina-Duverger, Sten Cornelissen, David G. Cox, Angela Cox, Simon S. Cross, Julie M. Cunningham, Kamila Czene, Mary B. Daly, Peter Devilee, Kimberly F. Doheny, Thilo Dörk, Isabel Dos-Santos-Silva, Martine Dumont, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Mingajeva Elvira, Christoph Engel, Mikael Eriksson, Peter A. Fasching, Jonine Figueroa, Dieter Flesch-Janys, Olivia Fletcher, Henrik Flyger, Lin Fritschi, Valerie Gaborieau, Marike Gabrielson, Manuela Gago-Dominguez, Yu-Tang Gao, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Nathalie Hamel, Susan Hankinson, Patricia Harrington, Steven N. Hart, Jaana M. Hartikainen, Mikael Hartman, Alexander Hein, Jane Heyworth, Belynda Hicks, Peter Hillemanns, Dona N. Ho, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Ming-Feng Hou, Chia-Ni Hsiung, Guanmengqian Huang, Keith Humphreys, Junko Ishiguro, Hidemi Ito, Motoki Iwasaki, Hiroji Iwata, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Kristine Jones, Michael Jones, Arja Jukkola-Vuorinen, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Daehee Kang, Yoshio Kasuga, Michael J. Kerin, Sofia Khan, Elza Khusnutdinova, Johanna I. Kiiski, Sung-Won Kim, Julia A. Knight, Veli-Matti Kosma, Vessela N. Kristensen, Ute Krüger, Ava Kwong, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Min Hyuk Lee, Jong Won Lee, Chuen Neng Lee, Flavio Lejbkowicz, Jingmei Li, Jenna Lilyquist, Annika Lindblom, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Artitaya Lophatananon, Jan Lubinski, Craig Luccarini, Michael P. Lux, Edmond S. K. Ma, Robert J. MacInnis, Tom Maishman, Enes Makalic, Kathleen E. Malone, Ivana Maleva Kostovska, Arto Mannermaa, Siranoush Manoukian, JoAnn E. Manson, Sara Margolin, Shivaani Mariapun, Maria Elena Martinez, Keitaro Matsuo, Dimitrios Mavroudis, James McKay, Catriona McLean, Hanne Meijers-Heijboer, Alfons Meindl, Primitiva Menéndez, Usha Menon, Jeffery Meyer, Hui Miao, Nicola Miller, Nur Aishah Mohd Taib, Kenneth Muir, Anna Marie Mulligan, Claire Mulot, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, Sune F. Nielsen, Dong-Young Noh, Børge G. Nordestgaard, Aaron Norman, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Curtis Olswold, Nick Orr, V. Shane Pankratz, Sue K. Park, Tjoung-Won Park-Simon, Rachel Lloyd, Jose I. A. Perez, Paolo Peterlongo, Julian Peto, Kelly-Anne Phillips, Mila Pinchev, Dijana Plaseska-Karanfilska, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Elizabeth Pugh, Katri Pylkäs, Brigitte Rack, Paolo Radice, Nazneen Rahman, Gadi Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Jane Romm, Kathryn J. Ruddy, Thomas Rüdiger, Anja Rudolph, Matthias Ruebner, Emiel J. T. Rutgers, Emmanouil Saloustros, Dale P. Sandler, Suleeporn Sangrajrang, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Peter Schürmann, Rodney J. Scott, Christopher Scott, Sheila Seal, Caroline Seynaeve, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Grace Sheng, Mark E. Sherman, Martha J. Shrubsole, Xiao-Ou Shu, Ann Smeets, Christof Sohn, Melissa C. Southey, John J. Spinelli, Christa Stegmaier, Sarah Stewart-Brown, Jennifer Stone, Daniel O. Stram, Harald Surowy, Anthony Swerdlow, Rulla Tamimi, Jack A. Taylor, Maria Tengström, Soo H. Teo, Mary Beth Terry, Daniel C. Tessier, Somchai Thanasitthichai, Kathrin Thöne, Rob A. E. M. Tollenaar, Ian Tomlinson, Ling Tong, Diana Torres, Thérèse Truong, Chiu-Chen Tseng, Shoichiro Tsugane, Hans-Ulrich Ulmer, Giske Ursin, Michael Untch, Celine Vachon, Christi J. van Asperen, David van den Berg, Ans M. W. van den Ouweland, Lizet van der Kolk, Rob B. van der Luijt, Daniel Vincent, Jason Vollenweider, Quinten Waisfisz, Shan Wang-Gohrke, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter Willett, Robert Winqvist, Alicja Wolk, Anna H. Wu, Lucy Xia, Taiki Yamaji, Xiaohong R. Yang, Cheng Har Yip, Keun-Young Yoo, Jyh-Cherng Yu, Wei Zheng, Ying Zheng, Bin Zhu, Argyrios Ziogas, Elad Ziv, Sunil R. Lakhani, Antonis C. Antoniou, Arnaud Droit, Irene L. Andrulis, Christopher I. Amos, Fergus J. Couch, Paul D. P. Pharoah, Jenny Chang-Claude, Per Hall, David J. Hunter, Roger L. Milne, Montserrat García-Closas, Marjanka K. Schmidt, Stephen J. Chanock, Alison M. Dunning, Stacey L. Edwards, Gary D. Bader, Georgia Chenevix-Trench, Jacques Simard, Peter Kraft, Douglas F. Easton

Date Published: 1st Nov 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association Between Loss-of-Function Mutations Within the FANCM Gene and Early-Onset Familial Breast Cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Importance Germline mutations in established moderately or highly penetrant risk genes for breast cancer (BC) and/or ovarian cancer (OC), including BRCA1 and BRCA2, explain fewer than half of all …l familial BC and/or OC cases. Based on the genotyping of 2 loss-of-function (LoF) variants c.5101C\textgreaterT (p.GIn1701Ter [rs147021911]) and c.5791C\textgreaterT (p.Arg1931Ter [rs144567652]), the FANCM gene has been suggested as a novel BC predisposition gene, while the analysis of the entire coding region of the FANCM gene in familial index cases and geographically matched controls is pending. Objectives To assess the mutational spectrum within the FANCM gene, and to determine a potential association of LoF germline mutations within the FANCM gene with BC and/or OC risk. Design, Setting, and Participants For the purpose of identification and characterization of novel BC and/or OC predisposition genes, a total of 2047 well-characterized familial BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for LoF mutations within the FANCM gene by next-generation sequencing. All patients previously tested negative for pathogenic BRCA1 and BRCA2 mutations. All data collection occurred between June 1, 2013, and April 30, 2016. Data analysis was performed from May 1, 2016, to July 1, 2016. Main Outcomes and Measures FANCM LoF mutation frequencies in patients with BC and/or OC were compared with the FANCM LoF mutation frequencies in geographically matched controls by univariate logistic regression. Positive associations were stratified by age at onset and cancer family history. Results In this case-control study, 2047 well-characterized familial female BC index cases, 628 OC cases, and 2187 geographically matched controls were screened for truncating FANCM alterations. Heterozygous LoF mutations within the FANCM gene were significantly associated with familial BC risk, with an overall odds ratio (OR) of 2.05 (95% CI, 0.94-4.54; P = .049) and a mutation frequency of 1.03% in index cases. In familial patients whose BC onset was before age 51 years, an elevated OR of 2.44 (95% CI, 1.08-5.59; P = .02) was observed. A more pronounced association was identified for patients with a triple-negative BC tumor phenotype (OR, 3.75; 95% CI, 1.00-12.85; P = .02). No significant association was detected for unselected OC cases (OR, 1.74; 95% CI, 0.57-5.08; P = .27). Conclusions and Relevance Based on the significant associations of heterozygous LoF mutations with early-onset or triple-negative BC, FANCM should be included in diagnostic gene panel testing for individual risk assessment. Larger studies are required to determine age-dependent disease risks for BC and to assess a potential role of FANCM mutations in OC pathogenesis.

Authors: Guido Neidhardt, Jan Hauke, Juliane Ramser, Eva Groß, Andrea Gehrig, Clemens R. Müller, Anne-Karin Kahlert, Karl Hackmann, Ellen Honisch, Dieter Niederacher, Stefanie Heilmann-Heimbach, André Franke, Wolfgang Lieb, Holger Thiele, Janine Altmüller, Peter Nürnberg, Kristina Klaschik, Corinna Ernst, Nina Ditsch, Frank Jessen, Alfredo Ramirez, Barbara Wappenschmidt, Christoph Engel, Kerstin Rhiem, Alfons Meindl, Rita K. Schmutzler, Eric Hahnen

Date Published: 1st Sep 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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