Literature DB >> 30366939

Polygenic Determinants for Subsequent Breast Cancer Risk in Survivors of Childhood Cancer: The St Jude Lifetime Cohort Study (SJLIFE).

Zhaoming Wang1, Jinghui Zhang2, Yutaka Yasui3, Leslie L Robison3, Qi Liu4, Carmen L Wilson3, John Easton2, Heather Mulder2, Ti-Cheng Chang2, Michael C Rusch2, Michael N Edmonson2, Stephen V Rice2, Matthew J Ehrhardt3,5, Rebecca M Howell6, Chimene A Kesserwan5, Gang Wu2, Kim E Nichols5, James R Downing7, Melissa M Hudson3,5.   

Abstract

PURPOSE: The risk of subsequent breast cancer among female childhood cancer survivors is markedly elevated. We aimed to determine genetic contributions to this risk, focusing on polygenic determinants implicated in breast cancer susceptibility in the general population. EXPERIMENTAL
DESIGN: Whole-genome sequencing (30×) was performed on survivors in the St Jude Lifetime Cohort, and germline mutations in breast cancer predisposition genes were classified for pathogenicity. A polygenic risk score (PRS) was constructed for each survivor using 170 established common risk variants. Relative rate (RR) and 95% confidence interval (95% CI) of subsequent breast cancer incidence were estimated using multivariable piecewise exponential regression.
RESULTS: The analysis included 1,133 female survivors of European ancestry (median age at last follow-up = 35.4 years; range, 8.4-67.4), of whom 47 were diagnosed with one or more subsequent breast cancers (median age at subsequent breast cancer = 40.3 years; range, 24.5-53.0). Adjusting for attained age, age at primary diagnosis, chest irradiation, doses of alkylating agents and anthracyclines, and genotype eigenvectors, RRs for survivors with PRS in the highest versus lowest quintiles were 2.7 (95% CI, 1.0-7.3), 3.0 (95% CI, 1.1-8.1), and 2.4 (95% CI, 0.1-81.1) for all survivors and survivors with and without chest irradiation, respectively. Similar associations were observed after excluding carriers of pathogenic/likely pathogenic mutations in breast cancer predisposition genes. Notably, the PRS was associated with the subsequent breast cancer rate under the age of 45 years (RR = 3.2; 95% CI, 1.2-8.3).
CONCLUSIONS: Genetic profiles comprised of small-effect common variants and large-effect predisposing mutations can inform personalized breast cancer risk and surveillance/intervention in female childhood cancer survivors. ©2018 American Association for Cancer Research.

Entities:  

Mesh：

Year:  2018        PMID： 30366939      PMCID： PMC6295266          DOI： 10.1158/1078-0432.CCR-18-1775

Source DB:  PubMed          Journal:  Clin Cancer Res        ISSN： 1078-0432            Impact factor:   12.531


  24 in total

1.  Genetic variants demonstrating flip-flop phenomenon and breast cancer risk prediction among women of African ancestry.

Authors:  Shengfeng Wang; Frank Qian; Yonglan Zheng; Temidayo Ogundiran; Oladosu Ojengbede; Wei Zheng; William Blot; Katherine L Nathanson; Anselm Hennis; Barbara Nemesure; Stefan Ambs; Olufunmilayo I Olopade; Dezheng Huo
Journal:  Breast Cancer Res Treat       Date:  2018-01-04       Impact factor: 4.872

Review 2.  Clinical Practice Recommendations Based on an Updated Review of Breast Cancer Risk Among Women Treated for Childhood Cancer.

Authors:  Yael E Derman
Journal:  J Pediatr Oncol Nurs       Date:  2017-09-01       Impact factor: 1.636

3.  Breast Cancer Risk in Childhood Cancer Survivors Without a History of Chest Radiotherapy: A Report From the Childhood Cancer Survivor Study.

Authors:  Tara O Henderson; Chaya S Moskowitz; Joanne F Chou; Angela R Bradbury; Joseph Phillip Neglia; Chau T Dang; Kenan Onel; Danielle Novetsky Friedman; Smita Bhatia; Louise C Strong; Marilyn Stovall; Lisa B Kenney; Dana Barnea; Elena Lorenzi; Sue Hammond; Wendy M Leisenring; Leslie L Robison; Gregory T Armstrong; Lisa R Diller; Kevin C Oeffinger
Journal:  J Clin Oncol       Date:  2015-12-23       Impact factor: 44.544

4.  Polygenic Scores in Epidemiology: Risk Prediction, Etiology, and Clinical Utility.

Authors:  Brion S Maher
Journal:  Curr Epidemiol Rep       Date:  2015-09-28

Review 5.  Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome.

Authors:  Junne Kamihara; Huma Q Rana; Judy E Garber
Journal:  Hum Mutat       Date:  2014-06       Impact factor: 4.878

6.  Gene-panel sequencing and the prediction of breast-cancer risk.

Authors:  Douglas F Easton; Paul D P Pharoah; Antonis C Antoniou; Marc Tischkowitz; Sean V Tavtigian; Katherine L Nathanson; Peter Devilee; Alfons Meindl; Fergus J Couch; Melissa Southey; David E Goldgar; D Gareth R Evans; Georgia Chenevix-Trench; Nazneen Rahman; Mark Robson; Susan M Domchek; William D Foulkes
Journal:  N Engl J Med       Date:  2015-05-27       Impact factor: 91.245

7.  Prediction of breast cancer risk based on profiling with common genetic variants.

Authors:  Nasim Mavaddat; Paul D P Pharoah; Kyriaki Michailidou; Jonathan Tyrer; Mark N Brook; Manjeet K Bolla; Qin Wang; Joe Dennis; Alison M Dunning; Mitul Shah; Robert Luben; Judith Brown; Stig E Bojesen; Børge G Nordestgaard; Sune F Nielsen; Henrik Flyger; Kamila Czene; Hatef Darabi; Mikael Eriksson; Julian Peto; Isabel Dos-Santos-Silva; Frank Dudbridge; Nichola Johnson; Marjanka K Schmidt; Annegien Broeks; Senno Verhoef; Emiel J Rutgers; Anthony Swerdlow; Alan Ashworth; Nick Orr; Minouk J Schoemaker; Jonine Figueroa; Stephen J Chanock; Louise Brinton; Jolanta Lissowska; Fergus J Couch; Janet E Olson; Celine Vachon; Vernon S Pankratz; Diether Lambrechts; Hans Wildiers; Chantal Van Ongeval; Erik van Limbergen; Vessela Kristensen; Grethe Grenaker Alnæs; Silje Nord; Anne-Lise Borresen-Dale; Heli Nevanlinna; Taru A Muranen; Kristiina Aittomäki; Carl Blomqvist; Jenny Chang-Claude; Anja Rudolph; Petra Seibold; Dieter Flesch-Janys; Peter A Fasching; Lothar Haeberle; Arif B Ekici; Matthias W Beckmann; Barbara Burwinkel; Frederik Marme; Andreas Schneeweiss; Christof Sohn; Amy Trentham-Dietz; Polly Newcomb; Linda Titus; Kathleen M Egan; David J Hunter; Sara Lindstrom; Rulla M Tamimi; Peter Kraft; Nazneen Rahman; Clare Turnbull; Anthony Renwick; Sheila Seal; Jingmei Li; Jianjun Liu; Keith Humphreys; Javier Benitez; M Pilar Zamora; Jose Ignacio Arias Perez; Primitiva Menéndez; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska-Bieniek; Katarzyna Durda; Natalia V Bogdanova; Natalia N Antonenkova; Thilo Dörk; Hoda Anton-Culver; Susan L Neuhausen; Argyrios Ziogas; Leslie Bernstein; Peter Devilee; Robert A E M Tollenaar; Caroline Seynaeve; Christi J van Asperen; Angela Cox; Simon S Cross; Malcolm W R Reed; Elza Khusnutdinova; Marina Bermisheva; Darya Prokofyeva; Zalina Takhirova; Alfons Meindl; Rita K Schmutzler; Christian Sutter; Rongxi Yang; Peter Schürmann; Michael Bremer; Hans Christiansen; Tjoung-Won Park-Simon; Peter Hillemanns; Pascal Guénel; Thérèse Truong; Florence Menegaux; Marie Sanchez; Paolo Radice; Paolo Peterlongo; Siranoush Manoukian; Valeria Pensotti; John L Hopper; Helen Tsimiklis; Carmel Apicella; Melissa C Southey; Hiltrud Brauch; Thomas Brüning; Yon-Dschun Ko; Alice J Sigurdson; Michele M Doody; Ute Hamann; Diana Torres; Hans-Ulrich Ulmer; Asta Försti; Elinor J Sawyer; Ian Tomlinson; Michael J Kerin; Nicola Miller; Irene L Andrulis; Julia A Knight; Gord Glendon; Anna Marie Mulligan; Georgia Chenevix-Trench; Rosemary Balleine; Graham G Giles; Roger L Milne; Catriona McLean; Annika Lindblom; Sara Margolin; Christopher A Haiman; Brian E Henderson; Fredrick Schumacher; Loic Le Marchand; Ursula Eilber; Shan Wang-Gohrke; Maartje J Hooning; Antoinette Hollestelle; Ans M W van den Ouweland; Linetta B Koppert; Jane Carpenter; Christine Clarke; Rodney Scott; Arto Mannermaa; Vesa Kataja; Veli-Matti Kosma; Jaana M Hartikainen; Hermann Brenner; Volker Arndt; Christa Stegmaier; Aida Karina Dieffenbach; Robert Winqvist; Katri Pylkäs; Arja Jukkola-Vuorinen; Mervi Grip; Kenneth Offit; Joseph Vijai; Mark Robson; Rohini Rau-Murthy; Miriam Dwek; Ruth Swann; Katherine Annie Perkins; Mark S Goldberg; France Labrèche; Martine Dumont; Diana M Eccles; William J Tapper; Sajjad Rafiq; Esther M John; Alice S Whittemore; Susan Slager; Drakoulis Yannoukakos; Amanda E Toland; Song Yao; Wei Zheng; Sandra L Halverson; Anna González-Neira; Guillermo Pita; M Rosario Alonso; Nuria Álvarez; Daniel Herrero; Daniel C Tessier; Daniel Vincent; Francois Bacot; Craig Luccarini; Caroline Baynes; Shahana Ahmed; Mel Maranian; Catherine S Healey; Jacques Simard; Per Hall; Douglas F Easton; Montserrat Garcia-Closas
Journal:  J Natl Cancer Inst       Date:  2015-04-08       Impact factor: 13.506

8.  Evaluation of three polygenic risk score models for the prediction of breast cancer risk in Singapore Chinese.

Authors:  Claire Hian Tzer Chan; Prabhakaran Munusamy; Sau Yeen Loke; Geok Ling Koh; Audrey Zhi Yi Yang; Hai Yang Law; Chui Sheun Yoon; Chow Yin Wong; Wei Sean Yong; Nan Soon Wong; Raymond Chee Hui Ng; Kong Wee Ong; Preetha Madhukumar; Chung Lie Oey; Gay Hui Ho; Puay Hoon Tan; Min Han Tan; Peter Ang; Yoon Sim Yap; Ann Siew Gek Lee
Journal:  Oncotarget       Date:  2018-01-31

9.  Association analysis identifies 65 new breast cancer risk loci.

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
Journal:  Nature       Date:  2017-10-23       Impact factor: 49.962

10.  The cumulative burden of surviving childhood cancer: an initial report from the St Jude Lifetime Cohort Study (SJLIFE).

Authors:  Nickhill Bhakta; Qi Liu; Kirsten K Ness; Malek Baassiri; Hesham Eissa; Frederick Yeo; Wassim Chemaitilly; Matthew J Ehrhardt; Johnnie Bass; Michael W Bishop; Kyla Shelton; Lu Lu; Sujuan Huang; Zhenghong Li; Eric Caron; Jennifer Lanctot; Carrie Howell; Timothy Folse; Vijaya Joshi; Daniel M Green; Daniel A Mulrooney; Gregory T Armstrong; Kevin R Krull; Tara M Brinkman; Raja B Khan; Deo K Srivastava; Melissa M Hudson; Yutaka Yasui; Leslie L Robison
Journal:  Lancet       Date:  2017-09-08       Impact factor: 79.321
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  7 in total

1.  Subsequent Breast Cancer in Female Childhood Cancer Survivors in the St Jude Lifetime Cohort Study (SJLIFE).

Authors:  Matthew J Ehrhardt; Carrie R Howell; Karen Hale; Malek J Baassiri; Carol Rodriguez; Carmen L Wilson; Surekha S Joshi; Thomas C Lemond; Sheila Shope; Rebecca M Howell; Zhaoming Wang; Deokumar Srivastava; Daniel A Mulrooney; Jinghui Zhang; Leslie L Robison; Kirsten K Ness; Melissa M Hudson
Journal:  J Clin Oncol       Date:  2019-05-10       Impact factor: 44.544

2.  Polygenic Risk Score Improves Risk Stratification and Prediction of Subsequent Thyroid Cancer after Childhood Cancer.

Authors:  Nan Song; Qi Liu; Yutaka Yasui; Zhaoming Wang; Carmen L Wilson; Yadav Sapkota; Matthew J Ehrhardt; Todd M Gibson; Lindsay M Morton; Stephen J Chanock; Joseph P Neglia; Michael A Arnold; J Robert Michael; Alexander M Gout; Heather L Mulder; John Easton; Smita Bhatia; Gregory T Armstrong; Jinghui Zhang; Angela Delaney; Melissa M Hudson; Leslie L Robison
Journal:  Cancer Epidemiol Biomarkers Prev       Date:  2021-08-31       Impact factor: 4.090

3.  Leveraging Therapy-Specific Polygenic Risk Scores to Predict Restrictive Lung Defects in Childhood Cancer Survivors.

Authors:  Daniel A Mulrooney; Yutaka Yasui; Cindy Im; Yan Yuan; Eric D Austin; Dennis C Stokes; Matthew J Krasin; Andrew M Davidoff; Yadav Sapkota; Zhaoming Wang; Kirsten K Ness; Carmen L Wilson; Gregory T Armstrong; Melissa M Hudson; Leslie L Robison
Journal:  Cancer Res       Date:  2022-08-16       Impact factor: 13.312

4.  Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

Authors:  Lindsay M Morton; Danielle M Karyadi; Stephen W Hartley; Megan N Frone; Joshua N Sampson; Rebecca M Howell; Joseph P Neglia; Michael A Arnold; Belynda D Hicks; Kristine Jones; Bin Zhu; Casey L Dagnall; Eric Karlins; Meredith S Yeager; Wendy M Leisenring; Yutaka Yasui; Lucie M Turcotte; Susan A Smith; Rita E Weathers; Jeremy Miller; Byron S Sigel; Diana M Merino; Amy Berrington de Gonzalez; Smita Bhatia; Leslie L Robison; Margaret A Tucker; Gregory T Armstrong; Stephen J Chanock
Journal:  JCO Precis Oncol       Date:  2020-08-21

Review 5.  A pediatric perspective on genomics and prevention in the twenty-first century.

Authors:  Bimal P Chaudhari; Kandamurugu Manickam; Kim L McBride
Journal:  Pediatr Res       Date:  2019-10-02       Impact factor: 3.756

6.  Generalizability of "GWAS Hits" in Clinical Populations: Lessons from Childhood Cancer Survivors.

Authors:  Cindy Im; Na Qin; Zhaoming Wang; Weiyu Qiu; Carrie R Howell; Yadav Sapkota; Wonjong Moon; Wassim Chemaitilly; Todd M Gibson; Daniel A Mulrooney; Kirsten K Ness; Carmen L Wilson; Lindsay M Morton; Gregory T Armstrong; Smita Bhatia; Jinghui Zhang; Melissa M Hudson; Leslie L Robison; Yutaka Yasui
Journal:  Am J Hum Genet       Date:  2020-09-17       Impact factor: 11.043

Review 7.  Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field.

Authors:  Tatiane Yanes; Mary-Anne Young; Bettina Meiser; Paul A James
Journal:  Breast Cancer Res       Date:  2020-02-17       Impact factor: 6.466
  7 in total

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