Abstract

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10−180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.

A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.

Details

Title
Polygenic hazard score is associated with prostate cancer in multi-ethnic populations
Author
Huynh-Le Minh-Phuong 1   VIAFID ORCID Logo  ; Fan, Chun Chieh 2   VIAFID ORCID Logo  ; Karunamuni Roshan 1 ; Thompson, Wesley K 3 ; Martinez, Maria Elena 4 ; Eeles, Rosalind A 5   VIAFID ORCID Logo  ; Kote-Jarai Zsofia 6 ; Muir, Kenneth 7   VIAFID ORCID Logo  ; Schleutker Johanna 8   VIAFID ORCID Logo  ; Pashayan Nora 9   VIAFID ORCID Logo  ; Batra Jyotsna 10   VIAFID ORCID Logo  ; Grönberg Henrik 11   VIAFID ORCID Logo  ; Neal, David E 12 ; Donovan, Jenny L 13 ; Hamdy, Freddie C 14 ; Martin, Richard M 15   VIAFID ORCID Logo  ; Nielsen, Sune F 16 ; Nordestgaard, Børge G 16   VIAFID ORCID Logo  ; Wiklund Fredrik 11   VIAFID ORCID Logo  ; Tangen, Catherine M 17 ; Giles, Graham G 18   VIAFID ORCID Logo  ; Wolk Alicja 19   VIAFID ORCID Logo  ; Albanes Demetrius 20 ; Travis, Ruth C 21   VIAFID ORCID Logo  ; Blot, William J 22 ; Zheng, Wei 23   VIAFID ORCID Logo  ; Sanderson, Maureen 24 ; Stanford, Janet L 25 ; Mucci, Lorelei A 26 ; West Catharine M L 27   VIAFID ORCID Logo  ; Kibel, Adam S 28 ; Cussenot Olivier 29 ; Berndt, Sonja I 20 ; Koutros Stella 20 ; Sørensen, Karina Dalsgaard 30   VIAFID ORCID Logo  ; Cybulski Cezary 31 ; Grindedal, Eli Marie 32 ; Menegaux Florence 33 ; Kay-Tee, Khaw 34 ; Park, Jong Y 35   VIAFID ORCID Logo  ; Ingles, Sue A 36 ; Maier Christiane 37 ; Hamilton, Robert J 38 ; Thibodeau, Stephen N 39 ; Rosenstein, Barry S 40 ; Yong-Jie, Lu 41 ; Watya, Stephen 42 ; Vega, Ana 43   VIAFID ORCID Logo  ; Kogevinas Manolis 44 ; Penney, Kathryn L 45 ; Huff, Chad 46 ; Teixeira, Manuel R 47   VIAFID ORCID Logo  ; Multigner Luc 48   VIAFID ORCID Logo  ; Leach, Robin J 49 ; Cannon-Albright, Lisa 50   VIAFID ORCID Logo  ; Brenner, Hermann 51 ; John, Esther M 52 ; Kaneva Radka 53 ; Logothetis, Christopher J 54 ; Neuhausen, Susan L 55 ; Kim, De Ruyck 56 ; Pandha Hardev 57 ; Razack Azad 58 ; Newcomb, Lisa F 59 ; Fowke, Jay H 60 ; Gamulin Marija 61   VIAFID ORCID Logo  ; Usmani Nawaid 62 ; Claessens, Frank 63 ; Gago-Dominguez, Manuela 64 ; Townsend, Paul A 65 ; Bush, William S 66   VIAFID ORCID Logo  ; Roobol, Monique J 67   VIAFID ORCID Logo  ; Parent Marie-Élise 68 ; Hu, Jennifer J 69 ; Mills, Ian G 70 ; Andreassen, Ole A 71   VIAFID ORCID Logo  ; Dale, Anders M 72 ; Seibert, Tyler M 73   VIAFID ORCID Logo 

1  University of California San Diego, Department of Radiation Medicine and Applied Sciences, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); University of California San Diego, Center for Multimodal Imaging and Genetics, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
2  University of California San Diego, Center for Multimodal Imaging and Genetics, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
3  University of California San Diego, Division of Biostatistics and Halicioğlu Data Science Institute, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); University of California San Diego, Department of Family Medicine and Public Health, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
4  Moores Cancer Center, Department of Family Medicine and Public Health, University of California San Diego, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
5  The Institute of Cancer Research, London, UK (GRID:grid.18886.3f) (ISNI:0000 0001 1271 4623); Royal Marsden NHS Foundation Trust, London, UK (GRID:grid.5072.0) (ISNI:0000 0001 0304 893X) 
6  The Institute of Cancer Research, London, UK (GRID:grid.18886.3f) (ISNI:0000 0001 1271 4623) 
7  University of Manchester, Oxford Road, Division of Population Health, Health Services Research and Primary Care, Manchester, UK (GRID:grid.5379.8) (ISNI:0000000121662407); University of Warwick, Warwick Medical School, Coventry, UK (GRID:grid.7372.1) (ISNI:0000 0000 8809 1613) 
8  Kiinamyllynkatu 10, FI-20014 University of Turku, Institute of Biomedicine, Turku, Finland (GRID:grid.1374.1) (ISNI:0000 0001 2097 1371); Turku University Hospital, Department of Medical Genetics, Genomics, Laboratory Division, Turku, Finland (GRID:grid.410552.7) (ISNI:0000 0004 0628 215X) 
9  University College London, Department of Applied Health Research, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201); University of Cambridge, Strangeways Laboratory, Worts Causeway, Centre for Cancer Genetic Epidemiology, Department of Oncology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University College London, Department of Applied Health Research, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201) 
10  Queensland University of Technology, Australian Prostate Cancer Research Centre-Qld, Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Brisbane, Australia (GRID:grid.1024.7) (ISNI:0000000089150953); Translational Research Institute, Brisbane, Australia (GRID:grid.489335.0) (ISNI:0000000406180938) 
11  Karolinska Institute, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
12  University of Oxford, John Radcliffe Hospital, Nuffield Department of Surgical Sciences, Headington, Oxford, UK (GRID:grid.4714.6); University of Cambridge, Addenbrooke’s Hospital, Department of Oncology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge, UK (GRID:grid.470869.4) (ISNI:0000 0004 0634 2060) 
13  Bristol Medical School, University of Bristol, Population Health Sciences, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603) 
14  University of Oxford, Nuffield Department of Surgical Sciences, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948); University of Oxford, John Radcliffe Hospital, Faculty of Medical Science, Oxford, UK (GRID:grid.4991.5) 
15  Bristol Medical School, University of Bristol, Population Health Sciences, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603); University of Bristol, National Institute for Health Research (NIHR) Biomedical Research Centre, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603); University of Bristol, Medical Research Council (MRC) Integrative Epidemiology Unit, Bristol, UK (GRID:grid.5337.2) (ISNI:0000 0004 1936 7603) 
16  University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X); Copenhagen University Hospital, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Herlev, Denmark (GRID:grid.4973.9) (ISNI:0000 0004 0646 7373) 
17  Fred Hutchinson Cancer Research Center, SWOG Statistical Center, Seattle, USA (GRID:grid.270240.3) (ISNI:0000 0001 2180 1622) 
18  Cancer Council Victoria, Cancer Epidemiology Division, Melbourne, Australia (GRID:grid.3263.4) (ISNI:0000 0001 1482 3639); The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); Monash University, Precision Medicine, School of Clinical Sciences at Monash Health, Clayton, Australia (GRID:grid.1002.3) (ISNI:0000 0004 1936 7857) 
19  Karolinska Institutet, Division of Nutritional Epidemiology, Institute of Environmental Medicine, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Uppsala University, Department of Surgical Sciences, Uppsala, Sweden (GRID:grid.8993.b) (ISNI:0000 0004 1936 9457) 
20  National Cancer Institute, NIH, Division of Cancer Epidemiology and Genetics, Bethesda, USA (GRID:grid.417768.b) (ISNI:0000 0004 0483 9129) 
21  University of Oxford, Cancer Epidemiology Unit, Nuffield Department of Population Health, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
22  Vanderbilt University Medical Center, Division of Epidemiology, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916); International Epidemiology Institute, Rockville, USA (GRID:grid.419344.f) (ISNI:0000 0004 0384 6204) 
23  Vanderbilt University Medical Center, Division of Epidemiology, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
24  Meharry Medical College, Department of Family and Community Medicine, Nashville, USA (GRID:grid.259870.1) (ISNI:0000 0001 0286 752X) 
25  Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, USA (GRID:grid.270240.3) (ISNI:0000 0001 2180 1622); School of Public Health, University of Washington, Department of Epidemiology, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
26  Harvard T. H. Chan School of Public Health, Department of Epidemiology, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
27  University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Division of Cancer Sciences, Manchester, UK (GRID:grid.38142.3c) 
28  Brigham and Womens Hospital, Division of Urologic Surgery, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
29  Tenon Hospital, 4 Rue de la Chine, Sorbonne Universite, GRC n°5, AP-HP, Paris, France (GRID:grid.413483.9) (ISNI:0000 0001 2259 4338); CeRePP, Tenon Hospital, Paris, France (GRID:grid.413483.9) (ISNI:0000 0001 2259 4338) 
30  Aarhus University Hospital, Department of Molecular Medicine, Aarhus, Denmark (GRID:grid.154185.c) (ISNI:0000 0004 0512 597X); Aarhus University, Department of Clinical Medicine, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722) 
31  Pomeranian Medical University, International Hereditary Cancer Center, Department of Genetics and Pathology, Szczecin, Poland (GRID:grid.107950.a) (ISNI:0000 0001 1411 4349) 
32  Oslo University Hospital, Department of Medical Genetics, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
33  University Paris-Sud, University Paris-Saclay, Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, Villejuif Cédex, France (GRID:grid.5842.b) (ISNI:0000 0001 2171 2558); Paris-Sud University, UMRS 1018, Villejuif Cedex, France (GRID:grid.5842.b) (ISNI:0000 0001 2171 2558) 
34  Clinical Gerontology Unit, University of Cambridge, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
35  Moffitt Cancer Center, Department of Cancer Epidemiology, Tampa, USA (GRID:grid.468198.a) (ISNI:0000 0000 9891 5233) 
36  University of Southern California/Norris Comprehensive Cancer Center, Department of Preventive Medicine, Keck School of Medicine, Los Angeles, USA (GRID:grid.42505.36) (ISNI:0000 0001 2156 6853) 
37  Humangenetik Tuebingen, Tuebingen, Germany (GRID:grid.42505.36) 
38  Princess Margaret Cancer Centre, Department of Surgical Oncology, Toronto, Canada (GRID:grid.415224.4) (ISNI:0000 0001 2150 066X); University of Toronto, Department of Surgery (Urology), Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
39  Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, USA (GRID:grid.66875.3a) (ISNI:0000 0004 0459 167X) 
40  Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Department of Radiation Oncology and Department of Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351); Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351) 
41  Queen Mary University of London, John Vane Science Centre, Charterhouse Square, Centre for Molecular Oncology, Barts Cancer Institute, London, UK (GRID:grid.4868.2) (ISNI:0000 0001 2171 1133) 
42  Uro Care, Kampala, Uganda (GRID:grid.4868.2) 
43  Fundación Pública Galega Medicina Xenómica, Santiago De Compostela, Spain (GRID:grid.443929.1) (ISNI:0000 0004 4688 8850); Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago De Compostela, Spain (GRID:grid.488911.d) (ISNI:0000 0004 0408 4897); Centro de Investigación en Red de Enfermedades Raras (CIBERER), Santiago De Compostela, Spain (GRID:grid.488911.d) 
44  ISGlobal, Barcelona, Spain (GRID:grid.434607.2) (ISNI:0000 0004 1763 3517); IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain (GRID:grid.411142.3) (ISNI:0000 0004 1767 8811); Universitat Pompeu Fabra (UPF), Barcelona, Spain (GRID:grid.5612.0) (ISNI:0000 0001 2172 2676) 
45  Brigham and Women’s Hospital/Harvard Medical School, Channing Division of Network Medicine, Department of Medicine, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
46  The University of Texas M. D. Anderson Cancer Center, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776) 
47  Portuguese Oncology Institute of Porto (IPO-Porto), Department of Genetics, Porto, Portugal (GRID:grid.435544.7); University of Porto, Biomedical Sciences Institute (ICBAS), Porto, Portugal (GRID:grid.5808.5) (ISNI:0000 0001 1503 7226) 
48  Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)—UMR_S 1085, Rennes, France (GRID:grid.410368.8) (ISNI:0000 0001 2191 9284) 
49  University of Texas Health Science Center at San Antonio, Department of Urology, Mays Cancer Center, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
50  University of Utah School of Medicine, Division of Epidemiology, Department of Internal Medicine, Salt Lake City, USA (GRID:grid.223827.e) (ISNI:0000 0001 2193 0096); George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, USA (GRID:grid.413886.0) 
51  German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, Division of Preventive Oncology, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584) 
52  Stanford University School of Medicine, Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
53  Medical University of Sofia, Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Sofia, Bulgaria (GRID:grid.410563.5) (ISNI:0000 0004 0621 0092) 
54  The University of Texas M. D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, Houston, USA (GRID:grid.240145.6) (ISNI:0000 0001 2291 4776) 
55  Beckman Research Institute of the City of Hope, Department of Population Sciences, Duarte, USA (GRID:grid.410425.6) (ISNI:0000 0004 0421 8357) 
56  Ghent University, Faculty of Medicine and Health Sciences, Basic Medical Sciences, Gent, Belgium (GRID:grid.5342.0) (ISNI:0000 0001 2069 7798) 
57  The University of Surrey, Guildford, UK (GRID:grid.5475.3) (ISNI:0000 0004 0407 4824) 
58  University of Malaya, Department of Surgery, Faculty of Medicine, Kuala Lumpur, Malaysia (GRID:grid.10347.31) (ISNI:0000 0001 2308 5949) 
59  Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, USA (GRID:grid.270240.3) (ISNI:0000 0001 2180 1622); University of Washington, Department of Urology, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
60  Vanderbilt University Medical Center, Department of Medicine and Urologic Surgery, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916); The University of Tennessee Health Science Center, Division of Epidemiology, Department of Preventive Medicine, Memphis, USA (GRID:grid.267301.1) (ISNI:0000 0004 0386 9246) 
61  University Hospital Centre Zagreb, University of Zagreb, School of Medicine, Department of Oncology, Zagreb, Croatia (GRID:grid.267301.1) 
62  University of Alberta, Department of Oncology, Cross Cancer Institute, Edmonton, Canada (GRID:grid.17089.37); Cross Cancer Institute, Division of Radiation Oncology, Edmonton, Canada (GRID:grid.17089.37) 
63  Molecular Endocrinology Laboratory, KU Leuven, Department of Cellular and Molecular Medicine, Leuven, Belgium (GRID:grid.5596.f) (ISNI:0000 0001 0668 7884) 
64  Instituto de Investigacion Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, Servicio Galego de Saúde, SERGAS, Genomic Medicine Group, Galician Foundation of Genomic Medicine, Santiago de Compostela, Spain (GRID:grid.411048.8) (ISNI:0000 0000 8816 6945); University of California San Diego, Moores Cancer Center, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
65  Manchester Academic Health Science Centre, NIHR Manchester Biomedical Research Centre, Health Innovation Manchester, University of Manchester, Division of Cancer Sciences, Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, Manchester, UK (GRID:grid.5379.8) (ISNI:0000000121662407) 
66  Cleveland Institute for Computational Biology, Case Western Reserve University, Department of Population and Quantitative Health Sciences, Cleveland, USA (GRID:grid.67105.35) (ISNI:0000 0001 2164 3847) 
67  Erasmus University Medical Center, Department of Clinical Chemistry, Rotterdam, The Netherlands (GRID:grid.5645.2) (ISNI:000000040459992X) 
68  Institut National de la Recherche Scientifique, Epidemiology and Biostatistics Unit, Centre Armand-Frappier Santé Biotechnologie, Laval, Canada (GRID:grid.418084.1) (ISNI:0000 0000 9582 2314); University of Montreal, Department of Social and Preventive Medicine, School of Public Health, Montreal, Canada (GRID:grid.14848.31) (ISNI:0000 0001 2292 3357) 
69  Sylvester Comprehensive Cancer Center, The University of Miami School of Medicine, Miami, USA (GRID:grid.419791.3) (ISNI:0000 0000 9902 6374) 
70  University of Oxford, Nuffield Department of Surgical Sciences, Oxford, UK (GRID:grid.4991.5) (ISNI:0000 0004 1936 8948) 
71  Oslo University Hospital and University of Oslo, NORMENT, KG Jebsen Centre, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
72  University of California San Diego, Center for Multimodal Imaging and Genetics, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); University of California San Diego, Department of Radiology, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
73  University of California San Diego, Department of Radiation Medicine and Applied Sciences, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); University of California San Diego, Center for Multimodal Imaging and Genetics, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); University of California San Diego, Department of Radiology, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242); University of California San Diego, Department of Bioengineering, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-021-21287-0
ProQuest document ID
2492469483
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.