Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?

Author:

Macauda Angelica12ORCID,Clay-Gilmour Alyssa3,Hielscher Thomas4,Hildebrandt Michelle A.T.5,Kruszewski Marcin6ORCID,Orlowski Robert Z.5ORCID,Kumar Shaji K.7ORCID,Ziv Elad8ORCID,Orciuolo Enrico9,Brown Elizabeth E.10,Försti Asta1112ORCID,Waller Rosalie G.13ORCID,Machiela Mitchell J.14ORCID,Chanock Stephen J.14ORCID,Camp Nicola J.15ORCID,Rymko Marcin16ORCID,Raźny Małgorzata17ORCID,Cozen Wendy18ORCID,Várkonyi Judit19,Piredda Chiara1ORCID,Pelosini Matteo9ORCID,Belachew Alem A.5ORCID,Subocz Edyta20ORCID,Hemminki Kari2122,Rybicka-Ramos Malwina23,Giles Graham G.242526ORCID,Milne Roger L.242526ORCID,Hofmann Jonathan N.14,Zaucha Jan Maciej27ORCID,Vangsted Annette Juul28ORCID,Goldschmidt Hartmut29ORCID,Rajkumar S. Vincent7ORCID,Tomczak Waldemar30ORCID,Sainz Juan3132ORCID,Butrym Aleksandra33,Watek Marzena34ORCID,Iskierka-Jazdzewska Elżbieta35ORCID,Buda Gabriele9ORCID,Robinson Dennis P.13,Jurczyszyn Artur36,Dudziński Marek37ORCID,Martinez-Lopez Joaquin38ORCID,Sinnwell Jason P.13ORCID,Slager Susan L.13ORCID,Jamroziak Krzysztof39,Reis Rui Manuel Vieira4041ORCID,Weinhold Niels2942ORCID,Bhatti Parveen4344ORCID,Carvajal-Carmona Luis G.454647ORCID,Zawirska Daria48ORCID,Norman Aaron D.13,Mazur Grzegorz33ORCID,Berndt Sonja I.14ORCID,Campa Daniele2,Vachon Celine M.49ORCID,Canzian Federico1ORCID

Affiliation:

1. 1Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.

2. 2Department of Biology, University of Pisa, Pisa, Italy.

3. 3Department of Epidemiology & Biostatistics, Arnold School of Public Health, University of South Carolina, Greenville, South Carolina.

4. 4Division of Biostatistics, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.

5. 5Department of Lymphoma - Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

6. 6Department of Hematology University Hospital Bydgoszcz, Bydgoszcz, Poland.

7. 7Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

8. 8Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California.

9. 9Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.

10. 10Department of Pathology, School of Medicine, University of Alabama, Birmingham, Alabama.

11. 11Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.

12. 12Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.

13. 13Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.

14. 14Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

15. 15Division of Hematology and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

16. 16Department of Haematology and Bone Marrow Transplantation, SSM im. M. Kopernika, Torun, Poland.

17. 17Department of Hematology, Rydygier Hospital, Cracow, Poland.

18. 18Division of Hematology/Oncology, Department of Medicine, School of Medicine, Department of Pathology, School of Medicine, Susan and Henry Samueli College of Health Sciences, Chao Family Comprehensive Cancer Center, University of California at Irvine, California.

19. 19Department of Hematology and Internal Medicine, Semmelweis University, Budapest, Hungary.

20. 20Department of Hematology, Military Institute of Medicine, Warsaw, Poland.

21. 21Biomedical Center, Faculty of Medicine, Charles University in Pilsen, Pilsen, Czech Republic.

22. 22Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

23. 23Department of Hematology Specialist Hospital No. 1 in Bytom, Bytom, Poland.

24. 24Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.

25. 25Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.

26. 26Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.

27. 27Department of Hematology and Transplantology, Medical Univeristy of Gdańsk, Gdańsk, Poland.

28. 28Department of Haematology, Rigshospitalet, Copenhagen University, Copenhagen, Denmark.

29. 29Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.

30. 30Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Poland.

31. 31Genomic Oncology Area, GENYO. Centre for Genomics and Oncological Research: Pfizer, University of Granada/Andalusian Regional Government, Granada, Spain.

32. 32Hematology department, Virgen de las Nieves University Hospital, Granada, Spain.

33. 33Department of Internal and Occupational Diseases, Medical University Wroclaw, Wroclaw, Poland.

34. 34Hematology Clinic, Holycross Cancer Center, Kielce, Poland.

35. 35Department of Hematology, Medical University of Lodz, Lodz, Poland.

36. 36Plasma Cell Dyscrasias Center, Department of Hematology, Faculty of Medicine, Jagiellonian University, Kraków, Poland.

37. 37Department of Hematology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszów, Rzeszów, Poland.

38. 38Servicio de Hematología Centro de Actividades Ambulatorias, Madrid, Spain.

39. 39Department of Hematology, Transplantation and Internal Disease, Medical University of Warsaw, Warsaw, Poland.

40. 40Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal and ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal.

41. 41Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.

42. 42CCU Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

43. 43Division of Population Oncology Cancer Control Research, BC Cancer, Vancouver, Bristish Columbia, Canada.

44. 44Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

45. 45Department of Biochemistry and Molecular Medicine, School of Medicine, University of California Davis, Sacramento, California.

46. 46Latinos United for Cancer Health Advancement Initiative, University of California Davis Comprehensive Cancer Center, Sacramento, California.

47. 47Community Engagement Program, Clinical and Translational Science Center, University of California Davis, Sacramento, California.

48. 48Department of Hematology, University Hospital of Cracow, Cracow, Poland.

49. 49Division of Epidemiology, Department of Quantitative Sciences, Mayo Clinic, Rochester, Minnesota.

Abstract

Abstract Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Publisher

American Association for Cancer Research (AACR)

Subject

Oncology,Epidemiology

Reference7 articles.

1. Genetic predisposition for multiple myeloma;Pertesi;Leukemia,2020

2. Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance;Clay-Gilmour;Blood Adv,2020

3. Comprehensive analysis of colorectal cancer-risk loci and survival outcome: a prognostic role for CDH1 variants;Summers;Eur J Cancer,2020

4. Melanoma risk loci as determinants of melanoma recurrence and survival;Rendleman;J Transl Med,2013

5. Genetics and molecular epidemiology of multiple myeloma: the rationale for the IMMEnSE consortium (review);Martino;Int J Oncol,2012

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