International Journal of Molecular Sciences (May 2023)
Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization
- Esther Clavero,
- José Manuel Sanchez-Maldonado,
- Angelica Macauda,
- Rob Ter Horst,
- Belém Sampaio-Marques,
- Artur Jurczyszyn,
- Alyssa Clay-Gilmour,
- Angelika Stein,
- Michelle A. T. Hildebrandt,
- Niels Weinhold,
- Gabriele Buda,
- Ramón García-Sanz,
- Waldemar Tomczak,
- Ulla Vogel,
- Andrés Jerez,
- Daria Zawirska,
- Marzena Wątek,
- Jonathan N. Hofmann,
- Stefano Landi,
- John J. Spinelli,
- Aleksandra Butrym,
- Abhishek Kumar,
- Joaquín Martínez-López,
- Sara Galimberti,
- María Eugenia Sarasquete,
- Edyta Subocz,
- Elzbieta Iskierka-Jażdżewska,
- Graham G. Giles,
- Malwina Rybicka-Ramos,
- Marcin Kruszewski,
- Niels Abildgaard,
- Francisco García Verdejo,
- Pedro Sánchez Rovira,
- Miguel Inacio da Silva Filho,
- Katalin Kadar,
- Małgorzata Razny,
- Wendy Cozen,
- Matteo Pelosini,
- Manuel Jurado,
- Parveen Bhatti,
- Marek Dudzinski,
- Agnieszka Druzd-Sitek,
- Enrico Orciuolo,
- Yang Li,
- Aaron D. Norman,
- Jan Maciej Zaucha,
- Rui Manuel Reis,
- Miroslaw Markiewicz,
- Juan José Rodríguez Sevilla,
- Vibeke Andersen,
- Krzysztof Jamroziak,
- Kari Hemminki,
- Sonja I. Berndt,
- Vicent Rajkumar,
- Grzegorz Mazur,
- Shaji K. Kumar,
- Paula Ludovico,
- Arnon Nagler,
- Stephen J. Chanock,
- Charles Dumontet,
- Mitchell J. Machiela,
- Judit Varkonyi,
- Nicola J. Camp,
- Elad Ziv,
- Annette Juul Vangsted,
- Elizabeth E. Brown,
- Daniele Campa,
- Celine M. Vachon,
- Mihai G. Netea,
- Federico Canzian,
- Asta Försti,
- Juan Sainz
Affiliations
- Esther Clavero
- Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain
- José Manuel Sanchez-Maldonado
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain
- Angelica Macauda
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Rob Ter Horst
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Belém Sampaio-Marques
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- Artur Jurczyszyn
- Plasma Cell Dyscrasias Center, Department of Hematology, Jagiellonian University Medical College, 31-066 Kraków, Poland
- Alyssa Clay-Gilmour
- Department of Biostatistics and Epidemiology, Arnold School of Public Health, University of South Carolina, Greenville, SC 29208, USA
- Angelika Stein
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Michelle A. T. Hildebrandt
- Department of Lymphoma–Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Niels Weinhold
- Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
- Gabriele Buda
- Haematology Unit, Department of Clinical and Experimental Medicine, University of Pisa/AOUP, 56126 Pisa, Italy
- Ramón García-Sanz
- Diagnostic Laboratory Unit in Hematology, University Hospital of Salamanca, IBSAL, CIBERONC, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), 37007 Salamanca, Spain
- Waldemar Tomczak
- Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-059 Lublin, Poland
- Ulla Vogel
- National Research Centre for the Working Environment, DK-2100 Copenhagen, Denmark
- Andrés Jerez
- Department of Hematology, Experimental Hematology Unit, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, 08035 Barcelona, Spain
- Daria Zawirska
- Department of Hematology, University Hospital, 30-688 Kraków, Poland
- Marzena Wątek
- Holycross Medical Oncology Center, 25-735 Kielce, Poland
- Jonathan N. Hofmann
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Stefano Landi
- Department of Biology, University of Pisa, 56126 Pisa, Italy
- John J. Spinelli
- Division of Population Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada
- Aleksandra Butrym
- Department of Cancer Prevention and Therapy, Wroclaw Medical University, 50-367 Wroclaw, Poland
- Abhishek Kumar
- Institute of Bioinformatics, International Technology Park, Bangalore 560066, India
- Joaquín Martínez-López
- Hospital 12 de Octubre, Complutense University, CNIO, CIBERONC, 28041 Madrid, Spain
- Sara Galimberti
- Haematology Unit, Department of Clinical and Experimental Medicine, University of Pisa/AOUP, 56126 Pisa, Italy
- María Eugenia Sarasquete
- Diagnostic Laboratory Unit in Hematology, University Hospital of Salamanca, IBSAL, CIBERONC, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), 37007 Salamanca, Spain
- Edyta Subocz
- Department of Hematology, Military Institute of Medicine, 04-141 Warsaw, Poland
- Elzbieta Iskierka-Jażdżewska
- Department of Hematology, Medical University of Lodz, 90-419 Lodz, Poland
- Graham G. Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia
- Malwina Rybicka-Ramos
- Department of Hematology, Specialist Hospital No. 1 in Bytom, Academy of Silesia, Faculty of Medicine, 40-055 Katowice, Poland
- Marcin Kruszewski
- Department of Hematology, University Hospital No. 2, 85-168 Bydgoszcz, Poland
- Niels Abildgaard
- Department of Hematology, Odense University Hospital, DK-5000 Odense, Denmark
- Francisco García Verdejo
- Department of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, Spain
- Pedro Sánchez Rovira
- Department of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, Spain
- Miguel Inacio da Silva Filho
- Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany
- Katalin Kadar
- St Johns Hospital, 62769 Budapest, Hungary
- Małgorzata Razny
- Department of Hematology, Rydygier Hospital, 31-826 Cracow, Poland
- Wendy Cozen
- Division 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, Irvine, CA 92697, USA
- Matteo Pelosini
- U.O. Dipartimento di Ematologia, Azienda USL Toscana Nord Ovest, 57124 Livorno, Italy
- Manuel Jurado
- Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain
- Parveen Bhatti
- Cancer Control Research, BC Cancer, Vancouver, BC V5Z 4E6, Canada
- Marek Dudzinski
- Department of Hematology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-310 Rzeszow, Poland
- Agnieszka Druzd-Sitek
- Department of Lymphoproliferative Diseases, Maria Skłodowska Curie National Research Institute of Oncology, 02-781 Warsaw, Poland
- Enrico Orciuolo
- Haematology Unit, Department of Clinical and Experimental Medicine, University of Pisa/AOUP, 56126 Pisa, Italy
- Yang Li
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Aaron D. Norman
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA
- Jan Maciej Zaucha
- Department of Hematology and Transplantology, Medical University of Gdansk, 80-210 Gdansk, Poland
- Rui Manuel Reis
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, 4710-057 Braga, Portugal and ICVS/3B’s-PT Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal
- Miroslaw Markiewicz
- Department of Hematology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-310 Rzeszow, Poland
- Juan José Rodríguez Sevilla
- Department of Hematology, Hospital del Mar, 08003 Barcelona, Spain
- Vibeke Andersen
- Molecular Diagnostics and Clinical Research Unit, Institute of Regional Health Research, University Hospital of Southern Denmark, DK-6200 Aabenraa, Denmark
- Krzysztof Jamroziak
- Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland
- Kari Hemminki
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Vicent Rajkumar
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902, USA
- Grzegorz Mazur
- Department of Internal Diseases, Occupational Medicine, Hypertension and Clinical Oncology, Wroclaw Medical University, 50-368 Wroclaw, Poland
- Shaji K. Kumar
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902, USA
- Paula Ludovico
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- Arnon Nagler
- Hematology Division, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel
- Stephen J. Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Charles Dumontet
- UMR INSERM 1052/CNRS 5286, University of Lyon, Hospices Civils de Lyon, 69008 Lyon, France
- Mitchell J. Machiela
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Judit Varkonyi
- Semmelweis University, 1083 Budapest, Hungary
- Nicola J. Camp
- Division of Hematology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
- Elad Ziv
- Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, USA
- Annette Juul Vangsted
- Department of Hematology, Rigshospitalet, Copenhagen University, DK-2100 Copenhagen, Denmark
- Elizabeth E. Brown
- Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Daniele Campa
- Department of Biology, University of Pisa, 56126 Pisa, Italy
- Celine M. Vachon
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA
- Mihai G. Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Federico Canzian
- Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Asta Försti
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany
- Juan Sainz
- Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain
- DOI
- https://doi.org/10.3390/ijms24108500
- Journal volume & issue
-
Vol. 24,
no. 10
p. 8500
Abstract
Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p −9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10−4−5.79 × 10−14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10−4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10−4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10−4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3− B cells, CD5+IgD− cells, IgM− cells, IgD−IgM− cells, and CD4−CD8− PBMCs (p = 4.9 × 10−4−8.6 × 10−4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27− cells (p = 9.3 × 10−4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3−, MCP-2−, and IL20-dependent pathways.
Keywords