Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Aaron D Norman, Vicent Rajkumar, Kari Hemminki, Krzysztof Jamroziak, Vibeke Andersen, Juan José Rodríguez Sevilla, Miroslaw Markiewicz, Rui Manuel Reis, Jan Maciej Zaucha, Grzegorz Mazur, Yang Li, Enrico Orciuolo, Agnieszka Druzd-Sitek, Marek Dudzinski, Parveen Bhatti, Manuel Jurado, Matteo Pelosini, Wendy Cozen, Elad Ziv, Juan Sainz, Asta Försti, Federico Canzian, Mihai G Netea, Celine M Vachon, Daniele Campa, Elizabeth E Brown, Annette Juul Vangsted, Małgorzata Razny, Nicola J Camp, Judit Varkonyi, Mitchell J Machiela, Charles Dumontet, Stephen J Chanock, Arnon Nagler, Paula Ludovico, Shaji K Kumar, Michelle A T Hildebrandt, Marzena Wątek, Daria Zawirska, Andrés Jerez, Ulla Vogel, Waldemar Tomczak, Ramón García-Sanz, Gabriele Buda, Niels Weinhold, Jonathan N Hofmann, Angelika Stein, Alyssa Clay-Gilmour, Artur Jurczyszyn, Belém Sampaio-Marques, Rob Ter Horst, Angelica Macauda, José Manuel Sanchez-Maldonado, Esther Clavero, Elzbieta Iskierka-Jażdżewska, Katalin Kadar, Miguel Inacio da Silva Filho, Pedro Sánchez Rovira, Francisco García Verdejo, Niels Abildgaard, Marcin Kruszewski, Malwina Rybicka-Ramos, Graham G Giles, Sonja I Berndt, Edyta Subocz, María Eugenia Sarasquete, Sara Galimberti, Joaquín Martínez-López, Abhishek Kumar, Aleksandra Butrym, John J Spinelli, Stefano Landi

Journal: International journal of molecular sciences 2023;24(10):8500

PMID: 37239846

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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; < 1 × 10) 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, , , , , , and associated with MM risk ( = 4.47 × 10-5.79 × 10). Mechanistically, we found that the SNP correlated with circulating concentrations of vitamin D3 ( = 4.0 × 10), whereas the SNP correlated with the number of transitional CD24CD38 B cells ( = 4.8 × 10) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 ( = 3.6 × 10). We also found that the SNP correlated with numbers of CD19 B cells, CD19CD3 B cells, CD5IgD cells, IgM cells, IgDIgM cells, and CD4CD8 PBMCs ( = 4.9 × 10-8.6 × 10) and circulating concentrations of interleukin (IL)-20 ( = 0.00082). Finally, we observed that the SNP correlated with levels of CD4EMCD45ROCD27 cells ( = 9.3 × 10). 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.

Address: Hematology Department, Virgen de las Nieves University Hospital, 18012 Granada, Spain.; Genomic Oncology Area, GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS, 18016 Granada, Spain.; Instituto de Investigación Biosanataria IBs, Granada, 18014 Granada, Spain.; Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.; Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal.; Plasma Cell Dyscrasias Center, Department of Hematology, Jagiellonian University Medical College, 31-066 Kraków, Poland.; Department of Biostatistics and Epidemiology, Arnold School of Public Health, University of South Carolina, Greenville, SC 29208, USA.; Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA.; Department of Lymphoma-Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.; Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.; Department of Internal Medicine V, University of Heidelberg, 69120 Heidelberg, Germany.; Haematology Unit, Department of Clinical and Experimental Medicine, University of Pisa/AOUP, 56126 Pisa, Italy.; Diagnostic Laboratory Unit in Hematology, University Hospital of Salamanca, IBSAL, CIBERONC, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), 37007 Salamanca, Spain.; Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, 20-059 Lublin, Poland.; National Research Centre for the Working Environment, DK-2100 Copenhagen, Denmark.; Department of Hematology, Experimental Hematology Unit, Vall d'Hebron Institute of Oncology (VHIO), University Hospital Vall d'Hebron, 08035 Barcelona, Spain.; Department of Hematology, University Hospital, 30-688 Kraków, Poland.; Holycross Medical Oncology Center, 25-735 Kielce, Poland.; Institute of Hematology and Transfusion Medicine, 00-791 Warsaw, Poland.; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.; Department of Biology, University of Pisa, 56126 Pisa, Italy.; Division of Population Oncology, BC Cancer, Vancouver, BC V5Z 4E6, Canada.; School of Population and Public Health, University of British Columbia, Vancouver, BC V6T 1Z4, Canada.; Department of Cancer Prevention and Therapy, Wroclaw Medical University, 50-367 Wroclaw, Poland.; Alfred Sokolowski Specialist Hospital in Walbrzych Oncology Support Centre for Clinical Trials, 58-309 Walbrzych, Poland.; Institute of Bioinformatics, International Technology Park, Bangalore 560066, India.; Manipal Academy of Higher Education (MAHE), Manipal 576104, India.; Hospital 12 de Octubre, Complutense University, CNIO, CIBERONC, 28041 Madrid, Spain.; Department of Hematology, Military Institute of Medicine, 04-141 Warsaw, Poland.; Department of Hematology, Medical University of Lodz, 90-419 Lodz, Poland.; Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia.; Centre for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.; Department of Hematology, Specialist Hospital No. 1 in Bytom, Academy of Silesia, Faculty of Medicine, 40-055 Katowice, Poland.; Department of Hematology, University Hospital No. 2, 85-168 Bydgoszcz, Poland.; Department of Hematology, Odense University Hospital, DK-5000 Odense, Denmark.; Department of Medical Oncology, Complejo Hospitalario de Jaén, 23007 Jaén, Spain.; Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.; St Johns Hospital, 62769 Budapest, Hungary.; Department of Hematology, Rydygier Hospital, 31-826 Cracow, Poland.; 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.; U.O. Dipartimento di Ematologia, Azienda USL Toscana Nord Ovest, 57124 Livorno, Italy.; Department of Medicine, University of Granada, 18012 Granada, Spain.; Cancer Control Research, BC Cancer, Vancouver, BC V5Z 4E6, Canada.; Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.; Department of Hematology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, 35-310 Rzeszow, Poland.; Department of Lymphoproliferative Diseases, Maria Skłodowska Curie National Research Institute of Oncology, 02-781 Warsaw, Poland.; Centre for Individualised Infection Medicine (CiiM) & TWINCORE, Joint Ventures between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), 30625 Hannover, Germany.; Genetic Epidemiology and Risk Assessment Program, Mayo Clinic Comprehensive Cancer Center, Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55902, USA.; Department of Hematology and Transplantology, Medical University of Gdansk, 80-210 Gdansk, Poland.; 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.; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil.; Department of Hematology, Hospital del Mar, 08003 Barcelona, Spain.; Molecular Diagnostics and Clinical Research Unit, Institute of Regional Health Research, University Hospital of Southern Denmark, DK-6200 Aabenraa, Denmark.; Department of Hematology, Transplantology and Internal Medicine, Medical University of Warsaw, 02-097 Warsaw, Poland.; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.; Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic.; Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55902, USA.; Department of Internal Diseases, Occupational Medicine, Hypertension and Clinical Oncology, Wroclaw Medical University, 50-368 Wroclaw, Poland.; Hematology Division, Chaim Sheba Medical Center, Tel Hashomer 52621, Israel.; UMR INSERM 1052/CNRS 5286, University of Lyon, Hospices Civils de Lyon, 69008 Lyon, France.; Semmelweis University, 1083 Budapest, Hungary.; Division of Hematology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.; Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, USA.; Department of Hematology, Rigshospitalet, Copenhagen University, DK-2100 Copenhagen, Denmark.; Department of Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.; Department for Immunology & Metabolism, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany.; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.; Hopp Children's Cancer Center (KiTZ), 69120 Heidelberg, Germany.; Department of Biochemistry and Molecular Biology I, University of Granada, 18071 Granada, Spain.

DOI: 10.3390/ijms24108500