A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk

Marco Dicanio; Matteo Giaccherini; Alyssa Clay-Gilmour; Angelica Macauda; Juan Sainz; Mitchell J Machiela; Malwina Rybicka-Ramos; Aaron D Norman; Agata Tyczyńska; Stephen J Chanock; Torben Barington; Shaji K Kumar; Parveen Bhatti; Wendy Cozen; Elizabeth E Brown; Anna Suska; Eva K Haastrup; Robert Z Orlowski; Marek Dudziński; Ramon Garcia-Sanz; Marcin Kruszewski; Joaquin Martinez-Lopez; Katia Beider; Elżbieta Iskierka-Jazdzewska; Matteo Pelosini; Sonja I Berndt; Małgorzata Raźny; Krzysztof Jamroziak; S Vincent Rajkumar; Artur Jurczyszyn; Annette Juul Vangsted; Pilar Garrido Collado; Ulla Vogel; Jonathan N Hofmann; Mario Petrini; Aleksandra Butrym; Susan L Slager; Elad Ziv; Edyta Subocz; Graham G Giles; Niels Frost Andersen; Grzegorz Mazur; Marzena Watek; Fabienne Lesueur; Michelle A T Hildebrandt; Daria Zawirska; Lene Hyldahl Ebbesen; Herlander Marques; Federica Gemignani; Charles Dumontet; Judit Várkonyi; Gabriele Buda; Arnon Nagler; Agnieszka Druzd-Sitek; Xifeng Wu; Katalin Kadar; Nicola J Camp; Norbert Grzasko; Rosalie G Waller; Celine Vachon; Federico Canzian; Daniele Campa

doi:10.1002/ijc.34278

A pleiotropic variant in DNAJB4 is associated with multiple myeloma risk

Int J Cancer. 2023 Jan 15;152(2):239-248. doi: 10.1002/ijc.34278. Epub 2022 Oct 1.

Authors

Marco Dicanio¹, Matteo Giaccherini¹, Alyssa Clay-Gilmour², Angelica Macauda³, Juan Sainz^{4

5

6}, Mitchell J Machiela⁷, Malwina Rybicka-Ramos⁸, Aaron D Norman^{9

10}, Agata Tyczyńska¹¹, Stephen J Chanock⁷, Torben Barington¹², Shaji K Kumar¹³, Parveen Bhatti^{14

15}, Wendy Cozen^{16

17}, Elizabeth E Brown¹⁸, Anna Suska¹⁹, Eva K Haastrup¹², Robert Z Orlowski²⁰, Marek Dudziński²¹, Ramon Garcia-Sanz²², Marcin Kruszewski²³, Joaquin Martinez-Lopez²⁴, Katia Beider²⁵, Elżbieta Iskierka-Jazdzewska²⁶, Matteo Pelosini²⁷, Sonja I Berndt⁷, Małgorzata Raźny²⁸, Krzysztof Jamroziak²⁹, S Vincent Rajkumar¹³, Artur Jurczyszyn¹⁹, Annette Juul Vangsted¹², Pilar Garrido Collado⁵, Ulla Vogel³⁰, Jonathan N Hofmann⁷, Mario Petrini³¹, Aleksandra Butrym³², Susan L Slager⁹, Elad Ziv³³, Edyta Subocz³⁴, Graham G Giles^{35

36

37}, Niels Frost Andersen¹², Grzegorz Mazur³⁸, Marzena Watek^{29

39}, Fabienne Lesueur⁴⁰, Michelle A T Hildebrandt²⁰, Daria Zawirska⁴¹, Lene Hyldahl Ebbesen¹², Herlander Marques⁴², Federica Gemignani¹, Charles Dumontet⁴³, Judit Várkonyi⁴⁴, Gabriele Buda³¹, Arnon Nagler²⁵, Agnieszka Druzd-Sitek⁴⁵, Xifeng Wu⁴⁶, Katalin Kadar⁴⁴, Nicola J Camp⁴⁷, Norbert Grzasko⁴⁸, Rosalie G Waller¹⁰, Celine Vachon⁹, Federico Canzian³, Daniele Campa¹

Affiliations

¹ Department of Biology, University of Pisa, Pisa, Italy.
² Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Greenville, South Carolina, USA.
³ Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴ Genomic Oncology Area, GENYO. Center for Genomics and Oncological Research: Pfizer, University of Granada/Andalusian Regional Government, Granada, Spain.
⁵ Department of Hematology, Virgen de las Nieves University Hospital, Granada, Spain.
⁶ Department of Medicine, University of Granada, Granada, Spain.
⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institues of Health, Bethesda, Maryland, USA.
⁸ Department of Hematology Specialist Hospital No. 1, Bytom, Poland.
⁹ Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Ontario, USA.
¹⁰ Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Ontario, USA.
¹¹ Department of Hematology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland.
¹² Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
¹³ Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Ontario, USA.
¹⁴ Cancer Control Research, BC Cancer, Vancouver, Canada.
¹⁵ Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
¹⁶ Division of Hematology/Oncology, Department of Medicine, School of Medicine, Susan and Henry Samueli College of Health Sciences, Chao Family Comprehensive Cancer Center, University of California, Irvine, California, USA.
¹⁷ Department of Pathology, School of Medicine, Susan and Henry Samueli College of Health Sciences, Chao Family Comprehensive Cancer Center, University of California, Irvine, California, USA.
¹⁸ Department of Pathology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹⁹ Plasma Cell Dyscrasia Center Department of Hematology Jagiellonian University Faculty of Medicine, Kraków, Poland.
²⁰ Department of Lymphoma - Myeloma, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
²¹ Department of Hematology, Institute of Medical Sciences, College of Medical Sciences, University of Rzeszow, Rzeszow, Poland.
²² Medina A. Department of Hematology, University Hospital of Salamanca (HUS/IBSAL), CIBERONC and Cancer Research Institute of Salamanca-IBMCC (USAL-CSIC), Salamanca, Spain.
²³ Department of Hematology, University Hospital No. 2 in Bydgoszcz, Bydgoszcz, Poland.
²⁴ Hospital 12 de Octubre, Compluntense University, CNIO, CIBERONC, Madrid, Spain.
²⁵ Hematology Division Chaim Sheba Medical Center, Tel Hashomer, Israel.
²⁶ Department of Hematology, Medical University of Lodz, Łódź, Poland.
²⁷ U.O. Dipartimento di Ematologia, Azienda USL Toscana Nord Ovest, Livorno, Italy.
²⁸ Department of Hematology, Rydygier Hospital, Cracow, Poland.
²⁹ Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
³⁰ National Research Center for the Working Environment, Copenhagen, Denmark.
³¹ Hematology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
³² Department of Cancer Prevention and Therapy, Wroclaw Medical University, Wroclaw, Poland.
³³ Department of Medicine, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, California, USA.
³⁴ Department of Hematology, Military Institute of Medicine, Warsaw, Poland.
³⁵ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
³⁶ Center for Epidemiology and Biostatistics, School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
³⁷ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
³⁸ Department of Internal Diseases, Occupational Medicine, Hypertension and Clinical Oncology, Wroclaw Medical University, Wroclaw, Poland.
³⁹ Department of Hematology, Holycross Cancer Center, Kielce, Poland.
⁴⁰ Inserm, U900, Institut Curie, PSL Research University, Mines ParisTech, Paris, France.
⁴¹ Department of Hematology, University Hospital in Cracow, Cracow, Poland.
⁴² Life 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.
⁴³ INSERM 1052/CNRS 5286/University of Lyon, Lyon, France.
⁴⁴ Department of Hematology and Internal Medicine, Semmelweis University, Budapest, Hungary.
⁴⁵ Department of Lymphoproliferative Diseases, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland.
⁴⁶ Department of Epidemiology, Division of Cancer Prevention and Population Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴⁷ Division of Hematology and Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
⁴⁸ Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland.

Abstract

Pleiotropy, which consists of a single gene or allelic variant affecting multiple unrelated traits, is common across cancers, with evidence for genome-wide significant loci shared across cancer and noncancer traits. This feature is particularly relevant in multiple myeloma (MM) because several susceptibility loci that have been identified to date are pleiotropic. Therefore, the aim of this study was to identify novel pleiotropic variants involved in MM risk using 28 684 independent single nucleotide polymorphisms (SNPs) from GWAS Catalog that reached a significant association (P < 5 × 10^-8 ) with their respective trait. The selected SNPs were analyzed in 2434 MM cases and 3446 controls from the International Lymphoma Epidemiology Consortium (InterLymph). The 10 SNPs showing the strongest associations with MM risk in InterLymph were selected for replication in an independent set of 1955 MM cases and 1549 controls from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and 418 MM cases and 147 282 controls from the FinnGen project. The combined analysis of the three studies identified an association between DNAJB4-rs34517439-A and an increased risk of developing MM (OR = 1.22, 95%CI 1.13-1.32, P = 4.81 × 10^-7 ). rs34517439-A is associated with a modified expression of the FUBP1 gene, which encodes a multifunctional DNA and RNA-binding protein that it was observed to influence the regulation of various genes involved in cell cycle regulation, among which various oncogenes and oncosuppressors. In conclusion, with a pleiotropic scan approach we identified DNAJB4-rs34517439 as a potentially novel MM risk locus.

Keywords: genetic susceptibility; multiple myeloma; pleiotropy; pleiotropy scan; polymorphisms.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
DNA-Binding Proteins / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study
HSP40 Heat-Shock Proteins / genetics
Humans
Multiple Myeloma* / epidemiology
Multiple Myeloma* / genetics
Oncogenes
Phenotype
Polymorphism, Single Nucleotide
RNA-Binding Proteins

Substances

DNAJB4 protein, human
HSP40 Heat-Shock Proteins
FUBP1 protein, human
DNA-Binding Proteins
RNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding