Citations 2
Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization
Clavero, Esther, Sánchez‐Maldonado, José Manuel , Macauda, Angelica , Sampaio‐Marques, Belém , Jurczyszyn, Artur , Clay‐Gilmour, Alyssa , Stein, Angelika, Weinhold, Niels , Buda, Gabriele , García‐Sánz, Ramón , Tomczak, Waldemar , Vogel, Ulla , Jerez, Andrés , Zawirska, Daria , Wątek, Marzena , Landi, Stefano , Spinelli, John J. , Butrym, Aleksandra , Martínez‐López, Joaquín , Galimberti, Sara , Sarasquete, María Eugenia , Subocz, Edyta , Iskierka‐Jazdzewska, Elżbieta , Giles, Graham G. , Rybicka‐Ramos, Malwina, Kruszewski, Marcin , Abildgaard, Niels , Verdejo, Francisco García, Sánchez‐Rovira, Pedro , Filho, Miguel Inácio da Silva, Kádár, Katalin , Raźny, Małgorzata , Pelosini, Matteo , Jurado, Manuel , Bhatti, Parveen , Dudziński, Marek , Druzd‐Sitek, Agnieszka , Li, Yang , Zaucha, Jan Maciej , Reis, Rui Manuel , Markiewicz, Mirosław , Rodríguez‐Sevilla, Juan José , Andersen, Vibeke , Hemminki, Kari , Berndt, Sonja I. , Rajkumar, Vicent, Mazur, Grzegorz , Kumar, Shaji , Ludovico, Paula , Nagler, Arnon , Machiela, Mitchell J. , Várkonyi, Judit , Camp, Nicola J. , Ziv, Elad , Brown, Elizabeth E. , Campa, Daniele , Vachon, Celine M. , Netea, Mihai G. , Canzian, Federico , Försti, Asta , Sáinz, Juan , Martinez-Lopez, Joaquin , Sampaio-Marques, Belém , Jurczyszyn, Artur , Clay-Gilmour, Alyssa, Tomczak, Waldemar , Vogel, Ulla , Jerez, Andrés , Landi, Stefano , Butrym, Aleksandra , Galimberti, Sara , Subocz, Edyta , Iskierka-Jazdzewska, Elżbieta , Giles, Graham G , Kadar, Katalin , Li, Yang , Zaucha, Jan Maciej , Reis, Rui Manuel , Markiewicz, Miroslaw , Rodríguez-Sevilla, Juan José , Andersen, Vibeke , Hemminki, Kari , Mazur, Grzegorz , Ludovico, Paula , Canzian, Federico , Försti, Asta , Sainz, Juan , Martinez-Lopez, Joaquin , Garcia-Sanz, Ramon , Bhatti, Parveen , Ziv, Elad , Machiela, Mitchell J , Watek, Marzena , Martinez-Lopez, Joaquin , Horst, Rob ter , Hildebrandt, Michelle A.T. , Hofmann, Jonathan N. , Kumar, Abhishek , Verdejo, Francisco José García, Cozen, Wendy , Orciuolo, Enrico , Norman, Aaron D. , Jamroziak, Krzysztof , Chanock, Stephen Jacob , Dumontet, Charles , Vangsted, Annette Juul , Vachon, Celine M. , Netea, M. G.
International Journal of Molecular Sciences | May 10, 2023 | Volume: 24 | Issue: 10 | Pages: 8500
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 < 1 × 10−9) 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.
Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients
Macauda, Angelica , Piredda, Chiara , Clay‐Gilmour, Alyssa , Sáinz, Juan , Buda, Gabriele , Markiewicz, Mirosław , Barington, Torben , Ziv, Elad , Hildebrandt, Michelle A.T. , Belachew, Alem A. , Várkonyi, Judit , Prejzner, Witold , Druzd‐Sitek, Agnieszka , Spinelli, John J. , Andersen, Niels Frost, Dudziński, Marek , Martínez‐López, Joaquín , Iskierka‐Jazdzewska, Elżbieta , Mazur, Grzegorz , Ebbesen, Lene Hyldahl, Rymko, Marcin , Subocz, Edyta , Reis, Rui Manuel , García‐Sánz, Ramón , Suska, Anna , Haastrup, Eva, Zawirska, Daria , Grząśko, Norbert , Kruszewski, Marcin , Dutka, Magdalena , Camp, Nicola J. , Waller, Rosalie, Pelosini, Matteo , Raźny, Małgorzata , Abildgaard, Niels , Wątek, Marzena , Brown, Elizabeth E. , Berndt, Sonja I. , Butrym, Aleksandra , Vachon, Celine M. , Gemignani, Federica , Campa, Daniele , Martinez-Lopez, Joaquin , Waller, Rosalie G. , Griffin, R. L. , Canzian, Federico , Campa, Daniele , Martinez-Lopez, Joaquin , Butrym, Aleksandra , Reis, Rui Manuel , Garcia-Sanz, Ramon , Ziv, Elad , Waller, Rosalie G , Rymko, Marcin , Subocz, Edyta , Tomczak, Waldemar , Sainz, Juan , Watek, Marzena , Iskierka-Jazdzewska, Elżbieta , Martinez-Lopez, Joaquin , Mazur, Grzegorz , Hildebrandt, Michelle A T , Markiewicz, Miroslaw , Macauda, Angelica , Griffin, Rosalie , Hofmann, Jonathan N. , Milne, Roger L. , Giles, Graham G. , Jamroziak, Krzysztof , Vangsted, Annette Juul , Dumontet, Charles , Tomczak, Waldemar , Marques, Herlander , Jurczyszyn, Artur , Vachon, Celine M. , Norman, Aaron D. , Slager, Susan L. , Canzian, Federico
International Journal of Cancer | March 6, 2021 | Volume: 149 | Issue: 2 | Pages: 327-336
AbstractGene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype‐tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10−7 either in EBV‐transformed B‐lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression‐free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4‐rs1992292, TBRG4‐rs2287535 and ENTPD1‐rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta‐analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4‐rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04‐1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.