TY - JOUR

T1 - Common gene variants within 3′-untranslated regions as modulators of multiple myeloma risk and survival

AU - Melaiu, Ombretta

AU - Macauda, Angelica

AU - Sainz, Juan

AU - Calvetti, Diego

AU - Facioni, Maria Sole

AU - Maccari, Giuseppe

AU - ter Horst, Rob

AU - Netea, Mihai G.

AU - Li, Yang

AU - Grząśko, Norbert

AU - Moreno, Victor

AU - Jurczyszyn, Artur

AU - Jerez, Andrés

AU - Watek, Marzena

AU - Varkonyi, Judit

AU - Garcia-Sanz, Ramon

AU - Kruszewski, Marcin

AU - Dudziński, Marek

AU - Kadar, Katalin

AU - Jacobsen, Svend Erik Hove

AU - Mazur, Grzegorz

AU - Andersen, Vibeke

AU - Rybicka, Malwina

AU - Zawirska, Daria

AU - Raźny, Malgorzata

AU - Zaucha, Jan Maciej

AU - Ostrovsky, Olga

AU - Iskierka-Jazdzewska, Elzbieta

AU - Reis, Rui Manuel

AU - Stępień, Anna

AU - Beider, Katia

AU - Nagler, Arnon

AU - Druzd-Sitek, Agnieszka

AU - Marques, Herlander

AU - Martìnez-Lopez, Joaquin

AU - Lesueur, Fabienne

AU - Avet-Loiseau, Hervé

AU - Vangsted, Annette Juul

AU - Krawczyk-Kulis, Malgorzata

AU - Butrym, Aleksandra

AU - Jamroziak, Krzysztof

AU - Dumontet, Charles

AU - Vogel, Ulla

AU - Rymko, Marcin

AU - Pelosini, Matteo

AU - Subocz, Edyta

AU - Szombath, Gergely

AU - Sarasquete, Maria Eugenia

AU - Silvestri, Roberto

AU - Morani, Federica

AU - Landi, Stefano

AU - Campa, Daniele

AU - Canzian, Federico

AU - Gemignani, Federica

N1 - Funding Information: This work was partially supported by intramural funds of University of Pisa and DKFZ and by grants from the FIBAO foundation (Granada, Spain), from the CRIS foundation against cancer, from the Cancer Network of Excellence (RD12/10 Red de Cáncer), from the Instituto de Salud Carlos III (Madrid, Spain; PI12/02688 and PI17/02276). Publisher Copyright: © 2020 Union for International Cancer Control

PY - 2021/4/15

Y1 - 2021/4/15

N2 - We evaluated the association between germline genetic variants located within the 3′-untranlsated region (polymorphic 3′UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3′-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.

AB - We evaluated the association between germline genetic variants located within the 3′-untranlsated region (polymorphic 3′UTR, ie, p3UTR) of candidate genes involved in multiple myeloma (MM). We performed a case-control study within the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 3056 MM patients and 1960 controls recruited from eight countries. We selected p3UTR of six genes known to act in different pathways relevant in MM pathogenesis, namely KRAS (rs12587 and rs7973623), VEGFA (rs10434), SPP1 (rs1126772), IRF4 (rs12211228) and IL10 (rs3024496). We found that IL10-rs3024496 was associated with increased risk of developing MM and with a worse overall survival of MM patients. The variant allele was assayed in a vector expressing eGFP chimerized with the IL10 3′-UTR and it was found functionally active following transfection in human myeloma cells. In this experiment, the A-allele caused a lower expression of the reporter gene and this was also in agreement with the in vivo expression of mRNA measured in whole blood as reported in the GTEx portal. Overall, these data are suggestive of an effect of the IL10-rs3024496 SNP on the regulation of IL10 mRNA expression and it could have clinical implications for better characterization of MM patients in terms of prognosis.

KW - 3′-untranslated region

KW - multiple myeloma

KW - overall survival

KW - risk

KW - single nucleotide polymorphisms

KW - susceptibility

U2 - 10.1002/ijc.33377

DO - 10.1002/ijc.33377

M3 - Journal article

C2 - 33152124

AN - SCOPUS:85096652041

VL - 148

SP - 1887

EP - 1894

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 8

ER -