Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients

Angelica Macauda; Chiara Piredda; Alyssa I. Clay-Gilmour; Juan Sainz; Gabriele Buda; Miroslaw Markiewicz; Torben Barington; Elad Ziv; Michelle A.T. Hildebrandt; Alem A. Belachew; Judit Varkonyi; Witold Prejzner; Agnieszka Druzd-Sitek; John Spinelli; Niels Frost Andersen; Jonathan N. Hofmann; Marek Dudziński; Joaquin Martinez-Lopez; Elzbieta Iskierka-Jazdzewska; Roger L. Milne; Grzegorz Mazur; Graham G. Giles; Lene Hyldahl Ebbesen; Marcin Rymko; Krzysztof Jamroziak; Edyta Subocz; Rui Manuel Reis; Ramon Garcia-Sanz; Anna Suska; Eva Kannik Haastrup; Daria Zawirska; Norbert Grzasko; Annette Juul Vangsted; Charles Dumontet; Marcin Kruszewski; Magdalena Dutka; Nicola J. Camp; Rosalie G. Waller; Waldemar Tomczak; Matteo Pelosini; Małgorzata Raźny; Herlander Marques; Niels Abildgaard; Marzena Wątek; Artur Jurczyszyn; Elizabeth E. Brown; Sonja Berndt; Aleksandra Butrym; Celine M. Vachon; Aaron D. Norman; Susan L. Slager; Federica Gemignani; Federico Canzian; Daniele Campa

doi:10.1002/ijc.33547

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients

Angelica Macauda, Chiara Piredda, Alyssa I. Clay-Gilmour, Juan Sainz, Gabriele Buda, Miroslaw Markiewicz, Torben Barington, Elad Ziv, Michelle A.T. Hildebrandt, Alem A. Belachew, Judit Varkonyi, Witold Prejzner, Agnieszka Druzd-Sitek, John Spinelli, Niels Frost Andersen, Jonathan N. Hofmann, Marek Dudziński, Joaquin Martinez-Lopez, Elzbieta Iskierka-Jazdzewska, Roger L. MilneGrzegorz Mazur, Graham G. Giles, Lene Hyldahl Ebbesen, Marcin Rymko, Krzysztof Jamroziak, Edyta Subocz, Rui Manuel Reis, Ramon Garcia-Sanz, Anna Suska, Eva Kannik Haastrup, Daria Zawirska, Norbert Grzasko, Annette Juul Vangsted, Charles Dumontet, Marcin Kruszewski, Magdalena Dutka, Nicola J. Camp, Rosalie G. Waller, Waldemar Tomczak, Matteo Pelosini, Małgorzata Raźny, Herlander Marques, Niels Abildgaard, Marzena Wątek, Artur Jurczyszyn, Elizabeth E. Brown, Sonja Berndt, Aleksandra Butrym, Celine M. Vachon, Aaron D. Norman, Susan L. Slager, Federica Gemignani, Federico Canzian, Daniele Campa

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Gene 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.

Original language	English (US)
Pages (from-to)	327-336
Number of pages	10
Journal	International Journal of Cancer
Volume	149
Issue number	2
DOIs	https://doi.org/10.1002/ijc.33547
State	Published - Jul 15 2021

Keywords

eQTL
genetic polymorphisms
multiple myeloma
overall survival
progression-free survival

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1002/ijc.33547

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Macauda, A., Piredda, C., Clay-Gilmour, A. I., Sainz, J., Buda, G., Markiewicz, M., Barington, T., Ziv, E., Hildebrandt, M. A. T., Belachew, A. A., Varkonyi, J., Prejzner, W., Druzd-Sitek, A., Spinelli, J., Andersen, N. F., Hofmann, J. N., Dudziński, M., Martinez-Lopez, J., Iskierka-Jazdzewska, E., ... Campa, D. (2021). Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients. International Journal of Cancer, 149(2), 327-336. https://doi.org/10.1002/ijc.33547

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients. / Macauda, Angelica; Piredda, Chiara; Clay-Gilmour, Alyssa I.; Sainz, Juan; Buda, Gabriele; Markiewicz, Miroslaw; Barington, Torben; Ziv, Elad; Hildebrandt, Michelle A.T.; Belachew, Alem A.; Varkonyi, Judit; Prejzner, Witold; Druzd-Sitek, Agnieszka; Spinelli, John; Andersen, Niels Frost; Hofmann, Jonathan N.; Dudziński, Marek; Martinez-Lopez, Joaquin; Iskierka-Jazdzewska, Elzbieta; Milne, Roger L.; Mazur, Grzegorz; Giles, Graham G.; Ebbesen, Lene Hyldahl; Rymko, Marcin; Jamroziak, Krzysztof; Subocz, Edyta; Reis, Rui Manuel; Garcia-Sanz, Ramon; Suska, Anna; Haastrup, Eva Kannik; Zawirska, Daria; Grzasko, Norbert; Vangsted, Annette Juul; Dumontet, Charles; Kruszewski, Marcin; Dutka, Magdalena; Camp, Nicola J.; Waller, Rosalie G.; Tomczak, Waldemar; Pelosini, Matteo; Raźny, Małgorzata; Marques, Herlander; Abildgaard, Niels; Wątek, Marzena; Jurczyszyn, Artur; Brown, Elizabeth E.; Berndt, Sonja; Butrym, Aleksandra; Vachon, Celine M.; Norman, Aaron D.; Slager, Susan L.; Gemignani, Federica; Canzian, Federico; Campa, Daniele.

In: International Journal of Cancer, Vol. 149, No. 2, 15.07.2021, p. 327-336.

Research output: Contribution to journal › Article › peer-review

Macauda, A, Piredda, C, Clay-Gilmour, AI, Sainz, J, Buda, G, Markiewicz, M, Barington, T, Ziv, E, Hildebrandt, MAT, Belachew, AA, Varkonyi, J, Prejzner, W, Druzd-Sitek, A, Spinelli, J, Andersen, NF, Hofmann, JN, Dudziński, M, Martinez-Lopez, J, Iskierka-Jazdzewska, E, Milne, RL, Mazur, G, Giles, GG, Ebbesen, LH, Rymko, M, Jamroziak, K, Subocz, E, Reis, RM, Garcia-Sanz, R, Suska, A, Haastrup, EK, Zawirska, D, Grzasko, N, Vangsted, AJ, Dumontet, C, Kruszewski, M, Dutka, M, Camp, NJ, Waller, RG, Tomczak, W, Pelosini, M, Raźny, M, Marques, H, Abildgaard, N, Wątek, M, Jurczyszyn, A, Brown, EE, Berndt, S, Butrym, A, Vachon, CM, Norman, AD, Slager, SL, Gemignani, F, Canzian, F & Campa, D 2021, 'Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients', International Journal of Cancer, vol. 149, no. 2, pp. 327-336. https://doi.org/10.1002/ijc.33547

Macauda, Angelica ; Piredda, Chiara ; Clay-Gilmour, Alyssa I. ; Sainz, Juan ; Buda, Gabriele ; Markiewicz, Miroslaw ; Barington, Torben ; Ziv, Elad ; Hildebrandt, Michelle A.T. ; Belachew, Alem A. ; Varkonyi, Judit ; Prejzner, Witold ; Druzd-Sitek, Agnieszka ; Spinelli, John ; Andersen, Niels Frost ; Hofmann, Jonathan N. ; Dudziński, Marek ; Martinez-Lopez, Joaquin ; Iskierka-Jazdzewska, Elzbieta ; Milne, Roger L. ; Mazur, Grzegorz ; Giles, Graham G. ; Ebbesen, Lene Hyldahl ; Rymko, Marcin ; Jamroziak, Krzysztof ; Subocz, Edyta ; Reis, Rui Manuel ; Garcia-Sanz, Ramon ; Suska, Anna ; Haastrup, Eva Kannik ; Zawirska, Daria ; Grzasko, Norbert ; Vangsted, Annette Juul ; Dumontet, Charles ; Kruszewski, Marcin ; Dutka, Magdalena ; Camp, Nicola J. ; Waller, Rosalie G. ; Tomczak, Waldemar ; Pelosini, Matteo ; Raźny, Małgorzata ; Marques, Herlander ; Abildgaard, Niels ; Wątek, Marzena ; Jurczyszyn, Artur ; Brown, Elizabeth E. ; Berndt, Sonja ; Butrym, Aleksandra ; Vachon, Celine M. ; Norman, Aaron D. ; Slager, Susan L. ; Gemignani, Federica ; Canzian, Federico ; Campa, Daniele. / Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients. In: International Journal of Cancer. 2021 ; Vol. 149, No. 2. pp. 327-336.

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title = "Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients",

abstract = "Gene 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.",

keywords = "eQTL, genetic polymorphisms, multiple myeloma, overall survival, progression-free survival",

author = "Angelica Macauda and Chiara Piredda and Clay-Gilmour, {Alyssa I.} and Juan Sainz and Gabriele Buda and Miroslaw Markiewicz and Torben Barington and Elad Ziv and Hildebrandt, {Michelle A.T.} and Belachew, {Alem A.} and Judit Varkonyi and Witold Prejzner and Agnieszka Druzd-Sitek and John Spinelli and Andersen, {Niels Frost} and Hofmann, {Jonathan N.} and Marek Dudzi{\'n}ski and Joaquin Martinez-Lopez and Elzbieta Iskierka-Jazdzewska and Milne, {Roger L.} and Grzegorz Mazur and Giles, {Graham G.} and Ebbesen, {Lene Hyldahl} and Marcin Rymko and Krzysztof Jamroziak and Edyta Subocz and Reis, {Rui Manuel} and Ramon Garcia-Sanz and Anna Suska and Haastrup, {Eva Kannik} and Daria Zawirska and Norbert Grzasko and Vangsted, {Annette Juul} and Charles Dumontet and Marcin Kruszewski and Magdalena Dutka and Camp, {Nicola J.} and Waller, {Rosalie G.} and Waldemar Tomczak and Matteo Pelosini and Ma{\l}gorzata Ra{\'z}ny and Herlander Marques and Niels Abildgaard and Marzena W{\c a}tek and Artur Jurczyszyn and Brown, {Elizabeth E.} and Sonja Berndt and Aleksandra Butrym and Vachon, {Celine M.} and Norman, {Aaron D.} and Slager, {Susan L.} and Federica Gemignani and Federico Canzian and Daniele Campa",

note = "Funding Information: The authors thank all site investigators that contributed to the studies within the Multiple Myeloma Working Group (Interlymph Consortium), staff involved at each site and, most importantly, the study participants for their contributions that made our study possible. This work was partially supported by intramural funds of University of Pisa and DKFZ. This work was supported in part by the National Institute of Health/National Cancer Institute (R25 CA092049, P30 CA016672, R01 CA134674, P30 CA042014, R01 CA186646, R21 CA155951, U54 CA118948, P30 CA13148, R25 CA47888, R01 CA235026, R01 CA107476, R01 CA168762, P50 CA186781 and the NCI Intramural Research Program), Leukemia Lymphoma Society (6067-09), Huntsman Cancer Institute Pilot Funds, Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of Utah, Canadian Institutes of Health Research (Grant number 81274), VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council (Grants 209057, 396414, 1074383), Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database and the Mayo Clinic Cancer Center. Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: {\textcopyright} 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.",

year = "2021",

month = jul,

day = "15",

doi = "10.1002/ijc.33547",

language = "English (US)",

volume = "149",

pages = "327--336",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "Wiley-Liss Inc.",

number = "2",

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TY - JOUR

T1 - Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients

AU - Macauda, Angelica

AU - Piredda, Chiara

AU - Clay-Gilmour, Alyssa I.

AU - Sainz, Juan

AU - Buda, Gabriele

AU - Markiewicz, Miroslaw

AU - Barington, Torben

AU - Ziv, Elad

AU - Hildebrandt, Michelle A.T.

AU - Belachew, Alem A.

AU - Varkonyi, Judit

AU - Prejzner, Witold

AU - Druzd-Sitek, Agnieszka

AU - Spinelli, John

AU - Andersen, Niels Frost

AU - Hofmann, Jonathan N.

AU - Dudziński, Marek

AU - Martinez-Lopez, Joaquin

AU - Iskierka-Jazdzewska, Elzbieta

AU - Milne, Roger L.

AU - Mazur, Grzegorz

AU - Giles, Graham G.

AU - Ebbesen, Lene Hyldahl

AU - Rymko, Marcin

AU - Jamroziak, Krzysztof

AU - Subocz, Edyta

AU - Reis, Rui Manuel

AU - Garcia-Sanz, Ramon

AU - Suska, Anna

AU - Haastrup, Eva Kannik

AU - Zawirska, Daria

AU - Grzasko, Norbert

AU - Vangsted, Annette Juul

AU - Dumontet, Charles

AU - Kruszewski, Marcin

AU - Dutka, Magdalena

AU - Camp, Nicola J.

AU - Waller, Rosalie G.

AU - Tomczak, Waldemar

AU - Pelosini, Matteo

AU - Raźny, Małgorzata

AU - Marques, Herlander

AU - Abildgaard, Niels

AU - Wątek, Marzena

AU - Jurczyszyn, Artur

AU - Brown, Elizabeth E.

AU - Berndt, Sonja

AU - Butrym, Aleksandra

AU - Vachon, Celine M.

AU - Norman, Aaron D.

AU - Slager, Susan L.

AU - Gemignani, Federica

AU - Canzian, Federico

AU - Campa, Daniele

N1 - Funding Information: The authors thank all site investigators that contributed to the studies within the Multiple Myeloma Working Group (Interlymph Consortium), staff involved at each site and, most importantly, the study participants for their contributions that made our study possible. This work was partially supported by intramural funds of University of Pisa and DKFZ. This work was supported in part by the National Institute of Health/National Cancer Institute (R25 CA092049, P30 CA016672, R01 CA134674, P30 CA042014, R01 CA186646, R21 CA155951, U54 CA118948, P30 CA13148, R25 CA47888, R01 CA235026, R01 CA107476, R01 CA168762, P50 CA186781 and the NCI Intramural Research Program), Leukemia Lymphoma Society (6067-09), Huntsman Cancer Institute Pilot Funds, Utah Population Database, Utah Cancer Registry, Huntsman Cancer Center Support Grant, Utah State Department of Health, University of Utah, Canadian Institutes of Health Research (Grant number 81274), VicHealth, Cancer Council Victoria, Australian National Health and Medical Research Council (Grants 209057, 396414, 1074383), Victorian Cancer Registry, Australian Institute of Health and Welfare, Australian National Death Index, Australian Cancer Database and the Mayo Clinic Cancer Center. Open Access funding enabled and organized by Projekt DEAL. Publisher Copyright: © 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.

PY - 2021/7/15

Y1 - 2021/7/15

N2 - Gene 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.

AB - Gene 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.

KW - eQTL

KW - genetic polymorphisms

KW - multiple myeloma

KW - overall survival

KW - progression-free survival

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UR - http://www.scopus.com/inward/citedby.url?scp=85103377152&partnerID=8YFLogxK

U2 - 10.1002/ijc.33547

DO - 10.1002/ijc.33547

M3 - Article

C2 - 33675538

AN - SCOPUS:85103377152

VL - 149

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EP - 336

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 2

ER -

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients

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