Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients

Angelica Macauda; Eleonora Castelli; Gabriele Buda; Matteo Pelosini; Aleksandra Butrym; Marzena Watek; Marcin Kruszewski; Annette Juul Vangsted; Marcin Rymko; Krzysztof Jamroziak; Niels Abildgaard; Eva Kannik Haastrup; Grzegorz Mazur; Rafael Ríos; Artur Jurczyszyn; Daria Zawirska; Marek Dudziński; Małgorzata Raźny; Magdalena Dutka; Waldemar Tomczak; Anna Suska; Agnieszka Druzd-Sitek; Herlander Marques; Mario Petrini; Miroslaw Markiewicz; Joaquin Martinez-Lopez; Lene Hyldahl Ebbesen; Elżbieta Iskierka-Jażdżewska; Juan Sainz; Federico Canzian; Daniele Campa

doi:10.1111/bjh.15521

Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients

Angelica Macauda, Eleonora Castelli, Gabriele Buda, Matteo Pelosini, Aleksandra Butrym, Marzena Watek, Marcin Kruszewski, Annette Juul Vangsted, Marcin Rymko, Krzysztof Jamroziak, Niels Abildgaard, Eva Kannik Haastrup, Grzegorz Mazur, Rafael Ríos, Artur Jurczyszyn, Daria Zawirska, Marek Dudziński, Małgorzata Raźny, Magdalena Dutka, Waldemar TomczakAnna Suska, Agnieszka Druzd-Sitek, Herlander Marques, Mario Petrini, Miroslaw Markiewicz, Joaquin Martinez-Lopez, Lene Hyldahl Ebbesen, Elżbieta Iskierka-Jażdżewska, Juan Sainz, Federico Canzian, Daniele Campa

Department of Clinical Medicine

6 Citations (Scopus)

Abstract

Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation.

Original language	English
Journal	British Journal of Haematology
Volume	183
Issue number	3
Pages (from-to)	375-384
Number of pages	10
ISSN	0007-1048
DOIs	https://doi.org/10.1111/bjh.15521
Publication status	Published - Nov 2018

Access to Document

10.1111/bjh.15521

bjh.15521Final published version, 164 KB

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/bjh.15521

Cite this

Macauda, A., Castelli, E., Buda, G., Pelosini, M., Butrym, A., Watek, M., Kruszewski, M., Vangsted, A. J., Rymko, M., Jamroziak, K., Abildgaard, N., Haastrup, E. K., Mazur, G., Ríos, R., Jurczyszyn, A., Zawirska, D., Dudziński, M., Raźny, M., Dutka, M., ... Campa, D. (2018). Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients. British Journal of Haematology, 183(3), 375-384. https://doi.org/10.1111/bjh.15521

Macauda, A, Castelli, E, Buda, G, Pelosini, M, Butrym, A, Watek, M, Kruszewski, M, Vangsted, AJ, Rymko, M, Jamroziak, K, Abildgaard, N, Haastrup, EK, Mazur, G, Ríos, R, Jurczyszyn, A, Zawirska, D, Dudziński, M, Raźny, M, Dutka, M, Tomczak, W, Suska, A, Druzd-Sitek, A, Marques, H, Petrini, M, Markiewicz, M, Martinez-Lopez, J, Ebbesen, LH, Iskierka-Jażdżewska, E, Sainz, J, Canzian, F & Campa, D 2018, 'Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients', British Journal of Haematology, vol. 183, no. 3, pp. 375-384. https://doi.org/10.1111/bjh.15521

@article{813f2ca7640547b2882b1a430ecab4a0,

title = "Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients",

abstract = "Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation.",

author = "Angelica Macauda and Eleonora Castelli and Gabriele Buda and Matteo Pelosini and Aleksandra Butrym and Marzena Watek and Marcin Kruszewski and Vangsted, {Annette Juul} and Marcin Rymko and Krzysztof Jamroziak and Niels Abildgaard and Haastrup, {Eva Kannik} and Grzegorz Mazur and Rafael R{\'i}os and Artur Jurczyszyn and Daria Zawirska and Marek Dudzi{\'n}ski and Ma{\l}gorzata Ra{\'z}ny and Magdalena Dutka and Waldemar Tomczak and Anna Suska and Agnieszka Druzd-Sitek and Herlander Marques and Mario Petrini and Miroslaw Markiewicz and Joaquin Martinez-Lopez and Ebbesen, {Lene Hyldahl} and El{\.z}bieta Iskierka-Ja{\.z}d{\.z}ewska and Juan Sainz and Federico Canzian and Daniele Campa",

note = "{\textcopyright} 2018 British Society for Haematology and John Wiley & Sons Ltd.",

year = "2018",

month = nov,

doi = "10.1111/bjh.15521",

language = "English",

volume = "183",

pages = "375--384",

journal = "British Journal of Haematology",

issn = "0007-1048",

publisher = "Wiley-Blackwell",

number = "3",

}

TY - JOUR

T1 - Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients

AU - Macauda, Angelica

AU - Castelli, Eleonora

AU - Buda, Gabriele

AU - Pelosini, Matteo

AU - Butrym, Aleksandra

AU - Watek, Marzena

AU - Kruszewski, Marcin

AU - Vangsted, Annette Juul

AU - Rymko, Marcin

AU - Jamroziak, Krzysztof

AU - Abildgaard, Niels

AU - Haastrup, Eva Kannik

AU - Mazur, Grzegorz

AU - Ríos, Rafael

AU - Jurczyszyn, Artur

AU - Zawirska, Daria

AU - Dudziński, Marek

AU - Raźny, Małgorzata

AU - Dutka, Magdalena

AU - Tomczak, Waldemar

AU - Suska, Anna

AU - Druzd-Sitek, Agnieszka

AU - Marques, Herlander

AU - Petrini, Mario

AU - Markiewicz, Miroslaw

AU - Martinez-Lopez, Joaquin

AU - Ebbesen, Lene Hyldahl

AU - Iskierka-Jażdżewska, Elżbieta

AU - Sainz, Juan

AU - Canzian, Federico

AU - Campa, Daniele

PY - 2018/11

Y1 - 2018/11

N2 - Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation.

AB - Over the past four decades, remarkable progress has been made in the treatment and prognosis of multiple myeloma (MM), although it remains an incurable disease. Chemotherapy resistance is a major hurdle for treatment efficacy. Drug resistance can be innate and so driven by genes involved in the drug metabolism pathways. We performed an association study of 71 germline variants within the major genes in those pathways (ABCB1, ABCC2, ABCG2, and their regulators NR1I2/PXR and NR1I3/CAR) in the International Multiple Myeloma rESEarch (IMMEnSE) consortium, consisting of 1365 MM cases with survival information recruited in 5 European countries. Two of the SNPs showed a significant association with the survival of MM patients, namely rs2235013, located in ABCB1 [Hazard ratio (HR) = 1·52, 95% confidence interval (CI) = 1·18-1·95, P = 0·00087], and rs4148388, located in ABCC2 (HR = 2·15, 95% CI = 1·44-3·22, P = 0·0001). ABCC2 plays an essential role in transporting various anticancer drugs, including several used against MM, out of the cell. In silico analyses predict that the variant alleles of four SNPs in linkage disequilibrium with ABCC2-rs4148388 are associated with increased gene expression. Overexpression of ABCC2 increases drug clearance and therefore may induce drug resistance mechanisms. In conclusion, we found a promising association between ABCC2-rs4148388 and MM outcome that is supported by a plausible biological explanation.

U2 - 10.1111/bjh.15521

DO - 10.1111/bjh.15521

M3 - Journal article

C2 - 30079960

SN - 0007-1048

VL - 183

SP - 375

EP - 384

JO - British Journal of Haematology

JF - British Journal of Haematology

IS - 3

ER -

Inherited variation in the xenobiotic transporter pathway and survival of multiple myeloma patients

Abstract

Access to Document

Fingerprint

Cite this