Polymorphisms in xenobiotic transporters ABCB1, ABCG2, ABCC2, ABCC1, ABCC3 and multiple myeloma risk: a case–control study in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium

Martino, Alessandro Di; Campa, Daniele; Buda, Gabriele; Sainz, Juan; Jamroziak, Krzysztof; Reis, Rui Manuel; Weinhold, Niels; Jurado, Manuel; Szemraj-Rogucka, Zofia; Marques, Herlander; Szemraj, Janusz; Stein, Angelika; Kumar, Rajiv; Orciuolo, Enrico; Gemignani, Federica; Landi, Stefano; Goldschmidt, H; Petrini, Mario; Dumontet, Charles; Canzian, Federico; Rossi, Anna Maria

doi:10.1038/leu.2011.352

Cited by 17 publications

(22 citation statements)

References 15 publications

(21 reference statements)

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“…3,4 Several risk loci have been proposed and a few have been identified through genomewide association studies (GWAS). 2,[5][6][7][8][9][10][11] The genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) gene regions could play a role in MM etiology for two reasons: first the two genes are responsible for crucial cellular processes, namely telomere homeostasis, second their polymorphic variants have been found to be associated with multiple cancer types and other human phenotypes. [12][13][14][15][16][17][18][19][20][21][22][23][24] TERT and TERC constitute the telomerase complex, 25 whose correct functioning is fundamental for the accurate de novo synthesis of telomeric ends.…”

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confidence: 99%

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Campa

Martino

Várkonyi

et al. 2014

Intl Journal of Cancer

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Compelling biological and epidemiological evidences point to a key role of genetic variants of the TERT and TERC genes in cancer development. We analyzed the genetic variability of these two gene regions using samples of 2,267 multiple myeloma (MM) cases and 2,796 healthy controls. We found that a TERT variant, rs2242652, is associated with reduced MM susceptibility (OR = 0.81; 95% CI: 0.72–0.92; p = 0.001). In addition we measured the leukocyte telomere length (LTL) in a subgroup of 140 cases who were chemotherapy‐free at the time of blood donation and 468 controls, and found that MM patients had longer telomeres compared to controls (OR = 1.19; 95% CI: 0.63–2.24; ptrend = 0.01 comparing the quartile with the longest LTL versus the shortest LTL). Our data suggest the hypothesis of decreased disease risk by genetic variants that reduce the efficiency of the telomerase complex. This reduced efficiency leads to shorter telomere ends, which in turn may also be a marker of decreased MM risk.

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confidence: 99%

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Campa

Martino

Várkonyi

et al. 2014

Intl Journal of Cancer

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“…2 Several risk loci have been proposed and a few have been identified through candidate gene and genome-wide association studies (GWAS). [3][4][5][6][7][8][9][10] Some of these loci are involved in complex pathways related to cell cycle, cell proliferation and DNA repair, in which micro-RNAs (miRNAs) have a proven regulatory role. 11 MiRNAs are small non-coding RNA molecules, 20-25 nucleotides long, highly conserved throughout evolution.…”

Section: Cancer Epidemiologymentioning

confidence: 99%

“…Converging evidence of MM in monozygotic twins and familial aggregation of MM strongly suggest that MM aetiology has a robust genetic component as well . Several risk loci have been proposed and a few have been identified through candidate gene and genome‐wide association studies (GWAS) . Some of these loci are involved in complex pathways related to cell cycle, cell proliferation and DNA repair, in which micro‐RNAs (miRNAs) have a proven regulatory role …”

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confidence: 99%

“…major allele (i.e., more common in controls); m 5 minor allele (less common in controls) 2. Numbers may not add up to 100% due to genotyping failure, DNA depletion or covariate missing values 3. OR: odds ratio; CI: confidence interval; OR het : odds ratio obtained comparing heterozygotes with homozygotes for the major allele; OR hom : odds ratio obtained comparing homozygotes for the minor allele with homozygotes for the major allele; all analyses were adjusted by age, sex and country of origin.…”

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confidence: 99%

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Identification of miRSNPs associated with the risk of multiple myeloma

et al. 2016

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Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA-binding sites in target genes (miRSNPs) may alter the strength of miRNA-mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome-wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta-analyzed with data from a previously published genome-wide association study (GWAS). The SNPs rs13409 (located in the 3'UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome-wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk.

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“…NR1I2 and NR1I3 belong to the nuclear receptors subfamily 1 and have a leading role in regulating the expression of genes involved in the xenobiotic metabolism and drug transport (Yan & Xie, ). The genetic variants of transporters and their regulators can lead to changes in the efficiency of the detoxification mechanism, as demonstrated by their effect on the risk of developing various cancer types (Campa et al , ,b; Martino et al , , ; Fletcher et al , ) and outcome. We investigated 71 SNPs belonging to the candidate genes in relation to measures of outcome of MM patients, within the International Multiple Myeloma rESEarch (IMMEnSE) consortium.…”

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

et al. 2018

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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.

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Polymorphisms in xenobiotic transporters ABCB1, ABCG2, ABCC2, ABCC1, ABCC3 and multiple myeloma risk: a case–control study in the context of the International Multiple Myeloma rESEarch (IMMEnSE) consortium

Cited by 17 publications

References 15 publications

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Risk of multiple myeloma is associated with polymorphisms within telomerase genes and telomere length

Identification of miRSNPs associated with the risk of multiple myeloma

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

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