Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC and FIRE-3

Alberto Puccini; Fotios Loupakis; Sebastian Stintzing; Shu Cao; Francesca Battaglin; Ryuma Togunaka; Madiha Naseem; Martin D Berger; Shivani Soni; Wu Zhang; Christoph Mancao; Bodour Salhia; Shannon M Mumenthaler; Daniel J Weisenberger; Gangning Liang; Chiara Cremolini; Volker Heinemann; Alfredo Falcone; Joshua Millstein; Heinz-Josef Lenz

doi:10.1016/j.ejca.2019.01.105

Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC and FIRE-3

Alberto Puccini, Fotios Loupakis, Sebastian Stintzing, Shu Cao, Francesca Battaglin, Ryuma Togunaka, Madiha Naseem, Martin D Berger, Shivani Soni, Wu Zhang, Christoph Mancao, Bodour Salhia, Shannon M Mumenthaler, Daniel J Weisenberger, Gangning Liang, Chiara Cremolini, Volker Heinemann, Alfredo Falcone, Joshua Millstein, Heinz-Josef Lenz

Istituto Oncologico Veneto

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

Abstract

BACKGROUND: CpG island DNA hypermethylation and global DNA hypomethylation are hallmark characteristics of colorectal cancer (CRC). Therefore, we aim to explore the effect of genetic variations within the genes that regulate the DNA methylation and demethylation pathways on outcomes in patients with metastatic CRC (mCRC) treated with first-line therapy and enrolled in three independent, randomised, open-label clinical trials.

METHODS: A total of 884 patients with mCRC enrolled in TRIBE, MAVERICC and FIRE-3 trials were included. Single-nucleotide polymorphisms (SNPs) within genes involved in DNA methylation and demethylation pathways were analysed. The prognostic value of each SNP across all treatment arms was quantified using the inverse-variance-weighted effect size, a meta-analysis approach implemented in the METASOFT software.

RESULTS: In the meta-analysis, DNMT3A rs11681717 was significantly associated with overall survival (hazard ratio = 1.26; 95% confidence interval [CI] 1.08-1.46; P = 0.002; false discovery rate [FDR] = 0.016), accounting for seven tests in the DNA methylation pathway. In addition, there was suggestive evidence of association for ten-eleven translocation (TET) genes variance with tumour response (TET1 rs3814177, odds ratio [OR] = 0.76, 95% CI 0.59-0.97, P = 0.025, FDR = 0.087; TET3 rs7560668, OR = 1.44; 95% CI 1.10-1.89; P = 0.009; FDR = 0.062).

CONCLUSIONS: We showed that polymorphisms within the genes responsible for the DNA methylation and demethylation machineries are correlated with outcomes in patients with mCRC who were enrolled in three independent, randomised, open-label, phase II/III clinical trials. In addition, we demonstrated the feasibility of a meta-analysis approach to identify stronger and more convincing association between gene polymorphisms and outcome, potentially leading the way to a new method of analysis for similar data set.

Original language	English
Pages (from-to)	138-147
Number of pages	10
Journal	Eur. J. Cancer
Volume	111
DOIs	https://doi.org/10.1016/j.ejca.2019.01.105
Publication status	Published - Apr 2019

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Puccini, A., Loupakis, F., Stintzing, S., Cao, S., Battaglin, F., Togunaka, R., Naseem, M., Berger, M. D., Soni, S., Zhang, W., Mancao, C., Salhia, B., Mumenthaler, S. M., Weisenberger, D. J., Liang, G., Cremolini, C., Heinemann, V., Falcone, A., Millstein, J., & Lenz, H-J. (2019). Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC and FIRE-3. Eur. J. Cancer, 111, 138-147. https://doi.org/10.1016/j.ejca.2019.01.105

Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials : a meta-analysis from TRIBE, MAVERICC and FIRE-3. / Puccini, Alberto; Loupakis, Fotios; Stintzing, Sebastian et al.

In: Eur. J. Cancer, Vol. 111, 04.2019, p. 138-147.

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

Puccini, A, Loupakis, F, Stintzing, S, Cao, S, Battaglin, F, Togunaka, R, Naseem, M, Berger, MD, Soni, S, Zhang, W, Mancao, C, Salhia, B, Mumenthaler, SM, Weisenberger, DJ, Liang, G, Cremolini, C, Heinemann, V, Falcone, A, Millstein, J & Lenz, H-J 2019, 'Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC and FIRE-3', Eur. J. Cancer, vol. 111, pp. 138-147. https://doi.org/10.1016/j.ejca.2019.01.105

Puccini A, Loupakis F, Stintzing S, Cao S, Battaglin F, Togunaka R et al. Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC and FIRE-3. Eur. J. Cancer. 2019 Apr;111:138-147. doi: 10.1016/j.ejca.2019.01.105

@article{0e95d4f6d585441a9ee06191d9005d0b,

title = "Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials: a meta-analysis from TRIBE, MAVERICC and FIRE-3",

abstract = "BACKGROUND: CpG island DNA hypermethylation and global DNA hypomethylation are hallmark characteristics of colorectal cancer (CRC). Therefore, we aim to explore the effect of genetic variations within the genes that regulate the DNA methylation and demethylation pathways on outcomes in patients with metastatic CRC (mCRC) treated with first-line therapy and enrolled in three independent, randomised, open-label clinical trials.METHODS: A total of 884 patients with mCRC enrolled in TRIBE, MAVERICC and FIRE-3 trials were included. Single-nucleotide polymorphisms (SNPs) within genes involved in DNA methylation and demethylation pathways were analysed. The prognostic value of each SNP across all treatment arms was quantified using the inverse-variance-weighted effect size, a meta-analysis approach implemented in the METASOFT software.RESULTS: In the meta-analysis, DNMT3A rs11681717 was significantly associated with overall survival (hazard ratio = 1.26; 95% confidence interval [CI] 1.08-1.46; P = 0.002; false discovery rate [FDR] = 0.016), accounting for seven tests in the DNA methylation pathway. In addition, there was suggestive evidence of association for ten-eleven translocation (TET) genes variance with tumour response (TET1 rs3814177, odds ratio [OR] = 0.76, 95% CI 0.59-0.97, P = 0.025, FDR = 0.087; TET3 rs7560668, OR = 1.44; 95% CI 1.10-1.89; P = 0.009; FDR = 0.062).CONCLUSIONS: We showed that polymorphisms within the genes responsible for the DNA methylation and demethylation machineries are correlated with outcomes in patients with mCRC who were enrolled in three independent, randomised, open-label, phase II/III clinical trials. In addition, we demonstrated the feasibility of a meta-analysis approach to identify stronger and more convincing association between gene polymorphisms and outcome, potentially leading the way to a new method of analysis for similar data set.",

author = "Alberto Puccini and Fotios Loupakis and Sebastian Stintzing and Shu Cao and Francesca Battaglin and Ryuma Togunaka and Madiha Naseem and Berger, {Martin D} and Shivani Soni and Wu Zhang and Christoph Mancao and Bodour Salhia and Mumenthaler, {Shannon M} and Weisenberger, {Daniel J} and Gangning Liang and Chiara Cremolini and Volker Heinemann and Alfredo Falcone and Joshua Millstein and Heinz-Josef Lenz",

year = "2019",

month = apr,

doi = "10.1016/j.ejca.2019.01.105",

language = "English",

volume = "111",

pages = "138--147",

journal = "Eur. J. Cancer",

issn = "0959-8049",

publisher = "Elsevier Ltd",

}

TY - JOUR

T1 - Impact of polymorphisms within genes involved in regulating DNA methylation in patients with metastatic colorectal cancer enrolled in three independent, randomised, open-label clinical trials

T2 - a meta-analysis from TRIBE, MAVERICC and FIRE-3

AU - Puccini, Alberto

AU - Loupakis, Fotios

AU - Stintzing, Sebastian

AU - Cao, Shu

AU - Battaglin, Francesca

AU - Togunaka, Ryuma

AU - Naseem, Madiha

AU - Berger, Martin D

AU - Soni, Shivani

AU - Zhang, Wu

AU - Mancao, Christoph

AU - Salhia, Bodour

AU - Mumenthaler, Shannon M

AU - Weisenberger, Daniel J

AU - Liang, Gangning

AU - Cremolini, Chiara

AU - Heinemann, Volker

AU - Falcone, Alfredo

AU - Millstein, Joshua

AU - Lenz, Heinz-Josef

PY - 2019/4

Y1 - 2019/4

N2 - BACKGROUND: CpG island DNA hypermethylation and global DNA hypomethylation are hallmark characteristics of colorectal cancer (CRC). Therefore, we aim to explore the effect of genetic variations within the genes that regulate the DNA methylation and demethylation pathways on outcomes in patients with metastatic CRC (mCRC) treated with first-line therapy and enrolled in three independent, randomised, open-label clinical trials.METHODS: A total of 884 patients with mCRC enrolled in TRIBE, MAVERICC and FIRE-3 trials were included. Single-nucleotide polymorphisms (SNPs) within genes involved in DNA methylation and demethylation pathways were analysed. The prognostic value of each SNP across all treatment arms was quantified using the inverse-variance-weighted effect size, a meta-analysis approach implemented in the METASOFT software.RESULTS: In the meta-analysis, DNMT3A rs11681717 was significantly associated with overall survival (hazard ratio = 1.26; 95% confidence interval [CI] 1.08-1.46; P = 0.002; false discovery rate [FDR] = 0.016), accounting for seven tests in the DNA methylation pathway. In addition, there was suggestive evidence of association for ten-eleven translocation (TET) genes variance with tumour response (TET1 rs3814177, odds ratio [OR] = 0.76, 95% CI 0.59-0.97, P = 0.025, FDR = 0.087; TET3 rs7560668, OR = 1.44; 95% CI 1.10-1.89; P = 0.009; FDR = 0.062).CONCLUSIONS: We showed that polymorphisms within the genes responsible for the DNA methylation and demethylation machineries are correlated with outcomes in patients with mCRC who were enrolled in three independent, randomised, open-label, phase II/III clinical trials. In addition, we demonstrated the feasibility of a meta-analysis approach to identify stronger and more convincing association between gene polymorphisms and outcome, potentially leading the way to a new method of analysis for similar data set.

AB - BACKGROUND: CpG island DNA hypermethylation and global DNA hypomethylation are hallmark characteristics of colorectal cancer (CRC). Therefore, we aim to explore the effect of genetic variations within the genes that regulate the DNA methylation and demethylation pathways on outcomes in patients with metastatic CRC (mCRC) treated with first-line therapy and enrolled in three independent, randomised, open-label clinical trials.METHODS: A total of 884 patients with mCRC enrolled in TRIBE, MAVERICC and FIRE-3 trials were included. Single-nucleotide polymorphisms (SNPs) within genes involved in DNA methylation and demethylation pathways were analysed. The prognostic value of each SNP across all treatment arms was quantified using the inverse-variance-weighted effect size, a meta-analysis approach implemented in the METASOFT software.RESULTS: In the meta-analysis, DNMT3A rs11681717 was significantly associated with overall survival (hazard ratio = 1.26; 95% confidence interval [CI] 1.08-1.46; P = 0.002; false discovery rate [FDR] = 0.016), accounting for seven tests in the DNA methylation pathway. In addition, there was suggestive evidence of association for ten-eleven translocation (TET) genes variance with tumour response (TET1 rs3814177, odds ratio [OR] = 0.76, 95% CI 0.59-0.97, P = 0.025, FDR = 0.087; TET3 rs7560668, OR = 1.44; 95% CI 1.10-1.89; P = 0.009; FDR = 0.062).CONCLUSIONS: We showed that polymorphisms within the genes responsible for the DNA methylation and demethylation machineries are correlated with outcomes in patients with mCRC who were enrolled in three independent, randomised, open-label, phase II/III clinical trials. In addition, we demonstrated the feasibility of a meta-analysis approach to identify stronger and more convincing association between gene polymorphisms and outcome, potentially leading the way to a new method of analysis for similar data set.

U2 - 10.1016/j.ejca.2019.01.105

DO - 10.1016/j.ejca.2019.01.105

M3 - Article

C2 - 30852420

SN - 0959-8049

VL - 111

SP - 138

EP - 147

JO - Eur. J. Cancer

JF - Eur. J. Cancer

ER -