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Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial

Background: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes RPA2 and GTF2H1 are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether RPA2 and GTF2...

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Autores principales: Suenaga, Mitsukuni, Schirripa, Marta, Cao, Shu, Zhang, Wu, Yang, Dongyun, Cremolini, Chiara, Murgioni, Sabina, Lonardi, Sara, Ning, Yan, Okazaki, Satoshi, Berger, Martin D., Miyamoto, Yuji, Barzi, Afsaneh, Loupakis, Fotios, Falcone, Alfredo, Lenz, Heinz-Josef
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408001/
https://www.ncbi.nlm.nih.gov/pubmed/32629861
http://dx.doi.org/10.3390/cancers12071742
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author Suenaga, Mitsukuni
Schirripa, Marta
Cao, Shu
Zhang, Wu
Yang, Dongyun
Cremolini, Chiara
Murgioni, Sabina
Lonardi, Sara
Ning, Yan
Okazaki, Satoshi
Berger, Martin D.
Miyamoto, Yuji
Barzi, Afsaneh
Loupakis, Fotios
Falcone, Alfredo
Lenz, Heinz-Josef
author_facet Suenaga, Mitsukuni
Schirripa, Marta
Cao, Shu
Zhang, Wu
Yang, Dongyun
Cremolini, Chiara
Murgioni, Sabina
Lonardi, Sara
Ning, Yan
Okazaki, Satoshi
Berger, Martin D.
Miyamoto, Yuji
Barzi, Afsaneh
Loupakis, Fotios
Falcone, Alfredo
Lenz, Heinz-Josef
author_sort Suenaga, Mitsukuni
collection PubMed
description Background: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes RPA2 and GTF2H1 are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether RPA2 and GTF2H1 SNPs predict the efficacy of oxaliplatin in metastatic CRC (mCRC) patients. Patients and methods: Genomic DNA was extracted from blood samples from 457 patients with mCRC enrolled in the TRIBE trial, which compared first-line FOLFOXIRI plus bevacizumab (BEV) (n = 230, discovery cohort) and first-line FOLFIRI plus BEV (n = 227, control cohort). SNPs were analyzed by PCR-based direct sequencing. Results: In the FOLFOXIRI + BEV-treated cohort expressing wild-type KRAS, progression-free survival (PFS) was shorter for the RPA2 rs7356 C/C variant subgroup than the any T allele subgroup in univariate analysis (9.1 versus 13.3 months respectively, hazard ratio (HR) 2.32, 95% confidence interval (CI): 1.07–5.03, p = 0.020) and this remained significant in multivariable analysis (HR 2.97, 95%CI: 1.27–6.94, p = 0.012). A similar trend was observed for overall survival. In contrast, patients expressing mutant RAS and RPA2 rs7356 C/C variant had longer PFS with FOLFOXIRI + BEV than with FOLFIRI + BEV (12.1 versus 7.6 months, HR 0.23, 95%CI: 0.09–0.62, p = 0.002) but no superiority of FOLFOXIRI + BEV was observed for the RAS mutant, RPA2 rs7356 any T variant subgroup (11.7 versus 9.6 months, HR 0.77, 95%CI: 0.56–1.07, p = 0.12) or the RAS wild-type, RPA2 rs7356 C/C variant subgroup. Conclusion: RPA2 SNPs may serve as predictive and prognostic markers of oxaliplatin responsiveness in a RAS status-dependent manner in mCRC patients receiving FOLFOXIRI + BEV.
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spelling pubmed-74080012020-08-12 Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial Suenaga, Mitsukuni Schirripa, Marta Cao, Shu Zhang, Wu Yang, Dongyun Cremolini, Chiara Murgioni, Sabina Lonardi, Sara Ning, Yan Okazaki, Satoshi Berger, Martin D. Miyamoto, Yuji Barzi, Afsaneh Loupakis, Fotios Falcone, Alfredo Lenz, Heinz-Josef Cancers (Basel) Article Background: The nucleotide excision repair (NER) pathway participates in platinum-induced DNA damage repair. Single nucleotide polymorphisms (SNPs) in miRNA-binding sites in the NER genes RPA2 and GTF2H1 are associated with the risk of colorectal cancer (CRC). Here, we analyzed whether RPA2 and GTF2H1 SNPs predict the efficacy of oxaliplatin in metastatic CRC (mCRC) patients. Patients and methods: Genomic DNA was extracted from blood samples from 457 patients with mCRC enrolled in the TRIBE trial, which compared first-line FOLFOXIRI plus bevacizumab (BEV) (n = 230, discovery cohort) and first-line FOLFIRI plus BEV (n = 227, control cohort). SNPs were analyzed by PCR-based direct sequencing. Results: In the FOLFOXIRI + BEV-treated cohort expressing wild-type KRAS, progression-free survival (PFS) was shorter for the RPA2 rs7356 C/C variant subgroup than the any T allele subgroup in univariate analysis (9.1 versus 13.3 months respectively, hazard ratio (HR) 2.32, 95% confidence interval (CI): 1.07–5.03, p = 0.020) and this remained significant in multivariable analysis (HR 2.97, 95%CI: 1.27–6.94, p = 0.012). A similar trend was observed for overall survival. In contrast, patients expressing mutant RAS and RPA2 rs7356 C/C variant had longer PFS with FOLFOXIRI + BEV than with FOLFIRI + BEV (12.1 versus 7.6 months, HR 0.23, 95%CI: 0.09–0.62, p = 0.002) but no superiority of FOLFOXIRI + BEV was observed for the RAS mutant, RPA2 rs7356 any T variant subgroup (11.7 versus 9.6 months, HR 0.77, 95%CI: 0.56–1.07, p = 0.12) or the RAS wild-type, RPA2 rs7356 C/C variant subgroup. Conclusion: RPA2 SNPs may serve as predictive and prognostic markers of oxaliplatin responsiveness in a RAS status-dependent manner in mCRC patients receiving FOLFOXIRI + BEV. MDPI 2020-06-30 /pmc/articles/PMC7408001/ /pubmed/32629861 http://dx.doi.org/10.3390/cancers12071742 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Suenaga, Mitsukuni
Schirripa, Marta
Cao, Shu
Zhang, Wu
Yang, Dongyun
Cremolini, Chiara
Murgioni, Sabina
Lonardi, Sara
Ning, Yan
Okazaki, Satoshi
Berger, Martin D.
Miyamoto, Yuji
Barzi, Afsaneh
Loupakis, Fotios
Falcone, Alfredo
Lenz, Heinz-Josef
Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial
title Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial
title_full Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial
title_fullStr Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial
title_full_unstemmed Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial
title_short Single Nucleotide Polymorphisms in MiRNA Binding Sites of Nucleotide Excision Repair-Related Genes Predict Clinical Benefit of Oxaliplatin in FOLFOXIRI Plus Bevacizumab: Analysis of the TRIBE Trial
title_sort single nucleotide polymorphisms in mirna binding sites of nucleotide excision repair-related genes predict clinical benefit of oxaliplatin in folfoxiri plus bevacizumab: analysis of the tribe trial
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408001/
https://www.ncbi.nlm.nih.gov/pubmed/32629861
http://dx.doi.org/10.3390/cancers12071742
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