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Pattern recognition receptor polymorphisms as predictors of oxaliplatin benefit in colorectal cancer

Pattern recognition receptor polymorphisms as predictors of oxaliplatin benefit in colorectal cancer
Pattern recognition receptor polymorphisms as predictors of oxaliplatin benefit in colorectal cancer

Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification. 

Methods: We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided. 

Results: Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P =. 07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P =. 66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P =. 27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P =. 40). 

Conclusion: In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.

0027-8874
828-836
Gray, Victoria
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Briggs, Sarah
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Palles, Claire
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Jaeger, Emma
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Iveson, Timothy
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Kerr, Rachel
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Saunders, Mark P.
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Paul, James
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Harkin, Andrea
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McQueen, John
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Summers, Matthew G.
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Johnstone, Elaine
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Wang, Haitao
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Gatcombe, Laura
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Maughan, Timothy S.
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Kaplan, Richard
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Escott-Price, Valentina
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Al-Tassan, Nada A.
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Meyer, Brian F.
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Wakil, Salma M.
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Houlston, Richard S.
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Cheadle, Jeremy P.
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Tomlinson, Ian
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Church, David N.
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Gray, Victoria
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Briggs, Sarah
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Palles, Claire
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Jaeger, Emma
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Iveson, Timothy
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Kerr, Rachel
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Saunders, Mark P.
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Paul, James
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Harkin, Andrea
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McQueen, John
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Summers, Matthew G.
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Johnstone, Elaine
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Wang, Haitao
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Gatcombe, Laura
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Maughan, Timothy S.
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Kaplan, Richard
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Escott-Price, Valentina
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Al-Tassan, Nada A.
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Meyer, Brian F.
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Wakil, Salma M.
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Houlston, Richard S.
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Cheadle, Jeremy P.
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Tomlinson, Ian
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Church, David N.
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Gray, Victoria, Briggs, Sarah, Palles, Claire, Jaeger, Emma, Iveson, Timothy, Kerr, Rachel, Saunders, Mark P., Paul, James, Harkin, Andrea, McQueen, John, Summers, Matthew G., Johnstone, Elaine, Wang, Haitao, Gatcombe, Laura, Maughan, Timothy S., Kaplan, Richard, Escott-Price, Valentina, Al-Tassan, Nada A., Meyer, Brian F., Wakil, Salma M., Houlston, Richard S., Cheadle, Jeremy P., Tomlinson, Ian and Church, David N. (2019) Pattern recognition receptor polymorphisms as predictors of oxaliplatin benefit in colorectal cancer. Journal of the National Cancer Institute, 111 (8), 828-836. (doi:10.1093/jnci/djy215).

Record type: Article

Abstract

Constitutional loss of function (LOF) single nucleotide polymorphisms (SNPs) in pattern recognition receptors FPR1, TLR3, and TLR4 have previously been reported to predict oxaliplatin benefit in colorectal cancer. Confirmation of this association could substantially improve patient stratification. 

Methods: We performed a retrospective biomarker analysis of the Short Course in Oncology Therapy (SCOT) and COIN/COIN-B trials. Participant status for LOF variants in FPR1 (rs867228), TLR3 (rs3775291), and TLR4 (rs4986790/rs4986791) was determined by genotyping array or genotype imputation. Associations between LOF variants and disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression, adjusted for confounders, using additive, dominant, and recessive genetic models. All statistical tests were two-sided. 

Results: Our validation study populations included 2929 and 1948 patients in the SCOT and COIN/COIN-B cohorts, respectively, of whom 2728 and 1672 patients had functional status of all three SNPs determined. We found no evidence of an association between any SNP and DFS in the SCOT cohort, or with OS in either cohort, irrespective of the type of model used. This included models for which an association was previously reported for rs867228 (recessive model, multivariable-adjusted hazard ratio [HR] for DFS in SCOT = 1.19, 95% confidence interval [CI] = 0.99 to 1.45, P =. 07; HR for OS in COIN/COIN-B = 0.92, 95% CI = 0.63 to 1.34, P =. 66), and rs4986790 (dominant model, multivariable-adjusted HR for DFS in SCOT = 0.86, 95% CI = 0.65 to 1.13, P =. 27; HR for OS in COIN/COIN-B = 1.08, 95% CI = 0.90 to 1.31, P =. 40). 

Conclusion: In this prespecified analysis of two large clinical trials, we found no evidence that constitutional LOF SNPs in FPR1, TLR3, or TLR4 are associated with differential benefit from oxaliplatin. Our results suggest these SNPs are unlikely to be clinically useful biomarkers.

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More information

Accepted/In Press date: 19 November 2018
e-pub ahead of print date: 14 January 2019
Published date: 1 August 2019

Identifiers

Local EPrints ID: 444684
URI: http://eprints.soton.ac.uk/id/eprint/444684
ISSN: 0027-8874
PURE UUID: a4d4ea22-8ca5-43f9-accf-032fb523ad66
ORCID for Timothy Iveson: ORCID iD orcid.org/0000-0002-4681-2712

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Date deposited: 29 Oct 2020 17:33
Last modified: 18 Mar 2024 02:47

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Contributors

Author: Victoria Gray
Author: Sarah Briggs
Author: Claire Palles
Author: Emma Jaeger
Author: Timothy Iveson ORCID iD
Author: Rachel Kerr
Author: Mark P. Saunders
Author: James Paul
Author: Andrea Harkin
Author: John McQueen
Author: Matthew G. Summers
Author: Elaine Johnstone
Author: Haitao Wang
Author: Laura Gatcombe
Author: Timothy S. Maughan
Author: Richard Kaplan
Author: Valentina Escott-Price
Author: Nada A. Al-Tassan
Author: Brian F. Meyer
Author: Salma M. Wakil
Author: Richard S. Houlston
Author: Jeremy P. Cheadle
Author: Ian Tomlinson
Author: David N. Church

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