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Pharmacogenetic association of MBL2 and CD95 polymorphisms with grade 3 infection following adjuvant therapy for breast cancer with doxorubicin and cyclophosphamide

Lookup NU author(s): Dr David Jamieson, Dr Nicola Sunter, Sara Muro, Dr Nicola Cresti, Julieann Sludden, Melanie Griffin, Professor James Allan, Dr Mark Verrill

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

Life-threatening infection as an adverse reaction to cytotoxic therapy of cancer remains a major problem, potentially limiting efficacy. Administration of colony-stimulation factors benefits only a minority of patients, and improved stratification guidelines are needed to identify those patients likely to benefit.We investigated single nucleotide polymorphisms (SNPs) in two genes related to immune function to identify associations with severe infection following treatment of breast cancer with doxorubicin and cyclophosphamide. CD95 mediates the extrinsic apoptosis pathway in haematopoietic cells and a CD95 promoter SNP (rs2234767) has been shown to result in reduced expression of the receptor. MBL2 activates the classical complement pathway in the presence of pathogens and independently of antibodies. Numerous SNPs have been described including a promoter SNP (rs7096206) which results in decreased expression of the protein.Homozygotes for the CD95 minor allele were more likely to experience a grade 3 infection than heterozygote and homozygote wild-type patients (29%, 3% and 5%, respectively p = 0.048). CD95 minor allele homozygotes also had higher basal white blood cell and neutrophil counts compared with wild-type allele carriers, which was sustained throughout therapy. There was an allele-dose association between the MBL2 SNP and grade 3 infection, with 2, 8 and 17% of wild-type homozygotes, heterozygotes and minor allele homozygotes, respectively, experiencing grade 3 infection (p = 0.02).These associations demonstrate the utility of a pharmacogenetic approach to identify individuals more likely to acquire a life-threatening infection during chemotherapy. The apparent association with a CD95 SNP and a mild neutrophilia merits further investigation.


Publication metadata

Author(s): Jamieson D, Sunter N, Muro S, Pouché L, Cresti N, Lee J, Sludden J, Griffin MJ, Allan JM, Verrill MW, Boddy AV

Publication type: Article

Publication status: Published

Journal: European Journal of Cancer

Year: 2017

Volume: 71

Pages: 15-24

Print publication date: 01/01/2017

Online publication date: 08/12/2016

Acceptance date: 24/10/2016

ISSN (print): 0959-8049

ISSN (electronic): 1879-0852

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/j.ejca.2016.10.035

DOI: 10.1016/j.ejca.2016.10.035


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