title: Pharmacogenetic association of MBL2 and CD95 polymorphisms with grade 3 infection following adjuvant therapy for breast cancer with doxorubicin and cyclophosphamide.
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.
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: David
authors.initials: D
authors.lastname: Jamieson
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Sunter
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Muro
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Lucie
authors.initials: L
authors.lastname: Pouché
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; Northern Centre for Cancer Care, Newcastle Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Cresti
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Johanne
authors.initials: J
authors.lastname: Lee
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Julieann
authors.initials: J
authors.lastname: Sludden
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Griffin
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Allan
authors.affiliation: Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; Northern Centre for Cancer Care, Newcastle Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Verrill
authors.affiliation: Faculty of Pharmacy, Pharmacy and Bank Building (A15), University of Sydney, Science Road, NSW 2006, Australia. Electronic address: alan.boddy@sydney.edu.au.
authors.forename: Alan V
authors.initials: AV
authors.lastname: Boddy
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects*; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005838:Genotype; D006801:Humans; D007239:Infections / Q000139:chemically induced* / Q000235:genetics; D037601:Mannose-Binding Lectin / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D016019:Survival Analysis; D019014:fas Receptor / Q000097:blood / Q000235:genetics*
chemical_list: C445619:MBL2 protein, human; D037601:Mannose-Binding Lectin; D019014:fas Receptor; D004317:Doxorubicin; D003520:Cyclophosphamide
keywords: CD95; Cancer chemotherapy drugs; Cyclophosphamide; Doxorubicin; Infection; MBL2; Pharmacogenetics