title: Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer.
abstract: CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers.
authors.affiliation: Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK and Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Nichola
authors.initials: N
authors.lastname: Johnson
authors.affiliation: Alan Walker Cancer Care Centre, Darwin, Australia.
authors.forename: Paolo
authors.initials: P
authors.lastname: De Ieso
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Migliorini
authors.affiliation: Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK and Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Orr
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
authors.affiliation: Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK.
authors.forename: Athena
authors.initials: A
authors.lastname: Matakidou
authors.affiliation: Department of Oncology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.|Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, UK.
authors.forename: Timothy
authors.initials: T
authors.lastname: Eisen
authors.affiliation: Imperial College, London, UK and The Harley Street Clinic, London, UK.
authors.forename: Christy
authors.initials: C
authors.lastname: Goldsmith
authors.affiliation: Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Dudbridge
authors.affiliation: Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Peto
authors.affiliation: Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Dos-Santos-Silva
authors.affiliation: Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK and Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.affiliation: The Royal Marsden NHS Foundation Trust, Fulham Road, London UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Ross
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
authors.affiliation: Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK and Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Olivia
authors.initials: O
authors.lastname: Fletcher
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000652:urine; D051544:Cytochrome P-450 CYP3A; D004970:Estrone / Q000652:urine; D005260:Female; D005838:Genotype; D020719:Glucuronides / Q000652:urine; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000652:urine; D008175:Lung Neoplasms / Q000235:genetics* / Q000652:urine; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055815:Young Adult
chemical_list: D020719:Glucuronides; D004970:Estrone; D001189:Aryl Hydrocarbon Hydroxylases; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A