Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer

Nichola Johnson, Paolo De Ieso, Gabriele Migliorini, Nick Orr, Peter Broderick, Daniel Catovsky, Athena Matakidou, Timothy Eisen, Christy Goldsmith, Frank Dudbridge, Julian Peto, Isabel Dos-Santos-Silva, Alan Ashworth, Gillian Ross, Richard S Houlston, Olivia Fletcher

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1485-1493
JournalCancer Research
Volume76
Issue number6
DOIs
Publication statusPublished - 14 Mar 2016
Externally publishedYes

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Alleles
  • Aryl Hydrocarbon Hydroxylases
  • Breast Neoplasms
  • Cytochrome P-450 CYP3A
  • Estrone
  • Female
  • Genotype
  • Glucuronides
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Lung Neoplasms
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Young Adult
  • Journal Article
  • Research Support, Non-U.S. Gov't

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