Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer
Open Access
- 14 March 2016
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 76 (6), 1485-1493
- https://doi.org/10.1158/0008-5472.can-15-1410
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. Cancer Res; 76(6); 1485–93. ©2016 AACR.This publication has 34 references indexed in Scilit:
- Novel Genetic Markers of Breast Cancer Survival Identified by a Genome-Wide Association StudyCancer Research, 2012
- Genome-Wide Association Study of Survival in Non–Small Cell Lung Cancer Patients Receiving Platinum-Based ChemotherapyJNCI Journal of the National Cancer Institute, 2011
- CYP2D6 gene variants: association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifenBreast Cancer Research, 2010
- A Genome-Wide Association Study of Prognosis in Breast CancerCancer Epidemiology, Biomarkers & Prevention, 2010
- Genotype-guided tamoxifen therapy: time to pause for reflection?The Lancet Oncology, 2009
- Prevalent cases in observational studies of cancer survival: do they bias hazard ratio estimates?British Journal of Cancer, 2009
- SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMapBioinformatics, 2008
- Identification of low penetrance alleles for lung cancer: The GEnetic Lung CAncer Predisposition Study (GELCAPS)BMC Cancer, 2008
- Interaction between CHEK2*1100delC and other low-penetrance breast-cancer susceptibility genes: a familial studyThe Lancet, 2005
- CYP3A4 Polymorphisms--Potential Risk Factors for Breast and Prostate Cancer: A HuGE ReviewAmerican Journal of Epidemiology, 2004