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 Ã 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 ¼ 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P ¼ 0.009), and CLL progression (HR, 1.62; P ¼ 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7 Ã 1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (P interaction ¼ 0.06). The CYP3A7 Ã 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 Ã 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 Ã 1C carriers.

Genome-wide association study of offspring birth weight in 86,577 women highlights maternal genetic effects that are independent of fetal genetics

“…The CYP3A7 gene is part of the cytochrome P450 family 3 subfamily A gene cluster, which encodes enzymes responsible for the metabolism of multiple and diverse endogenous and exogenous molecules (48), and SNP rs45446698 tags a haplotype of 7 highly correlated variants in the CYP3A7 promoter, known as the CYP3A7*1C allele (49,50). The CYP3A7 gene is predominantly expressed in fetal development, but CYP3A7*1C results in expression in adult carriers (50,51).…”

Continuum of Host-Gut Microbial Co-metabolism: Host CYP3A4/3A7 are Responsible for Tertiary Oxidations of Deoxycholate Species

“…(234.8 6 123.1 pmol/mg microsomal protein, mean 6 S.D., n = 54) (Leeder et al, 2005), the CYP3A7 protein was detected in approximately one of 10 adult livers (n = 59), amounting to 24-90 pmol/mg of microsomal protein (Sim et al, 2005). Recent studies have increasingly showed that gene variances of CYP3A7 are associated with various clinical outcomes, including bone mineral density in postmenopausal women independent of serum levels of dehydroepiandrosterone sulfate (Bácsi et al, 2007); decreased dehydroepiandrosterone sulfate levels in women with polycystic ovary syndrome (Goodarzi et al, 2008); adverse outcomes in chronic lymphocytic leukemia, breast, and lung cancer (Johnson et al, 2016); reduced levels of 2-hydroxylation pathway estrogen metabolites (Sood et al, 2017); and maternal determinants of fetal growth independent of fetal genetics (Beaumont et al, 2018). There is, therefore, an increasing need for a specific in vivo CYP3A7 biomarker.…”

Machine Learning-Assisted Network Inference Approach to Identify a New Class of Genes that Coordinate the Functionality of Cancer Networks

“…Among these, Class II cancer genes involved in transcriptional regulation are prevalent. For example, an allele of CYP3A7 is associated with poor outcomes in leukemia, breast and lung cancers 45 . Intriguingly, some of the Class II genes interacting with the CYP3A7-CYP3AP1 cassette, such as SLC19A1 46 , were reported to associate with clinical outcomes.…”