The frameshift polymorphism CYP3A43_74_delA is associated with poor differentiation of breast tumors

Abstract

for the GENICA Network BACKGROUND: CYP3A enzymes, due to their role in the metabolism of steroid hormones, are suggested to affect carcinogenesis of hormone-related cancers. The purpose of the present study was to evaluate the association between polymorphisms located in CYP3A43, breast cancer risk, and tumor characteristics. METHODS: A 3-plex matrix-assisted laser desorption ionization time of flight mass spectrometry assay has been established for CYP3A43_74_delA (CYP3A43*2A), CYP3A43_1018_C>G (CYP3A43*3), and CYP3A43_1047_C>T (CYP3A43*1B) polymorphisms, and 1021 breast cancer cases and 1015 age-matched, population-based controls from the German GENICA collection have been genotyped. RESULTS: No differences in genotype frequencies between cases and controls were observed, indicating that CYP3A43_74_delA is not associated with breast cancer risk. Subgroup analyses showed an association between the CYP3A43_74_delA allele and high-grade tumors (odds ratio, 1.74; 95% confidence interval, 1.14-2.65 [P ¼ .010 and P trend ¼ .012]). CONCLUSIONS: The data support the notion that the CYP3A43_74_delA variant may result in decreased protein and/or activity levels, and this may further lead to increased hormone levels to promote tumor cell growth and hinder differentiation. Cancer 2010;116:5358-64.

The UGT1A6_19_GG genotype is a breast cancer risk factor

“…However, a shortcoming of this powerful approach is the lack of a sufficient coverage of polymorphisms in gene regions with high sequence similarities to other genes or pseudo genes. Genetic variations in such gene regions require an adapted primer design and amplification conditions which allow specific genotyping of the loci of interest (Justenhoven et al, 2010; The MARIE-GENICA Consortium, 2010). Therefore, polymorphic loci in homologous sequences are usually exempted from GWAS arrays, and can be analyzed in specially designed low-plex genotyping assays or small scale microarrays, e.g., the AmpliChip® CYP450 Test (Roche Diagnostic GmbH, Germany), the DMET™ Plus Solution (Affymetrix Inc. CA, USA) or the VeraCode® ADME Core Panel (Illumina, Inc. CA, USA) (Justenhoven, 2012).…”

Pharmacogenetic assessment of clinical outcome in patients with metastatic breast cancer treated with docetaxel plus capecitabine

“…Whereas genetic polymorphisms in drug metabolizing enzymes can affect 20-25% of all drug therapies to an extent that therapy outcome is altered (Ingelman-Sundberg 2004), and cytochrome P450 (CYP450) plays a critical role because it involves in about 80% of all phase I drug metabolisms. Furthermore, genetic polymorphisms of CYP450 have been reported to be associated with breast cancer risk (Ma et al 2010;Sergentanis and Economopoulos 2010), differentiation (Justenhoven et al 2010), clinical outcome of hormonal therapy (Kiyotani et al 2010;Ruiter et al 2010), and response and survival after some regimens of chemotherapy (Bray et al 2010;Gor et al 2010;Petros et al 2005). But to the best of our knowledge, there is no evidence whether genetic polymorphisms in CYP450 can affect clinical outcomes of a commonly used chemotherapeutic regimen of docetaxel plus capecitabine in patients with MBC.…”

Polymorphisms of Phase I and Phase II Enzymes and Breast Cancer Risk

“…This particular genomic architecture hampers specific genotyping due to the potential co-amplification of homolog gene sequences. Therefore, the establishment of accurate analysis methods requires primer selection by eye inspection, adapted amplification protocols, and verification of genotype calls by an independent method (Justenhoven et al, 2010). An example for the particular need of an appropriate genotyping procedure is the analysis of the SULT1A1 638 G > A (rs9282861) polymorphism.…”

“…Other gene families and subfamilies with a similar degree of sequence homologies are known for CYP3A , CYP2C , GST s, as well as NAT s and UGT s (Salinas and Wong, 1999; Gellner et al, 2001; Tukey and Strassburg, 2001; Nelson et al, 2004; Sim et al, 2008). So far individual assays for some of these polymorphisms have been established by researchers, e.g., for CYP3A (Justenhoven et al, 2010; The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk, 2010), CYP2D6 (Schaeffeler et al, 2003; Morike et al, 2008), CYP2C19 (Justenhoven et al, 2012), GST , UGT , and SULT1A (The MARIE-GENICA Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk, 2010) as well as companies (e.g., Applied Biosystems and Third Wave Technologies) 1 , 2 . Moreover, particular panels and arrays for the genetic analysis of metabolic enzymes and transporters have been developed within recent years: the AmpliChip ® CYP P450 Test 3 , the DMET Plus Panel DNA Chip 4 , VeraCode ADME Core Panel 5 , and the iPLEX ADME PGx Panel 6 .…”

“…One study reported an association between the rs61469810 polymorphism of CYP3A43 ( CYP3A43 *2A) and poorly differentiated breast tumors which may be explained by a potential contribution of the variant allele to increased sex hormone levels (Justenhoven et al, 2010). Another investigation suggested that the rs1058930 polymorphism of CYP2C8 ( CYP2C8 *4) affects lymph node status of breast cancer patients (Jernstrom et al, 2009).…”