Xenobiotic là gì

Drug và xenobiotic metabolizing enzymes (DXME) play important roles in drug responses và carcinogenesis. Recent studies have found that expression of DXME in cancer cells significantly affects drug clearance & the onset of drug resistance. In this study we compared the expression of DXME in breast tumor tissue samples from patients representing three ethnic groups: Caucasian Americans (CA), African Americans (AA), and Asian Americans (AS). We further combined DXME gen expression data with eQTL data from the GTEx project & with allele frequency data from the 1000 Genomes project to lớn identify SNPs that may be associated with differential expression of DXME genes. We identified substantial differences aý muốn CA, AA, and AS populations in the expression of DXME genes and in activation of pathways involved in drug metabolism, including those involved in metabolizing chemotherapy drugs that are commonly used in the treatment of breast cancer. These data suggest that differential expression of DXME may associate with health disparities in breast cancer outcomes observed amuốn these three ethnic groups. Our study suggests that development of personalized treatment strategies for breast cancer patients could be improved by considering both germline genotypes và tumor specific mutations and expression profiles related to lớn DXME genes.

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Breast cancer (BRCA) is a heterogeneous disease và understanding this heterogeneity is a key challenge in the development of effective personalized treatment strategies. Individual breast cancer patients with pathologically similar tumors may respond very differently to lớn the same standard treatments; the mechanisms for this disparity are not well understood. The incidence và death rates of breast cancer differ aao ước people from different ethnic groups. From 2008–2012, the incidence rates of breast cancer per 100,000 people were 128.1, 124.3, and 88.3 for non-Hispanic trắng, non-Hispanic black, and Asian and Pacific islander populations, respectively1. Additionally, the breast cancer specific death rates per 100,000 people are 21.9, 31.0, & 11.4 for non-Hispanic Trắng, non-Hispanic blaông chồng, & Asian and Pacific islander, respectively1, 2. In addition to differences in socioeconomic status and lifestyle3,4,5, genetic factors likely are critical in establishing breast cancer health disparities aý muốn these three ethnic groups1, 6,7,8,9,10,11, and identifying these genetic factors will lead khổng lồ development of more effective sầu personalized medicine. Drug & xenobiotic metabolizing enzymes (DXME) play important roles in patients’ responses to lớn treatment & in the development of drug resistance.

The study of DXME has generally focused on enzyme activities in the liver or blood, và association studies have mostly examined germline variants in DXME coding regions from patients. In recent years it has been reported that intratumoral expression of DXME significantly affects tumor drug response & the onset of resistance to lớn therapy, & it has been suggested that drug concentrations in plasma or tissues alone cannot completely explain the efficacy of drugs in target organs or tumor tissues. Although variability of drug metabolism in the liver must be considered as a potential factor mediating drug sensitivity or resistance, intracellular penetration, accumulation, distribution, metabolism, and elimination are important parameters governing the efficacy of drugs that interact with targets localized within cancer cells12. For example, induction of cytochrome P450 (CYP) activity may facilitate the onmix of drug resistance by accelerating the degradation and clearance of anti-cancer agents in cancer cells13.

In solid tumors, the extracellular and intracellular distribution of drugs exhibits a high degree of variability, and is largely controlled by DXME và influx & efflux systems that transport drugs into & out from cells. Expression of DXME within tumor cells is known khổng lồ play a role in tumor cell survival và in tumor-specific absorption, distribution, metabolism, và excretion (ADME) of drugs14. In cancer subclones, there tends to be a svào genomic instability that leads lớn highly variable expression of DXME. Cancer cell drug resistance or sensitivity is critically impacted by expression of DMXE within tumors, & understanding which specific DXME contribute khổng lồ response lớn particular drugs will lead lớn better precision medicine12, 15.

Patient ethnithành phố may influence differences in the pharmacokinetics (PK) và pharmacodynamics (PD) of drugs, resulting in variability in responses khổng lồ drug therapy and contributing lớn ethnic disparities in patient outcomes16. A previous study had profiled the expression of 21 CYP family genes in 170 breast tumor tissues and found that the expression of several CYP family genes was correlated with tumor grade, molecular subtype, or patient survival17. By comparing DXME ren expression, pathway activation, & associated genotypes in breast cancers of patients from different ethnic backgrounds, we could gain important insight on the variation of these enzymes in diverse patient populations, which would provide useful guidance in the development of precision treatment strategies.

In this study we used breast cancer gene expression data obtained from The Cancer Genome Atlas (TCGA) lớn study the expression patterns of DXME across Americans from three different ethnic backgrounds: Caucasian American (CA), African American (AA), and Asian American (AS). We combined gen expression data with eQTL data from the Genotype-Tissue Expression (GTEx) Project và genotype information from the 1000 Genomes Project to lớn perkhung an integrative study to identify Single-nucleotide polymorphisms (SNPs) that may associate with differential DXME ren expression between these different racial groups. This approach not only identified SNPs potentially associated with DXME expression, but also provided valuable insight inlớn the mechanisms by which ren expression liên kết genotype (different allele frequencies in different ethnic groups) và phenotype (different incidence and death rates ahy vọng different ethnic groups).

This current study may help researchers better underst& the biological factors causing the health disparity aao ước diverse ethnic groups, while also improving understanding of breast cancer heterogeneity through studying the expression of DXME. Characterizing differential expression và activity of DXME in breast tumors from a diverse patient population may identify novel factors and mechanisms that underlie ethnic disparities in breast cancer outcomes.


Drug and xenobiotics metabolizing enzymes (DXME)

Names và gene symbols for DXME genes were obtained from several KEGG pathways, including “drug metabolism - cytochrome P450”, “metabolism of xenobiotics by cytochrome P450”, và “drug metabolism - other enzymes”18,19,trăng tròn. In total, 88 genes representing 13 enzyme classes were identified (Supplementary Material). Among these 88 genes, there are 24 cytochrome P450 (CYPhường family) genes.

Differential expression of DXME across CA, AS, and AA breast cancers

Differential expression of DXME genes aước ao the CA, AS, and AA breast cancers was analyzed using DESeq2 (Fig. 1). The mean expressions in CA BRCA were used as a reference & relative sầu mean expression values from AA và AS BRCA were plotted using a color scheme to lớn show qualitative differences. The genes in Fig. 1 represent 42 DXME genes that display significant differential expression between at least two ethnic groups (fold change ≥ 2.0 and adjusted p-value ≤ 0.05). The expression differences for many of the genes across the three ethnicities are quite large, which is consistent with previous observations of a large number of genetic variants in these genes21,22,23,24,25,26. It is noteworthy that AS BRCA have overall lower expressions for many DXME genes compared to lớn either CA or AA BRCA. The number of DXME genes that exhibited higher expression in AA compared to CA BRCA was similar khổng lồ the number of DXME genes that exhibited lower expression in AA compared to CA BRCA (Fig. 1). Overall, the greathử nghiệm differential expression of DXME genes was seen in AA vs. AS BRCA, followed by the differences between AS và CA BRCA. Expression of DXME genes was the most similar between AA và CA BRCA.


Figure 1

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The expression of 42 drug và xenobiotics metabolizing enzymes across breast cancers for Caucasian American (CA), African American (AA), Asian American (AS), all BRCA cancer samples from the three races (Tumor), và all normal samples from the three races (Normal). The mean expressions of all tumor BRCA samples (Tumor) were used as a reference & relative sầu mean expression values from other groups were plotted using a color scheme to show qualitative differences. The values represent fold changes of different groups vs. Tumor group. There are totally 42 DXME genes that display significant differential expression between at least two comparisons (Tables 1 và S2, fold change ≥ 2 và adjusted p-value ≤ 0.05).


CYP4Z1

The mean expression (in reads per million, or RPM) of CYP4Z1 in adjacent normal tissue (all matched normal tissue samples at TCGA combined), BRCA tissue (all racial groups combined), & separately for CA, AS, & AA breast tumor tissue was 36.9, 92.2, 101, 52.7, & 63.6, respectively. Expression of CYP4Z1 in normal breast tissue was lower than in breast tumor tissue; among mỏi the three ethnic groups, AS breast cancer displays the lowest expression of this gen. While the substrate of CYP4Z1 is unknown, CYP4Z1 mRNA was detected in breast carcinoma tissue & in normal mammary glvà tissue, whereas only marginal expression was found in all other tissues27. Additionally, it was reported that expression of the CYP4Z1 ren is upregulated by activated glucocorticoid and progesterone receptors28. Overexpression of CYP4Z1 is associated with increased production of 20-hydroxyeicosatetraenoic acid (20-HETE) in BRCA, & it has been hypothesized that CYP4Z1 metabolizes arachidonic acid to lớn 20-HETE, resulting in enhanced growth & spread of breast cancer cells29, 30. These studies suggest that CYP4Z1 could be a valuable marker to distinguish between benign and malignant breast & ovarian disease growths và could be a prognostic biomarker for malignant progression in these tissues. The data we present are consistent with previous reports & suggest that CYP4Z1 may be associated with the breast cancer health disparity ahy vọng the three ethnicities.

CYP2A6

CYP2A6, the primary enzyme responsible for the oxidation of nicotine and cotinine, is also involved in the metabolism of several pharmaceuticals, carcinogens, & a number of coumarin-type alkaloids. Additional substrates metabolized by CYP2A6 include cyclophosphamide, ifosfamide, fluorouracil, & aflatoxin24. The mean expression values in RPM of CYP2A6 in adjacent normal tissue, all BRCA tissue, CA, AS, & AA breast tumor tissues are 5.63, 75.7, 96.3, 4.89, và 37.0, respectively. CYP2A6 expression is elevated in CA, AA tumor, & all BRCA tissue compared lớn normal breast tissue. CYP2A6 is significantly differentially expressed in all pair-wise comparisons by ethniđô thị (CA vs. AA; CA vs. AS; AA vs. AS), và in some stage & subtype specific comparisons (Table 1). The dysregulation of this gen may play a role in the health disparity between different ethnicities and in breast cancer in general.

CYP2A7

The differential expression pattern of this gen is similar to lớn that of CYP2A6, wherein the mean normalized expression values in adjacent normal tissue, all BRCA tissue, CA, AS, và AA breast tumor tissues are 0.63, 30.8, 28.6, 1.80, và 24.9, respectively. The substrate of this enzyme is still unknown. CYP2A7 is part of a large cluster of CYPhường genes from the CYP2A subfamily located on chromosome 19q, & it is likely that differential expression of both CYP2A6 and CYP2A7 is caused by a single genetic variant.

CYP1B1

The enzyme encoded by CYP1B1 localizes lớn the endoplasmic reticulum (ER) and metabolizes procarcinogens, such as polycyclic aromatic hydrocarbons and 17beta-estradiol31. The mean expression values in adjacent normal tissue, all BRCA tissue, CA, AS, and AA breast tumor tissues are 87.0, 113, 126, 84.8, và 104, respectively. The differential expression pattern is similar khổng lồ that of CYP2A6, but the scale of differential expression is much smaller for this gene. CYP1B1 expression is significantly higher in CA triple-negative BRCA (TNBC) than in AA TNBC (Table 1).

Alcohol dehydrogenase (ADH)

Several alcohol dehydrogenases are down-regulated in BRCA tissues compared khổng lồ adjacent normal tissues, including ADH1A, ADH1B, ADH1C, & ADH4. Members of ADH enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. It is unclear whether this differential expression plays any role in breast cancer or contributes khổng lồ racial disparities in BRCA outcomes. The expression values for the down-regulated ADH genes are given in supplementary materials (Table S3).

UDP-glucuronosyltransferases (UGTs)

Glucuronidation, catalyzed by UGTs, is an important process of metabolism & detoxification of estrogens. Some UGTs have sầu been reported to lớn be differentially expressed in breast cancer32. Several UGT family genes are differentially expressed in various comparisons across the three race groups (Table S2).

Drug & xenobiotics metabolism pathways

Pathway enrichment analyses in KEGG pathways using all the significantly differentially expressed DXME genes from AA, CA and AS BRCA samples were conducted for three different pair-wise combinations: AA vs. CA, AA vs. AS, và CA vs. AS. The analyses identified that the KEGG “pathway drug metabolism - cytochrome P450”, is significantly up-regulated in AA BRCA samples, compared lớn AS BRCA samples with an adjusted p-value of 0.0078. The pathway “Metabolism of xenobiotics by cytochrome P450” is also significantly up-regulated in AA as compared khổng lồ AS BRCA samples with adjusted p-value of 0.026. Metabolic disorders of biological oxidation enzymes pathway (adjusted p-value = 0.0071) is significant between CA & AS BRCA tumor samples when also including Reactome pathways in the analysis. Differential analysis results for all the genes are used as input đầu vào for Pathview analysis and the overview for drug metabolism pathway is given in Figures S1–S3 (Supplementary materials). Metabolism pathways for several anticancer drugs commonly used in the treatment of breast cancer (detailed below) were identified as being differentially regulated ahy vọng CA, AA, and AS BRCA patients.

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Tamoxifen metabolism

Tamoxifen is a selective estrogen receptor modulator which is used in the treatment & prevention of breast cancer, specifically ER-positive sầu BRCA. Tamoxifen is metabolized in human body to the active sầu metabolite 4-hydroxytamoxifen (4OHT) by several enzymes, including CYP2D6, CYD3A4, CYP1A1, CYP2B6, and CYP3A533. Changes in expression of these genes may affect the concentration and bioavailability of active tamoxifen in breast tumors. It is known that patients with variant forms of the gene CYP2D6 may not receive sầu full benefit from tamoxifen because of slower metabolism of the tamoxifen prodrug into active sầu 4OHT34, 35. Furthermore, some patients, called “ultra-fast metabolizers”, metabolize tamoxifen too rapidly to lớn keep enough active 4OHT available long enough khổng lồ achieve the desired therapeutic effect. We report that expression of CYP2D6 is higher in AA breast tumor samples compared khổng lồ AS và CA BRCA (Fig. 2). Other genes involved in tamoxifen metabolism are also differentially expressed in BRCA tissues in pair-wise comparisons aý muốn the three ethnicities (Table 1). For example, CYP3A4 & CYP2D6 are both down-regulated in AS BRCA compared khổng lồ AA BRCA, indicating reduced activity of the tamoxifen metabolism pathway (Fig. 3).


Figure 2

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Differential gen expression in the tamoxifen metabolism pathway. (A) Asian American vs African American. Up or down regulation means increase or decrease of ren expression in Asian American BRCA patient tumor tissues. (B) Asian American vs Caucasian American. Up or down regulation means increase or decrease of gene expression in Asian American BRCA patient tumor tissues. (C) African American vs Caucasian American. Up or down regulation means increase or decrease of gen expression in African American BRCA patient tumor tissues. The pathway diagrams with differential gene expression were made using Pathview package47, where pathway diagrams were originally obtained from KEGG database18,19,đôi mươi.


Cyclophosphamide và Ifosfamide

Cyclophosphamide và ifosfamide are alkylating agents of the nitrogene mustard type that are commonly used as chemotherapy khổng lồ treat various cancers, including breast cancer. As prodrugs, they are converted by CYP enzymes khổng lồ khung the metabolite 4-hydroxy cyclophosphamide that has chemotherapeutic activity. Multiple enzymes in the cyclophosphamide và ifosfamide metabolism pathways are differentially expressed in BRCA tissues aý muốn the three ethnic groups, including CYP2B6, CYP3A4, CYP3A5, & enzymes in classes 2.5.1.18, 1.1.1.1 và 1.2.1.5 (Figure S4). Similar lớn the tamoxifen metabolism pathway, AS BRCA had lower expression of genes in these pathways than either AA or CA BRCA.

Fluorouracil

Fluorouracil belongs lớn a family of drugs called antimetabolites & is widely used in the treatment of various cancers, including breast cancer. CYP2A6 metabolizes the prodrug tegafur into active sầu fluorouracil (Figure S5). CYP2A6 expression is significantly lower in AS BRCA compared khổng lồ AA and CA BRCA và is lower in AA BRCA compared to lớn CA BRCA. In addition to lớn CYP2A6, enzymes in several classes including class 3.5.4.5, class 2.4.2.4, class 2.4.2.3, class 2.7.1.48, and class 2.7.1.21 are also differentially expressed between CA, AA, & AS BRCA (Figure S5).

Metabolism of xenobiotics by cytochrome P450 (CYP)

We next performed pathway analysis for pathways involved in xenobiotics metabolism by CYP.. genes. Metabolism of xenobiotics by CYPhường enzymes in breast tissues may play important roles in breast cancer risk. Several types of xenobiotics, including many carcinogens, are included in the KEGG pathways, including Benzo pyrene, DMBA, Naphthalene, Nicotine, Aflatoxin, 1-nitronaphthalene, trichloroethylene, 1,2-dichloroethylene, bromobenzene, và 1,2-dibromoethane. We found that AS breast tumor tissues have lower expression for the majority of the enzymes in xenobiotic metabolism pathways compared to both CA (Fig. 4) và AA (Figure S6, Supplementary material) breast tumor tissues. AA breast tumor has comparable number of differentially expressed genes in this pathway compared lớn CA breast tumor (Figure S7, Supplementary Material). Increased activities of these xenobiotics metabolism enzymes in CA or AA patients may produce extra amount of carcinogens in breast tissue and cause increased breast cancer risk. It is well known that AS have lower breast cancer incidence than CA và AA1, và the difference in the expression profiles of the xenobiotics metabolizing enzymes may play a role in that health disparity.


Figure 4

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SNPs associated with the differential expressions of DXME

An important question in disease studies is to lớn identify the underlying genotypes directly responsible for an observed phenotype. In this study we focus on several phenotypes of interest: the outcomes disparity among CA, AA, và AS BRCA patients, ethnic disparity in BRCA risk, and expression profiles of DXME genes from breast cancer tissues. To identify genotypes associated with these phenotypes, we combined gen expression data with eQTL data from the GTEx project & genotype information from the 1000 Genomes project. Using this approach we searched for SNPs that may be associated with the differential expression of DXME genes in breast cancer tissues from CA, AA, & AS patients. To illustrate our approach we detail this analysis for identification of SNPs associated with differential expression of the CYP2D6 ren. We first identified 138 SNPs that associate with CYP2D6 expression in breast tissue from the GTEx eQTL database. In addition lớn SNPhường. IDs we also obtained the effect size for each SNP. Using data from 1000 Genomes project we calculated the alternative sầu allele frequency for each SNPhường in three different ethnic groups: African, Caucasian, & Asian populations. The allele frequencies and effect sizes are then used to calculate relative sầu expression of each SNP. (see Methods for details). In Table 2, we danh mục the SNPs identified as associated with CYP2D6 expression (p-value ≤ 0.01). The SNPs were discovered using gene expression from AA và CA tumors và were independently confirmed in analysis of SNPs associated with CYP2D6 expression in AS BRCA (Table 2). These SNPs fall into lớn two clusters of linkage disequilibrium with the first three in one cluster & the last three in another cluster. These SNPs are all cthua trận khổng lồ one another và are distant from the CYP2D6 locus (chromosome 22, base location 42126499–42130906). Examination of the genomic region of these SNPs in the UCSC genome browser, revealed three genes in this region: SERHL, RRP7A, and SERHL2. The expression of these genes is not significantly correlated with that of CYP2D6, suggesting that regulation of CYP2D6 through this genomic region may not be related khổng lồ the products of any of these three genes. Previous studies have sầu mostly looked at variants on the coding regions or locations cthua thảm khổng lồ the coding region of DXME, which may affect the gene function by changing the protein sequence of the ren hàng hóa. Our approach will likely find new SNPs that affect the function of CYP2D6 and other DXME genes by affecting trans-regulation of gen expression. SNPs such as these can be difficult to lớn find using existing methods, and our approach illustrates an improved method for finding SNPs associated with ren expression by performing integrated secondary analyses on existing data. SNPs identified in this manner may be causal factors contributing to lớn differential expression of DXME & may underlie ethnic disparities in BRCA incidence & outcomes.


Table 2 SNPs that may be associated with the differential expression of CYP2D6 in breast cancer cells.
Full size table

Correlation between the expressions of some DXME genes with clinical variables

Using TCGA data analysis results obtained from the Broad Institute’s GDAC database we examined correlations between expression of CYPhường. genes and clinical characteristics, including patient age, disease stage, node status, metastatic status, và survival time. We found that expressions of certain CYP genes is correlated with node status (N stage) of breast cancer including CYP2A6 (p-value = 0.025), CYP2C8 (p-value = 0.035), CYP2D6 (p-value = 0.027), CYP2J2 (p-value = 0.036), CYP3A7 (p-value = 0.026), & CYP4B1 (p-value = 0.046). Expression of CYP4Z1 is correlated with metastatic stage (M stage; p-value = 0.011). Expression of CYP4F12 correlates with T stage (p-value = 0.0029). Expression of CYP2E1 correlates with disease stage (p-value = 0.000742). The expression of several CYP.. genes correlates strongly with age, including CYP1B1 (p-value = 1.01E-08), CYP2A6 (p-value = 0.000198), CYP4X1 (p-value = 2.92E-08), & CYP4Z1 (p-value = 1.11E-09). Whether these correlations are associated with increased breast cancer risk as people get older needs khổng lồ be investigated in future studies.


Discussion


The involvement of DXME in cancer, particularly regarding contributions khổng lồ the emergence of therapeutic resistance, is an area of active sầu study. It has been reported that ovarian cancer cells can express functional taxane-metabolizing enzymes that enhance the ability of cancer cells khổng lồ metabolize the chemotherapeutic agent docetaxel, representing a novel mechanism of chemotherapy resistance36. Additionally, it was also shown that human colorectal cancer cells are able lớn inactivate the anticancer drug paclitaxel through metabolism by CYP2C8 and CYP3A4, demonstrating an example of acquired therapeutic resistance through induction of DXME37. A study in lung tissue showed that DXME involved in the metabolism of anti-cancer drugs influence how tumors respond lớn chemotherapy, và suggested that DXME should be a factor lớn consider when determining therapeutic options38. In addition to lớn their role in the metabolism of anticancer drugs, DXMEs, including cytochrome P450 genes (CYPs), may also have sầu an important role in cancer initiation and progression. For example, high levels of CYP1B1 expression in breast tumor tissues was reported to lớn be associated with significantly increased breast cancer risk39, based on the observation that high CYP1B1 expression in breast cancer cells can evoke changes in their response khổng lồ drugs that are substrates of CYP1B1, thus influencing the metabolism or activation of environmental carcinogens40. Additionally, CYP2E1 expression was demonstrated lớn be a potential prognostic biomarker in breast cancer40.

It is well-established that rates of breast cancer incidence and mortality differ amuốn different ethnic groups. Many studies have been conducted lớn underst& the factors underlying this phenomenon, và it has been suggested that genetic factors may play important roles in this health disparity7,8,9,10.

In this study, we performed an integrative analysis of gene expression, eQTL, SNPhường., và pathway data associated with the expression of drug và xenobiotics metabolizing enzymes (DXME) in breast cancer (BRCA) tissues from patients across three major ethnic groups, Caucasian American (CA), African American (AA), & Asian American (AS). These analyses (1) revealed that expression of DXME genes in breast cancer tissue differs aao ước CA, AA, and AS patients; (2) indicated that pathways involving DXME genes are differentially regulated in CA, AA, & AS breast cancer patients; và (3) identified SNPs that may not only be associated with the differentially expressed DXME genes and pathways, but that also may contribute to BRCA health disparities among mỏi these three ethnic groups. These data provide further evidence clarifying the biological & genetic contributions to observed breast cancer disparities aý muốn patients from different ethnic groups.

We report that 42 DXME genes are significantly differentially expressed in at least one group-wise comparison aước ao CA, AA, and AS breast cancers. Moreover, DXME expression from AS BRCA was the most significantly different compared lớn CA or AA BRCA. We also found that AS breast tumors tkết thúc lớn exhibit ren expression indicative of repression of xenobiotic metabolism pathways compared to lớn both AA và CA breast tumors.

In particular, the CYPhường genes may critically contribute to breast cancer health disparities between CA, AA, & AS populations. Using CYP2D6 as an example, we identified several SNPs that may be associated with the differential expression of CYP2D6 ahy vọng CA, AA, & AS breast cancer tissues. This approach could be applied to lớn other genes lớn identify more expression-associated SNPs in breast cancer. As many associations indicate trans-regulation, these associations may help better underst& the ren và protein interactions & driver genes in breast cancer. In addition khổng lồ contributing to health disparities, these SNPs may also be associated with breast cancer risk and progression in general. The specific role of these SNPs in regulation of DXME expression và pathway activation needs to be elucidated in future studies.

A previous study examined the expression profile of 21 CYPhường genes in breast cancer cells using a tissue microarray containing 170 breast cancers and reported that the highest percentage of svào immunopositivity was seen for CYP4X1, CYP2S1 and CYP2U1, while CYP2J and CYP3A43 frequently displayed no immunoreactivity17. In this study we report consistent observations regarding CYP4X1 and CYP3A43, although expression patterns for other CYPhường genes were inconsistent with the previous report. This discrepancy may be due lớn different experimental method (IHC) that was used khổng lồ measure CYPhường protein expression in the previous study17. We report that the CYPhường genes with highest expression, ranked by the mean expression in tumor tissues for all patients, are: CYP1B1 (mean normalized expression 112.8), CYP4Z1 (92.2), CYP2A6 (75.7), CYP4X1 (65.1), CYP4B1 (31.5), CYP2A7 (30.8), and CYP4F8 (11.6). The CYP.. genes with the lowest expression in the TCGA breast cancer cohort were: CYP1A2 (0.010), CYP3A43 (0.029), CYP3A7 (0.033), CYP2C9 (0.044) & CYP3A4 (0.044).

In this study, we took an integrative sầu approach using multiple types of data. The ethnic information available through public data repositories, including the TCGA, serves as a key liên kết through which we were able to: (1) identify patterns of DXME expression within breast tumor tissues for a diverse breast cancer patient population; (2) persize differential gene expression analysis to identify genes that may be associated with breast cancer health disparities và breast cancer incidence and progression in general; và (3) combine the data from the 1000 Genomes project lớn identify SNPs associated with DXME expression/pathway activation và ethnic disparities in breast cancer. This novel integrative approach can be applied to other cancer types to discover genetic features that underlie disparities in disease incidence và outcomes.

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Precision cancer medicine aims lớn provide personalized cancer therapies to lớn individuals according to their characteristic responses to lớn available therapies. It requires in-depth understanding of cancer heterogeneity, which manifests itself at both phenotype (response to lớn treatment) và genotype (including both genetics and epigenetics) levels. While the goal is usually to understvà how genotype variations cause the phenotype differences, understanding the heterogeneity at gene expression levels can provide very valuable link between heterogeneities at phenotype và genotype (or epigenomic) levels. Genome wide association studies (GWAS) examining large number of genomic variants often have lớn khuyến mãi with multiple testing issues, which tkết thúc lớn produce large numbers of false positives. Race, as a natural stratification of human population, provides a different angle to investigate the heterogeneity at phenotypic, gen expression, & genotypic levels when race information is available across data sets at these different levels. The differentially expressed genes among mỏi different race groups discovered in this study are likely relevant in precision medicine. Some can be potential candidates for biomarkers for personalized cancer therapy. If clinically validated, they may be used independent of race information of the patients.

Better mechanistic understanding of how differences in DXME expression and pathway regulation contribute to lớn BRCA incidence & outcome disparities will facilitate the development of better personalized chemoprevention strategies. Our study suggests that development of personalized treatment strategies và prognostic/diagnostic tools incorporating DXME should take multiple genetic factors into lớn trương mục simultaneously và should consider both germline genotypes & tumor-specific mutations and expression profiles


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