Cyclophosphamide- metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study

Abstract Introduction Cyclophosphamide-based adjuvant chemotherapy is a mainstay of treatment for women with node-positive breast cancer, but is not universally effective in preventing recurrence. Pharmacogenetic variability in drug metabolism is one possible mechanism of treatment failure. We hypothesize that functional single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs) that activate (CYPs) or metabolize (GSTs) cyclophosphamide account for some of the observed variability in disease outcomes. Methods We performed a retrospective cohort study of 350 women enrolled in a multicenter, randomized, adjuvant breast cancer chemotherapy trial (ECOG-2190/INT-0121). Subjects in this trial received standard-dose cyclophosphamide, doxorubicin and fluorouracil (CAF), followed by either observation or high-dose cyclophosphamide and thiotepa with stem cell rescue. We used bone marrow stem cell-derived genomic DNA from archival specimens to genotype CYP2B6, CYP2C9, CYP2D6, CYP3A4, CYP3A5, GSTM1, GSTT1, and GSTP1. Cox regression models were computed to determine associations between genotypes (individually or in combination) and disease-free survival (DFS) or overall survival (OS), adjusting for confounding clinical variables. Results In the full multivariable analysis, women with at least one CYP3A4 *1B variant allele had significantly worse DFS than those who were wild-type *1A/*1A (multivariate hazard ratio 2.79; 95% CI 1.52, 5.14). CYP2D6 genotype did not impact this association among patients with estrogen receptor (ER) -positive tumors scheduled to receive tamoxifen. Conclusions These data support the hypothesis that genetic variability in cyclophosphamide metabolism independently impacts outcome from adjuvant chemotherapy for breast cancer

High Resolution Genome-Wide Analysis of Chromosomal Alterations in Burkitt's Lymphoma

Additional chromosomal abnormalities are currently detected in Burkitt's lymphoma. They play major roles in the progression of BL and in prognosis. The genes involved remain elusive. A whole-genome oligonucleotide array CGH analysis correlated with karyotype and FISH was performed in a set of 27 Burkitt's lymphoma-derived cell lines and primary tumors. More than half of the 145 CNAs<2 Mb were mapped to Mendelian CNVs, including GSTT1, glutathione s-transferase and BIRC6, an anti-apoptotic protein, possibly predisposing to some cancers. Somatic cell line-specific CNVs localized to the IG locus were consistently observed with the 244 K aCGH platform. Among 136 CNAs >2 Mb, gains were found in 1q (12/27), 13q (7/27), 7q (6/27), 8q(4/27), 2p (3/27), 11q (2/27) and 15q (2/27). Losses were found in 3p (5/27), 4p (4/27), 4q (4/27), 9p (4/27), 13q (4/27), 6p (3/27), 17p (3/27), 6q (2/27),11pterp13 (2/27) and 14q12q21.3 (2/27). Twenty one minimal critical regions (MCR), (range 0.04–71.36 Mb), were delineated in tumors and cell lines. Three MCRs were localized to 1q. The proximal one was mapped to 1q21.1q25.2 with a 6.3 Mb amplicon (1q21.1q21.3) harboring BCA2 and PIAS3. In the other 2 MCRs, 1q32.1 and 1q44, MDM4 and AKT3 appeared as possible drivers of these gains respectively. The 13q31.3q32.1 <89.58–96.81> MCR contained an amplicon and ABCC4 might be the driver of this amplicon. The 40 Kb 2p16.1 <60.96–61> MCR was the smallest gained MCR and specifically encompassed the REL oncogene which is already implicated in B cell lymphomas. The most frequently deleted MCR was 3p14.1 <60.43–60.53> that removed the fifth exon of FHIT. Further investigations which combined gene expression and functional studies are essential to understand the lymphomagenesis mechanism and for the development of more effective, targeted therapeutic strategies

Proline homozygosity in codon 72 of p53 is a factor of susceptibility for thyroid cancer

A common germline polymorphism of p53 gene produces an Arginine to Proline change at aminoacid position 72. The resulting codon 72 variants have been reported associated with tumor susceptibility since they reduce p53 ability to activate apoptosis. Codon 72 polymorphism may play a role in subside vulnerability to different carcinogens and might account for ethnic variations in cancer frequency. Using an allele-specific polymerase chain reaction (PCR), we tested peripheral blood samples from 98 patients with thyroid cancer, including 21 follicular (FC) and 77 papillary carcinomas (PC), 44 patients with benign nodules, including 14 follicular adenomas and 30 goiters and 153 healthy individuals from the same geographical region. Data on lifetime occupational history, smoking history, general health conditions, previous diseases and other anamnestic data were obtained through interviews. Patients with FC (Pro/Pro = 19.0%, Arg/Arg = 42.9%, Arg/Pro = 38%) and with PC (Pro/Pro = 10.3%, Arg/Arg = 36.36%, Arg/Pro = 53.24%) showed a significant overrepresentation of codon 72 variants compared to the control population (Pro/Pro = 1.9%, Arg/Arg = 33.3%, Arg/Pro = 64.7%) (P = 0.0015). The Pro/Pro genotype, after adjusting for gender, age, tobacco and drugs, was associated with a markedly higher risk of FC (OR = 9.714; CI: 2.334-40.436) and of PC (OR = 5.299; CI: 2.334-40.436). These results provide evidence that p53 polymorphism is implicated in thyroid carcinogenesis and that individuals harboring the Pro/Pro genotype have an increased risk of developing thyroid cancer. (C) 2004 Elsevier Ireland Ltd. All rights reserved.210215115

GST profiling may be useful in the screening for thyroid nodule malignancy

Screening tools are of utmost necessity in order to identify individuals at risk for thyroid nodule cancer. The polymorphic inheritance of human drug-metabolizing enzymes, such as those encoded by the Glutathione-S-Transferase (GST) system, ;plays an important role in the development of most human cancers. GSTP1 enzyme is the most important detoxification enzyme in human head and neck tissues. An aminoacid substitution (1105V) in the GSTP1 gene result in two genotypes, GSTP1AB and GSTP1BB. Those produce a variant enzyme with lower activity and less capability of effective detoxification of carcinogens than the wild type GSTP1 AA. In order to look for the influence of GSTP1 enzymes inheritance pattern on thyroid cancer risk we used a PCR-SSCP-sequencing approach to compare the genotypes of 98 malignant nodules, including 77 papillary carcinomas (PC) and 21 follicular carcinomas (FC), to 44 benign nodules and to 157 healthy control individuals. Individuals with history of previous thyroid disease, exposure to radiation and antecedents of malignancy were excluded. Patients with PC and FC showed a significant over-representation of the variants of GSTP1 allele compared to the control population (p < 0.0001). The risk for thyroid cancer in individuals with the variant GSTP1 enzymes, after adjusting for gender, age, tobacco and drugs use, increased 7,092 (CI: 2,307-21,802) and 9,625 (CI: 2.484-37.291) times for PC and FC, respectively. We suggest that GST genotype may be associated with an increased susceptibility to thyroid cancer. GSTP1 profiling from peripheral blood may be a simple and useful tool in the screening for thyroid nodule malignancy. Glutathione-S-Transferase system; GSTP; Thyroid cancer; Screening. (C) 2004 Elsevier Ltd. All rights reserved.209212913

GSTO polymorphism analysis in thyroid nodules suggest that GSTO1 variants do not influence the risk for malignancy

A new class of glutathione S-transferase enzymes named omega (GSTO) has been recently identified and shown to be expressed in a wide range of human tissues. A genetic polymorphism of the GSTO1 gene causing an alanine-to-aspartate (A140D) substitution in amino acid 140 produces a variant with lowered enzyme activities in the biotransformation of inorganic arsenic, a common contaminant of drinking water in many regions of the world and a well known carcinogen. In order to investigate the role of GSTO1 inheritance pattern on thyroid cancer risk we used a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)-sequencing approach to compare the genotypes of 173 (87 women, 86 men; 18-81 years old; 47 18 years old) healthy control individuals with those of 145 patients with thyroid nodules (84 women, 61 men; 17-81 years old; 49 14 years old) including 17 follicular carcinomas, 76 papillary carcinomas, 21 follicular adenomas and 31 multinodular goiters. The incidence of GSTO1 variants was similar in the control population and population with the benign and malignant nodules. There was no association between genotype and the patients' clinical features, tumour parameters of aggressiveness at diagnosis or behaviour during follow-up. We conclude that GSTO1 variants do not influence the risk for thyroid nodules or their pathologic and clinical characteristics. (c) 2005 Lippincott Williams & Wilkins.14327728

Multi-objective prioritisation and reconfiguration for the control of constrained hybrid systems

In many applications, the control objectives and constraints can be assigned a hierarchy of levels of priority. Often a disturbance or a fault occurs, resulting in some constraints or objectives being violated. Inadequate handling of this situation might result in component or even system-wide failures. This paper presents several methods for handling a large class of multi-objective formulations and prioritisations for model predictive control of hybrid systems, using the new mixed logic dynamical (MLD) framework. A new method, which does not require logic variables for prioritising soft constraints, is also presente

Cutaneous Metastasis From a Classic Papillary Thyroid Cancer With Positive Immunohistochemical Staining for Sodium Iodide Symporter but No Response to Radioiodine Therapy

A 76-year-old man presented with small reddish, painless nodular lesions of the chest and on neck surgical scars. The patient had, 5 years before, a T3N1M0 classic papillary thyroid carcinoma that evolved with recurrent cervical lymph node metastasis despite 3 surgeries and a cumulative dose of 500 mCi of (131)Iodine. Investigations included the lesion biopsy and Tg immunohistochemistry, which led to the diagnosis of rare skin metastasis from a well differentiated thyroid tumor. The cutaneous lesions also tested positive for sodium iodide symporter protein, with clear membrane immunohistochemical staining. However, the patient did not respond to an additional dose of 400 mCi of radioiodine, suggesting a nonfunctional sodium iodide symporter protein. The lesions rapidly spread to the chest wall and erythematous red-purple inflamed nodules became confluent over a 3-month period. The tumor invaded the trachea causing the patient's death.19521421

The null genotype of glutathione S-transferase M1 and T1 locus increases the risk for thyroid cancer

Susceptibility to chemical carcinogens plays an important role in the development of most cancers. Several polymorphisms of human drug-metabolizing enzymes influence this individual susceptibility. The genes that encode the isoenzymes of the glutathione s-transferase (GST) system present a polymorphic inheritance. The GST mu 1 (GSTM1) and GST theta 1 (GSTT1) genes have a null allele variant in which the entire gene is absent. The null genotype for both enzymes has been associated with many different types of tumors. To look for the influence of the inheritance pattern of these enzymes on thyroid cancer risk, we used a triplex PCR that included beta-globin gene as a DNA quality control to compare 300 normal individuals of our population to 116 goiter patients. There were 49 cases of benign and 67 cases of malignant nodules: 50 papillary and 17 follicular carcinomas. Comparison between thyroid tumor specimens and normal corresponding samples of 35 cancer patients demonstrated identical patterns, suggesting that the GST system is not involved in the process of follicular dedifferentiation. There was no statistical difference between the prevalence of the deleted alleles in the normal individuals and in the goiter patients. However, papillary carcinoma patients (10%) and follicular carcinoma patients (17%) presented a higher prevalence of the null genotype than the normal population individuals (5%; P < 0.05). We found a 2.6 increased risk of thyroid cancer in individuals with the GSTT1 and GSTM1 combined null inheritance, suggesting that this genotype may be associated with an increased susceptibility to thyroid cancer.11111485148

Functional Variations in the ATM Gene and Susceptibility to Differentiated Thyroid Carcinoma

Context: ATM is critical in response to ionizing radiation-induced DNA damage. Objective: Variations in ATM are hypothesized to affect individual susceptibility to thyroid cancer. Our objective was to evaluate the association between ATM polymorphisms and thyroid cancer risk. Design, Participants, and Methods: Six ATM single nucleotide polymorphisms (SNP) were genotyped in two independent case-control series including 592 patients with differentiated thyroid carcinoma (DTC) and 885 healthy individuals. An unconditional logistic regression model was applied to calculate odds ratios (OR) and 95% confidence intervals (CI) for each SNP with respect to risk of DTC and the combination effect of SNP on cancer risk. Results: The risk-allele frequencies of all the SNP were similar in the two case-control populations. Under a dominant model of inheritance, the G allele of ATM rs189037 exhibited a protective effect against DTC (adjusted OR = 0.8; 95% CI, 0.6 -1.0; P = 0.04), and the G allele of rs1800057 was associated with increased risk of DTC (adjusted OR = 1.9; 95% CI, 1.1-3.1; P = 0.02). A protective haplotype (A-G-C-T-C-A) was associated with decreased risk of DTC in non-Hispanic whites (adjusted OR = 0.2; 95% CI, 0.0-0.8; P = 0.03). A significant dose-response relationship was observed between the total number of risk alleles of ATM and DTC risk (P = 0.01). Carriers of a combination of six to seven and eight to 10 risk alleles were at 30% (adjusted OR = 1.3; 95% CI, 1.0-1.7) and 50% (adjusted OR = 1.5; 95% CI, 1.1-2.1) increased risk of DTC, respectively. Conclusion: Individual susceptibility to DTC may be attributable to polymorphisms of ATM, and the associations warrant confirmation in independent studies. (J Clin Endocrinol Metab 97: 1913-1921, 2012)O TEXTO COMPLETO DESTE ARTIGO, ESTARÁ DISPONÍVEL À PARTIR DE FEVEREIRO DE 2015.97619131921American Thyroid AssociationNational Institutes of Health [U01 D019765-01]National Institutes of Environmental Health Sciences [R01 ES-11740]Cancer Center Support Grant [CA016672]The University of Texas MD Anderson Cancer CenterNational Institutes of Health [U01 D019765-01]National Institutes of Environmental Health Sciences [R01 ES-11740]Cancer Center Support Grant [CA016672

Genetic polymorphisms associated with cigarette smoking and the risk of Graves' disease

Objective Cigarette smoking is a well-recognized risk factor of Graves' disease and, particularly, Graves' ophthalmopathy. Hence, germline polymorphisms of detoxification genes and genes belonging to the major DNA repair-apoptosis pathways might have an important role in disease susceptibility. In addition, as some of these genes are regulated by thyroid hormones, they may affect the patients' outcomes. We aimed to assess the influence of the GST, CYP and TP53 gene polymorphisms in the risk of Graves' disease and its outcome. Design Prospective case-control study. Patients A PCR-based strategy was used for GSTT1, GSTM1, GSTP1, CYP1A1 and TP53 codon 72 genotypes in a group of 400 Graves' disease patients, and to compare them to 574 control individuals with similar environmental exposure features. Results GSTM1 and GSTT1 genotypes were equally distributed in cases and controls, repectively. However, GSTP1 (P < 0.0001), CYP1A1 (P < 0.0033) and Pro/ProTP53 (P < 0.0035) variants appeared more frequently in Graves' disease patients than in controls. A multivariate analysis indicated that cigarette smoking and inheritance of GSTP1, CYP1A1 and Pro/ProTP53 variants were important risk factors for Graves' disease, but only smoking appeared as an independent risk factor for Graves' ophthalmopathy. There was no association between clinical features, including ophthalmopathy or treatment outcome, and the studied genotypes. Conclusion We concluded that GSTP1, CYP1A1 and TP53, but not GSTT1 and GSTM1 germline polymorphisms, may be associated with smoking-related Graves' disease susceptibility and configure a risk profile for the disease. However, these polymorphisms do not influence the patients' response to treatment.68698298