Pharmacogenetics findings in Brazilian cancer patients.

e13607 Background: Pharmacogenetic is the study of genetic modifications influence on drugs action. Recent studies have suggested that some genetic polymorphisms may have an influence on patient outcomes. Thus, the objective of this thesis is to evaluate the frequency of genetic polymorphisms in cancer patients. Methods: Cross-sectional study at the Oncology Center of São Paulo. The reports presented a SNP evaluation (saliva - PCR-Multiplex, PCR-RFLP or capillary sequencing - Genotypic variants: 1 allele, 2 alleles and no allelic alteration). Polymorphs were validated according to the localized gene and its relationship to drugs using PharmGKB, NCBI SNP Database, NCBI Gene Database and DrugBank Database. Results: Sample mean aging was 49.92 years (SD = 22.73), with breast cancer (n = 26 /% = 26.3) and stage IV (n = 51 /% = 51.6). Among the evaluated platinum components, it is possible to verify that the presence of polymorphisms was more frequent. Of these, all had the highest frequency of polymorphisms in only 1 allele (xpc__rs2228001 = 25.4%; ercc1_rs11615 = 21.2%; xrcc3_rs861539 = 22.2%; mthfr_rs1801133 = 44.4%). This was repeated when evaluating the Cyclophosphamide, Fluoropyrimidines, Taxanes, Anastrozole and Epirubicin-related polymorphisms. When we evaluated the Tamoxifen-related genes, the polymorphisms absence was more frequent (cyp2d6_rs3892097 = 26.3%; cyp3a4_rs2740574 = 61.6%). Evaluating all medications the highest frequency was polymorphism in only 1 allele. Consequently, for the irinotecan drug evaluation, two polymorphisms were evaluated and presence of polymorphism (xrcc3_rs861539 = 58%), mostly in only 1 allele (44%). Conclusions: Therefore we can evaluate that the allelic frequency variability of the polymorphs observed, despite the great variability, shows most evaluated individuals present some type of genotypic modification, being the majority in only 1 allele.

Complement-mediated Opsonization of Invasive Group A Streptococcus pyogenes Strain AP53 Is Regulated by the Bacterial Two-component Cluster of Virulence Responder/Sensor (CovRS) System

Group A Streptococcus pyogenes (GAS) strain AP53 is a primary isolate from a patient with necrotizing fasciitis. These AP53 cells contain an inactivating mutation in the sensor component of the cluster of virulence (cov) responder (R)/sensor (S) two-component gene regulatory system (covRS), which enhances the virulence of the primary strain, AP53/covR+S−. However, specific mechanisms by which the covRS system regulates the survival of GAS in humans are incomplete. Here, we show a key role for covRS in the regulation of opsonophagocytosis of AP53 by human neutrophils. AP53/covR+S− cells displayed potent binding of host complement inhibitors of C3 convertase, viz. Factor H (FH) and C4-binding protein (C4BP), which concomitantly led to minimal C3b deposition on AP53 cells, further showing that these plasma protein inhibitors are active on GAS cells. This resulted in weak killing of the bacteria by human neutrophils and a corresponding high death rate of mice after injection of these cells. After targeted allelic alteration of covS− to wild-type covS (covS+), a dramatic loss of FH and C4BP binding to the AP53/covR+S+ cells was observed. This resulted in elevated C3b deposition on AP53/covR+S+ cells, a high level of opsonophagocytosis by human neutrophils, and a very low death rate of mice infected with AP53/covR+S+. We show that covRS is a critical transcriptional regulator of genes directing AP53 killing by neutrophils and regulates the levels of the receptors for FH and C4BP, which we identify as the products of the fba and enn genes, respectively.

Polymerase Chain Reaction-Based Microsatellite Polymorphism Analysis of Follicular and Hürthle Cell Neoplasms of the Thyroid1

Follicular and Hürthle cell carcinomas of the thyroid cannot be differentiated from adenomas by either preoperative fine needle aspiration or intraoperative frozen section examination, and yet there exist potentially significant differences in the recommended surgical management. We examined, by PCR-based microsatellite polymorphism analysis, DNA obtained from 83 thyroid neoplasms [22 follicular adenomas, 29 follicular carcinomas, 20 Hürthle cell adenomas (HA), and 12 Hürthle cell carcinomas (HC)] to determine whether a pattern of allelic alteration exists that could help distinguish benign from malignant lesions. Alterations were found in only 7.5% of informative PCR reactions from follicular neoplasms, whereas they were found in 23.3% of reactions from Hürthle cell neoplasms. Although there were no significant differences between follicular adenoma and follicular carcinoma, HC demonstrated a significantly greater percentage of allelic alteration than HA on chromosomal arms 1q (P < 0.001) and 2p (P < 0.05) by Fisher’s exact test. The documentation of an alteration on either 1q or 2p was 100% sensitive and 65% specific in the detection of HC (P < 0.0005, by McNemar’s test). In conclusion, PCR-based microsatellite polymorphism analysis may be a useful technique in distinguishing HC from HA. Potentially, the application of this technique to aspirated material may allow this distinction preoperatively and thus facilitate more optimal surgical management. Consistent regions of allelic alteration may also indicate the locations of critical genes, such as tumor suppressor genes or oncogenes, that are important in the progression from adenoma to carcinoma. Finally, this study demonstrates that Hürthle cell neoplasms, now considered variants of follicular neoplasms, differ significantly from follicular neoplasms on a molecular level.