Nuclear receptor gene polymorphisms and warfarin dose requirements in the Quebec Warfarin Cohort.

Pharmacogenomics J. 2018 Jan 03;:

Authors: Shahabi P, Lamothe F, Dumas S, Rouleau-Mailloux É, Feroz Zada Y, Provost S, Asselin G, Mongrain I, Valois D, Gaulin Marion MJ, Lemieux Perreault LP, Perreault S, Dubé MP

Abstract
Warfarin is primarily metabolized by cytochrome 2C9, encoded by gene CYP2C9. Here, we investigated whether variants in nuclear receptor genes which regulate the expression of CYP2C9 are associated with warfarin response. We used data from 906 warfarin users from the Quebec Warfarin Cohort (QWC) and tested the association of warfarin dose requirement at 3 months following the initiation of therapy in nine nuclear receptor genes: NR1I3, NR1I2, NR3C1, ESR1, GATA4, RXRA, VDR, CEBPA, and HNF4A. Three correlated SNPs in the VDR gene (rs4760658, rs11168292, and rs11168293) were associated with dose requirements of warfarin (P = 2.68 × 10-5, P = 5.81 × 10-4, and P = 5.94 × 10-4, respectively). Required doses of warfarin were the highest for homozygotes of the minor allele at the VDR variants (P < 0.0026). Variants in the VDR gene were associated with the variability in response to warfarin, emphasizing the possible clinical relevance of nuclear receptor gene variants on the inter-individual variability in drug metabolism.

PMID: 29298995 [PubMed - as supplied by publisher]

Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine.

Pharmacogenomics J. 2018 Jan 03;:

Authors: Girardin FR, Poncet A, Perrier A, Vernaz N, Pletscher M, F Samer C, Lieberman JA, Villard J

Abstract
Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

PMID: 29298994 [PubMed - as supplied by publisher]

[Multiple lncRNAs affect the incidence and 
development of melanoma].

Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2017 Feb 28;42(2):134-138

Authors: Yan H, Tan D, Xie P, Liu Z, Li X

Abstract
OBJECTIVE: To find the relationship between long non-coding RNA (lncRNA) based on data mining methods.
 Methods: We use a whole genome mRNA expression data set (GSE15605) from the gene expression ominibus database to find the lncRNAs which relate to melanoma.
 Results: Four lncRNAs (LINC01213, PGM5-AS1, LINC01133 and LOC284578) were significantly associated with the incidence and development of melanoma. Meanwhile, LINC01213, LINC01133 and LOC284578 were correlated with BRAF mutation, and PGM5-AS1 was related to NRAS mutation. Data mining study found that the model based on the expression values of these 4 lncRNAs can easily preferable classify the study samples.
 Conclusion: LncRNAs may play important roles in the incidence and development of melanoma.

PMID: 28255113 [PubMed - indexed for MEDLINE]

Identification of novel variants associated with warfarin stable dosage by use of a two-stage extreme phenotype strategy.

J Thromb Haemost. 2017 Jan;15(1):28-37

Authors: Luo Z, Li X, Zhu M, Tang J, Li Z, Zhou X, Song G, Liu Z, Zhou H, Zhang W

Abstract
Essentials Required warfarin doses for mechanical heart valves vary greatly. A two-stage extreme phenotype design was used to identify novel warfarin dose associated mutation. We identified a group of variants significantly associated with extreme warfarin dose. Four novel identified mutations account for 2.2% of warfarin dose discrepancies.
SUMMARY: Background The variation among patients in warfarin response complicates the management of warfarin therapy, and an improper therapeutic dose usually results in serious adverse events. Objective To use a two-stage extreme phenotype strategy in order to discover novel warfarin dose-associated mutations in heart valve replacement patients. Patients/method A total of 1617 stable-dose patients were enrolled and divided randomly into two cohorts. Stage I patients were genotyped into three groups on the basis of VKORC1-1639G>A and CYP2C9*3 polymorphisms; only patients with the therapeutic dose at the upper or lower 5% of each genotype group were selected as extreme-dose patients for resequencing of the targeted regions. Evaluation of the accuracy of the sequence data and the potential value of the stage I-identified significant mutations were conducted in a validation cohort of 420 subjects. Results A group of mutations were found to be significantly associated with the extreme warfarin dose. The validation work finally identified four novel mutations, i.e. DNMT3A rs2304429 (24.74%), CYP1A1 rs3826041 (47.35%), STX1B rs72800847 (7.01%), and NQO1 rs10517 (36.11%), which independently and significantly contributed to the overall variability in the warfarin dose. After addition of these four mutations, the estimated regression equation was able to account for 56.2% (R2Adj = 0.562) of the overall variability in the warfarin maintenance dose, with a predictive accuracy of 62.4%. Conclusion Our study provides evidence linking genetic variations in STX1B, DNMT3A and CYP1A1 to warfarin maintenance dose. The newly identified mutations together account for 2.2% of warfarin dose discrepancy.

PMID: 27740732 [PubMed - indexed for MEDLINE]

Epidemiology, pathophysiology and putative genetic basis of carbamazepine- and oxcarbazepine-induced hyponatremia.

Eur J Neurol. 2016 Sep;23(9):1393-9

Authors: Berghuis B, de Haan GJ, van den Broek MP, Sander JW, Lindhout D, Koeleman BP

Abstract
The use of carbamazepine (CBZ) and oxcarbazepine (OXC) as first-line antiepileptic drugs in the treatment of focal epilepsy is limited by hyponatremia, a known adverse effect. Hyponatremia occurs in up to half of people taking CBZ or OXC and, although often assumed to be asymptomatic, it can lead to symptoms ranging from unsteadiness and mild confusion to seizures and coma. Hyponatremia is probably due to the antidiuretic properties of CBZ and OXC that are, at least partly, explained by stimulation of the vasopressin 2 receptor/aquaporin 2 pathway. No known genetic risk variants for CBZ- and OXC-induced hyponatremia exist, but likely candidate genes are part of the vasopressin water reabsorption pathway.

PMID: 27333872 [PubMed - indexed for MEDLINE]

Second-Generation Antipsychotics in Adolescent Psychiatric Patients: Metabolic Effects and Impact of an Early Weight Change to Predict Longer Term Weight Gain.

J Child Adolesc Psychopharmacol. 2018 Jan 03;:

Authors: Vandenberghe F, Najar-Giroud A, Holzer L, Conus P, Eap CB, Ambresin AE

Abstract
OBJECTIVES: To examine the metabolic profile of adolescents at baseline and to determine the potential predictive power of a 1-month weight gain (WG) on weight changes during longer term second-generation antipsychotic (SGA) treatment.
METHODS: A retrospective chart review study, including patients between 13 and 18 years of age and treated with SGA, was conducted. Available data at baseline, 1, 3, and 12 months of treatment were recorded.
RESULTS: Four hundred fifty-six patients were included, with a median age of 15 years. Ten percent of the patients were obese (>95th percentile) and abdominal obesity (>90th percentile) was observed in 12% of patients. In a subgroup of 42 patients with both baseline, 1, and 3-month weight data available, WG >4.5% after 1 month was found to be the best predictor (sensitivity: 100; specificity: 66; area under the curve: 83) for a WG >15% after 3 months. After adjusting for potential confounders, a threshold of WG >4% was found as being the best predictor.
CONCLUSIONS: A worrisome prevalence of metabolic disorders was observed in an adolescent psychiatric cohort. In such patients, a WG >4% during the first month of treatment should raise concerns about weight controlling strategies. Further research is needed to confirm the present results and to determine the impact of a 1-month WG on a 1-year weight change.

PMID: 29297696 [PubMed - as supplied by publisher]

MicroRNAs sequencing unveils distinct molecular subgroups of plasmablastic lymphoma.

Oncotarget. 2017 Dec 08;8(64):107356-107373

Authors: Ambrosio MR, Mundo L, Gazaneo S, Picciolini M, Vara PS, Sayed S, Ginori A, Lo Bello G, Del Porro L, Navari M, Ascani S, Yonis A, Leoncini L, Piccaluga PP, Lazzi S

Abstract
Plasmablastic lymphoma (PBL) is an aggressive lymphoma, often arising in the context of immunodeficiency and associated with Epstein-Barr virus (EBV) infection. The most frequently detected genetic alteration is the deregulation of MYC gene through the translocation - t(8;14)(q24;q32). The diagnosis of PBL is often challenging because it has an overlap in morphology, immunophenotype, cytogenetics and virus association with other lymphomas and plasma cell neoplasms; further, its molecular basis remains elusive. In the present study we aimed to better define the possible contribution of EBV infection as well as miRNA deregulation in PBL pathogenesis. We studied 23 cases of PBL, 19 Burkitt lymphomas (BL), and 17 extra-medullary plasmacytoma (EMPC). We used qPCR and immunohistochemistry to assess EBV latency patterns, while micro-RNA (miRNA) profiling was performed by next generation sequencing (Illumina) and validated by qPCR. Our analysis revealed a non-canonical EBV latency program with the partial expression of some proteins characterizing latency II and the activation of an abortive lytic cycle. Moreover, we identified miRNA signatures discriminating PBL from BL and EMPC. Interestingly, based on the miRNA profile, PBL appeared constituted by two discrete subgroups more similar to either BL or EMPC, respectively. This pattern was confirmed in an independent set of cases studied by qPCR and corresponded to different clinico-pathological features in the two groups, including HIV infection, MYC rearrangement and disease localization. In conclusion, we uncovered for the first time 1) an atypical EBV latency program in PBL; 2) a miRNA signature distinguishing PBL from the closest malignant counterparts; 3) the molecular basis of PBL heterogeneity.

PMID: 29296171 [PubMed]

The endoplasmic reticulum-residing chaperone BiP is short-lived and metabolized through N-terminal arginylation.

Sci Signal. 2018 Jan 02;11(511):

Authors: Shim SM, Choi HR, Sung KW, Lee YJ, Kim ST, Kim D, Mun SR, Hwang J, Cha-Molstad H, Ciechanover A, Kim BY, Kwon YT

Abstract
BiP and other endoplasmic reticulum (ER)-resident proteins are thought to be metabolically stable and to function primarily in the ER lumen. We sought to assess how the abundance of these proteins dynamically fluctuates in response to various stresses and how their subpopulations are relocated to non-ER compartments such as the cytosol. We showed that the molecular chaperone BiP (also known as GRP78) was short-lived under basal conditions and ER stress. The turnover of BiP was in part driven by its amino-terminal arginylation (Nt-arginylation) by the arginyltransferase ATE1, which generated an autophagic N-degron of the N-end rule pathway. ER stress elicited the formation of R-BiP, an effect that was increased when the proteasome was also inhibited. Nt-arginylation correlated with the cytosolic relocalization of BiP under the types of stress tested. The cytosolic relocalization of BiP did not require the functionality of the unfolded protein response or the Sec61- or Derlin1-containing translocon. A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane-integrated protein that is an essential component of ER-associated protein degradation. Pharmacological inhibition of the ER-Golgi secretory pathway also suppressed R-BiP formation. Finally, we showed that cytosolic R-BiP induced by ER stress and proteasomal inhibition was routed to autophagic vacuoles and possibly additional metabolic fates. These results suggest that Nt-arginylation is a posttranslational modification that modulates the function, localization, and metabolic fate of ER-resident proteins.

PMID: 29295953 [PubMed - in process]

Technical Challenges and Opportunities when Implementing Pharmacogenomics Decision Support Integrated in the Electronic Health Record.

Stud Health Technol Inform. 2017;245:1255

Authors: Caraballo PJ, Sutton JA, Moyer AM, Blair D, Hines LC, Rao PS, Adams MF, Murthy S, Garza T, Karow ME, Singh H, Giri J, Gabrielson DB, Sauver JS, Bielinski SJ, Parkulo MA

Abstract
Clinical use of pharmacogenomic (PGx) knowledge at the bedside is new and complex. Our program has implemented multiple PGx-CDS interventions in different clinical settings and in multiple commercial EHRs. Herein, we discuss lessons learned and propose general technical guidelines related to PGx implementation.

PMID: 29295340 [PubMed - in process]

Clinical Decision Support and Primary Care Acceptance of Genomic Medicine.

Stud Health Technol Inform. 2017;245:700-703

Authors: Chase DA, Baron S, Ash JS

Abstract
Clinical decision support systems (CDS) have an important role in the implementation of precision medicine, particularly for pharmacogenomics. This study examines potential factors for their acceptance by primary care clinicians. For this qualitative study we purposively selected five U.S. primary care sites with a variety of sizes, electronic health record vendors, and patients. We interviewed an average of seven clinicians per site. Clinicians placed a low priority on incorporating pharmacogenomics into practice. Other themes included the potential of precision medicine, clinician unfamiliarity with genomics, minimal evidence for primary care uses, additional costs and time burdens, workload, and a need to first successfully complete other electronic health record interventions. This study outlines issues in implementing primary care precision medicine and the role for genomic CDS. Currently there are signficiant barriers. With more evidence and the development of effective CDS, however, there is potential for turning each of the barriers into facilitators.

PMID: 29295188 [PubMed - in process]

Personalized Medicine in Psychiatry: Concepts for Bringing Associated Testing Into Clinical Practice.

Mayo Clin Proc. 2016 07;91(7):827-9

Authors: Preskorn SH

PMID: 27289412 [PubMed - indexed for MEDLINE]

Sestd1 Encodes a Developmentally Dynamic Synapse Protein That Complexes With BCR Rac1-GAP to Regulate Forebrain Dendrite, Spine and Synapse Formation.

Cereb Cortex. 2017 Dec 26;:

Authors: Yang XY, Stanley RE, Ross AP, Robitaille AM, Gray JA, Cheyette BNR

Abstract
SEC14 and Spectrin domain-1 (Sestd1) is a synapse protein that exhibits a striking shift from the presynaptic to postsynaptic space as neurons mature postnatally in the mouse hippocampus. Hippocampal pyramidal neurons from mice with global genetic deletion of Sestd1 have reduced dendrite arbors, spines, and excitatory synapses. Electrophysiologically this correlates with cell-autonomous reductions in both AMPA- and NMDA-excitatory postsynaptic currents in individual hippocampal neurons from which Sestd1 has been deleted in vivo. These neurodevelopmental and functional deficits are associated with increased activation of the Rho family GTPases Rac1 and RhoA. Co-immunoprecipitation and mass spectrometry reveal that the Breakpoint Cluster Region protein, a Rho GTPase activating protein (GAP), forms complexes with Sestd1 in brain tissue. This complements earlier findings that Sestd1 can also partner with other Rho family GAPs and guanine nucleotide exchange factors. Our findings demonstrate that Sestd1 is a developmentally dynamic synaptic regulator of Rho GTPases that contributes to dendrite and excitatory synapse formation within differentiating pyramidal neurons of the forebrain.

PMID: 29293918 [PubMed - as supplied by publisher]

The future of telomere length in personalized medicine.

Front Biosci (Landmark Ed). 2018 Mar 01;23:1628-1654

Authors: Gorenjak V, Akbar S, Stathopoulou MG, Visvikis-Siest S

Abstract
Telomere length has been subject of studies for many decades, aiming to elucidate its role in physiological processes, in process of aging and in diverse pathologies. Yet today, there is still no "big title" discovery that would lead to a practical use of telomeres as a reliable biomarker or target for a new drug. However, therapies for chronic disease patients are being tested and companies are already offering commercial tests for telomere length measurement. The strong genetic heritability of telomeres is opening the place for pharmacogenomics researches that could promote the personalized treatment of diverse diseases. In this article, we present the recent knowledge of telomeres genetic determination obtained by genome-wide association studies (GWAS), important biomarkers related to telomere length and review the possibilities of telomere's practical implementation in the medical treatment of diverse diseases and as a potential biomarker in personalized medicine. Furthermore, we summarise commercial offers of telomere length measurements available and we discuss the actions that should be taken to make steps forward into final application of the accumulated knowledge into practical use.

PMID: 29293454 [PubMed - in process]

Towards precision medicine in ischemic stroke and transient ischemic attack.

Front Biosci (Landmark Ed). 2018 Mar 01;23:1338-1359

Authors: Lin Y, Li Z, Liu C, Wang Y

Abstract
Although there is no consensus on the exact definition of precision medicine, it is generally agreed upon that the term entails diagnosis and therapy tailored to the individual patient. Precision medicine has seen major advances in the past two decades, many of which are relevant to ischemic stroke or transient ischemic attack (TIA). Advances include substantial improvements in high-throughput technologies, collaborations between the fields of biology and medicine, increasingly advanced biomedical informatics, the development of multimodal brain imaging techniques, as well as the widespread usage of electronic medical records and big data. Precision medicine in ischemic stroke or TIA is still in its infancy, but there have already been changes in clinical care from a one-size-fits-all model to a more precise, individualized approach. However, further studies are urgently needed to bridge the gaps between clinical studies and precision clinical practice. We discuss here the advances and challenges for precision medicine in ischemic stroke or TIA at its current stage, focusing on genetic predispositions, pharmacogenetics, omics, brain imaging and big data.

PMID: 29293437 [PubMed - in process]

DNA polymorphisms predict time to progression from uncomplicated to complicated Crohn's disease.

Eur J Gastroenterol Hepatol. 2017 Dec 29;:

Authors: Pernat Drobež C, Repnik K, Gorenjak M, Ferkolj I, Weersma RK, Potočnik U

Abstract
OBJECTIVE: Most patients with Crohn's disease (CD) are diagnosed with the uncomplicated inflammatory form of the disease (Montreal stage B1). However, the majority of them will progress to complicated stricturing (B2) and penetrating (B3) CD during their lifetimes. The aim of our study was to identify the genetic factors associated with time to progression from uncomplicated to complicated CD.
PATIENTS AND METHODS: Patients with an inflammatory phenotype at diagnosis were followed up for 10 years. Genotyping was carried out using Illumina ImmunoChip. After quality control, association analyses, Bonferroni's adjustments, linear and Cox's regression, and Kaplan-Meier analysis were carried out for 111 patients and Manhattan plots were constructed.
RESULTS: Ten years after diagnosis, 39.1% of the patients still had the inflammatory form and 60.9% progressed to complicated disease, with an average time to progression of 5.91 years. Ileal and ileocolonic locations were associated with the complicated CD (P=1.08E-03). We found that patients with the AA genotype at single-nucleotide polymorphism rs16857259 near the gene CACNA1E progressed to the complicated form later (8.80 years) compared with patients with the AC (5.11 years) or CC (2.00 years) genotypes (P=3.82E-07). In addition, nine single-nucleotide polymorphisms (near the genes RASGRP1, SULF2, XPO1, ZBTB44, HLA DOA/BRD2, HLA DRB1/HLA DQA1, PPARA, PUDP, and KIAA1614) showed a suggestive association with disease progression (P<10). Multivariate Cox's regression analysis on the basis of clinical and genetic data confirmed the association of the selected model with disease progression (P=5.73E-16).
CONCLUSION: Our study confirmed the association between the locus on chromosome 1 near the gene CACNA1E with time to progression from inflammatory to stricturing or penetrating CD. Predicting the time to progression is useful to the clinician in terms of individualizing patients' management.

PMID: 29293112 [PubMed - as supplied by publisher]

Considerations About the Use of Biomarkers in Cancer Clinical Trials.

Clin Pharmacol Ther. 2018 Jan;103(1):25-27

Authors: Chabner BA

Abstract
The rapid evolution of our understanding of cancer biology has affected every phase of patient management, from early detection to drug development and clinical management. Central to this issue is the challenge of using biomarkers to identify the driving mutations present and identifiable by current assays in many tumors. These biomarkers are integral to the process of selecting patients for the testing of new drugs, many of which are specifically designed to inhibit oncogenic pathways.

PMID: 29134628 [PubMed - indexed for MEDLINE]

Volitional regulation of brain responses to food stimuli in overweight and obese subjects: A real-time fMRI feedback study.

Appetite. 2017 May 01;112:188-195

Authors: Spetter MS, Malekshahi R, Birbaumer N, Lührs M, van der Veer AH, Scheffler K, Spuckti S, Preissl H, Veit R, Hallschmid M

Abstract
Obese subjects who achieve weight loss show increased functional connectivity between dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC), key areas of executive control and reward processing. We investigated the potential of real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback training to achieve healthier food choices by enhancing self-control of the interplay between these brain areas. We trained eight male individuals with overweight or obesity (age: 31.8 ± 4.4 years, BMI: 29.4 ± 1.4 kg/m2) to up-regulate functional connectivity between the dlPFC and the vmPFC by means of a four-day rt-fMRI neurofeedback protocol including, on each day, three training runs comprised of six up-regulation and six passive viewing trials. During the up-regulation runs of the four training days, participants successfully learned to increase functional connectivity between dlPFC and vmPFC. In addition, a trend towards less high-calorie food choices emerged from before to after training, which however was associated with a trend towards increased covertly assessed snack intake. Findings of this proof-of-concept study indicate that overweight and obese participants can increase functional connectivity between brain areas that orchestrate the top-down control of appetite for high-calorie foods. Neurofeedback training might therefore be a useful tool in achieving and maintaining weight loss.

PMID: 28131758 [PubMed - indexed for MEDLINE]

Silencing RIF1 decreases cell growth, migration and increases cisplatin sensitivity of human cervical cancer cells.

Oncotarget. 2017 Dec 05;8(63):107044-107051

Authors: Mei Y, Peng C, Liu YB, Wang J, Zhou HH

Abstract
Replication timing regulatory factor 1 (RIF1) plays an important role in DNA replication regulation, stem cell pluripotency and DNA repair pathway. However, little is known about the molecular mechanisms and physiological significance of RIF1 in cancer and chemotherapy efficacy. In this study, we found that RIF1 is upregulated in cervical cancer tissues compared with normal tissues both at mRNA and protein levels through online databases. RIF1 knockdown reduced cervical cancer cell growth, colony formation, migration and epithelial-mesenchymal transition (EMT) markers. Flow cytometry analysis indicated that RIF1 knockdown induced apoptosis and G2 cell cycle arrest. Furthermore, RIF1 knockdown increased cisplatin sensitivity, cisplatin-induced G2/M phase arrest, apoptosis and led to defects in DNA repair in a concentration-dependent manner. In terms of mechanism research, increased CDKN1A expression and Bax/Bcl-2/caspase-3 signaling pathway might be involved in the G2/M phase arrest and increased apoptosis in RIF1-silenced cervical cancer cells. Thus, these findings indicate that RIF1 knockdown prior to chemotherapy may be a potential effective therapeutic strategy for cervical cancer.

PMID: 29291010 [PubMed]

Pseudogenes of annexin A2, novel prognosis biomarkers for diffuse gliomas.

Oncotarget. 2017 Dec 05;8(63):106962-106975

Authors: Li S, Zou H, Shao YY, Mei Y, Cheng Y, Hu DL, Tan ZR, Zhou HH

Abstract
Diffuse gliomas is a kind of common malignant primary brain tumor. Pseudogenes have multilayered biological function in the progression of human cancers. In this study, Differentially Expressed Pseudogenes (DEPs) between glioblastomas and non-tumor controls were found by bioinformatics analysis, of which the annexin A2 pseudogenes (ANXA2P1, ANXA2P2 and ANXA2P3) were significantly up-regulated, along with the parent gene annexin A2 (ANXA2). Among four glioblastoma subtypes, ANXA2P1 and ANXA2P2 were preferentially expressed in mesenchymal subtype and less expressed in proneural subtype. Meanwhile, Pearson's correlation analysis revealed that the expression level of ANXA2 was positively correlated with ANXA2 pseudogenes expression. Then, the expression patterns of ANXA2 and its pseudogenes were validated in diffuse glioma specimens (n=99) and non-tumor tissues (n=12) by quantitative real-time PCR (qRT-PCR). Additionally, Kaplan-Meier analysis revealed that highly expressed ANXA2 and annexin A2 pseudogenes were associated with the poor survival outcome of glioma patients. Cox regression analyses suggested that ANXA2, ANXA2P1 and ANXA2P2 were the independent prognosis factors for gliomas. Furthermore, down-regulation of ANXA2 and ANXA2 pseudogenes might contribute to the improvement of patients' survival who received chemotherapy and radiotherapy. These results demonstrated that ANXA2 pseudogenes and ANXA2 could be used as the novel biomarkers for diagnosis, prognosis and target therapy of gliomas.

PMID: 29291003 [PubMed]

Pharmacogenetics of response to neoadjuvant paclitaxel treatment for locally advanced breast cancer.

Oncotarget. 2017 Dec 05;8(63):106454-106467

Authors: Perez-Ortiz AC, Ramírez I, Cruz-López JC, Villarreal-Garza C, Luna-Angulo A, Lira-Romero E, Jiménez-Chaidez S, Díaz-Chávez J, Matus-Santos JA, Sánchez-Chapul L, Mendoza-Lorenzo P, Estrada-Mena FJ

Abstract
Locally advanced breast cancer (LABC) cases have a varying five-year survival rate, mainly influenced by the tumor response to chemotherapy. Paclitaxel activity (response rate) varies across populations from 21.5% to 84%. There are some reports on genetic traits and paclitaxel; however, there is still considerable residual unexplained variability. In this study, we aimed to test the association between eleven novel markers and tumor response to paclitaxel and to explore if any of them influenced tumor protein expression. We studied a cohort of 140 women with LABC. At baseline, we collected a blood sample (for genotyping), fine needle aspirates (for Western blot), and tumor measurements by imaging. After follow-up, we ascertained the response to paclitaxel monotherapy by comparing the percent change in the pre-, post- tumor measurements after treatment. To allocate exposure, we genotyped eleven SNPs with TaqMan probes on RT-PCR and regressed them to tumor response using linear modeling. In addition, we compared protein expression, between breast tumors and healthy controls, of those genes whose genetic markers were significantly associated with tumor response. After adjusting for multiple clinical covariates, SNPs on the LPHN2, ROBO1, SNTG1, and GRIK1 genes were significant independent predictors of poor tumor response (tumor growth) despite paclitaxel treatment. Moreover, proteins encoded by those genes are significantly downregulated in breast tumor samples.

PMID: 29290962 [PubMed]