ACPP

Gene Summary

Gene:ACPP; acid phosphatase, prostate
Aliases: ACP3, 5'-NT, ACP-3
Location:3q22.1
Summary:This gene encodes an enzyme that catalyzes the conversion of orthophosphoric monoester to alcohol and orthophosphate. It is synthesized under androgen regulation and is secreted by the epithelial cells of the prostate gland. An alternatively spliced transcript variant encoding a longer isoform has been found for this gene. This isoform contains a transmembrane domain and is localized in the plasma membrane-endosomal-lysosomal pathway. [provided by RefSeq, Sep 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:prostatic acid phosphatase
HPRD
Source:NCBIAccessed: 28 February, 2015

Ontology:

What does this gene/protein do?
Show (16)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 28 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Prostatic Hyperplasia
  • Signal Transduction
  • Chromosome Mapping
  • Northern Blotting
  • Homeodomain Proteins
  • Gene Expression
  • Adenocarcinoma
  • Paired Box Transcription Factors
  • Cancer DNA
  • Chromosome 3
  • DNA-Binding Proteins
  • Endometrial Cancer
  • Isoenzymes
  • Prostate Cancer
  • Prostate-Specific Antigen
  • Cervical Cancer
  • Staging
  • Polymerase Chain Reaction
  • PAX4
  • DNA
  • TCGA-specific type II deoxyribonucleases
  • Acid Phosphatase
  • Bayes Theorem
  • Biopsy
  • Transcription Factors
  • DNA Primers
  • Prostate
  • Tumor Markers
  • Cancer Gene Expression Regulation
  • Genotype
  • Restriction Fragment Length Polymorphism
  • Base Sequence
  • Tumor Antigens
  • Bladder Cancer
  • ACPP
  • Immunohistochemistry
  • Chromosome Banding
  • Lymphatic Metastasis
  • Genes, Neoplasm
  • DNA Probes
Tag cloud generated 28 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ACPP (cancer-related)

Spence JM, Abumoussa A, Spence JP, Burack WR
Intraclonal diversity in follicular lymphoma analyzed by quantitative ultradeep sequencing of noncoding regions.
J Immunol. 2014; 193(10):4888-94 [PubMed] Article available free on PMC after 15/11/2015 Related Publications
Cancers are characterized by genomic instability, and the resulting intraclonal diversity is a prerequisite for tumor evolution. Therefore, metrics of tumor heterogeneity may prove to be clinically meaningful. Intraclonal heterogeneity in follicular lymphoma (FL) is apparent from studies of somatic hypermutation (SHM) caused by activation-induced deaminase (AID) in IGH. Aberrant SHM (aSHM), defined as AID activity outside of the IG loci, predominantly targets noncoding regions causing numerous "passenger" mutations, but it has the potential to generate rare significant "driver" mutations. The quantitative relationship between SHM and aSHM has not been defined. To measure SHM and aSHM, ultradeep sequencing (>20,000-fold coverage) was performed on IGH (~1650 nt) and nine other noncoding regions potentially targeted by AID (combined 9411 nt), including the 5' untranslated region of BCL2. Single-nucleotide variants (SNVs) were found in 12/12 FL specimens (median 136 SHMs and 53 aSHMs). The aSHM SNVs were associated with AID motifs (p < 0.0001). The number of SNVs at BCL2 varied widely among specimens and correlated with the number of SNVs at eight other potential aSHM sites. In contrast, SHM at IGH was not predictive of aSHM. Tumor heterogeneity is apparent from SNVs at low variant allele frequencies; the relative number of SNVs with variable allele frequency < 5% varied with clinical grade, indicating that tumor heterogeneity based on aSHM reflects a clinically meaningful parameter. These data suggest that genome-wide aSHM may be estimated from aSHM of BCL2 but not SHM of IGH. The results demonstrate a practical approach to the quantification of intratumoral genetic heterogeneity for clinical specimens.

Chatterjee S, Thyagarajan K, Kesarwani P, et al.
Reducing CD73 expression by IL1β-Programmed Th17 cells improves immunotherapeutic control of tumors.
Cancer Res. 2014; 74(21):6048-59 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
T cells of the T helper (Th)17 subset offer promise in adoptive T-cell therapy for cancer. However, current protocols for ex vivo programming of Th17 cells, which include TGFβ exposure, increase the expression of CD39 and CD73, two cell surface ATP ectonucleotidases that reduce T-cell effector functions and promote immunosuppression. Here, we report that ATP-mediated suppression of IFNγ production by Th17 cells can be overcome by genetic ablation of CD73 or by using IL1β instead of TGFβ to program Th17 cells ex vivo. Th17 cells cultured in IL1β were also highly polyfunctional, expressing high levels of effector molecules and exhibiting superior short-term control of melanoma in mice, despite reduced stem cell-like properties. TGFβ addition at low doses that did not upregulate CD73 expression but induced stemness properties drastically improved the antitumor effects of IL1β-cultured Th17 cells. Effector properties of IL1β-dependent Th17 cells were likely related to their high glycolytic capacity, since ex vivo programming in pyruvate impaired glycolysis and antitumor effects. Overall, we show that including TGFβ in ex vivo cultures used to program Th17 cells blunts their immunotherapeutic potential and demonstrate how this potential can be more fully realized for adoptive T-cell therapy.

Boele J, Persson H, Shin JW, et al.
PAPD5-mediated 3' adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease.
Proc Natl Acad Sci U S A. 2014; 111(31):11467-72 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Next-generation sequencing experiments have shown that microRNAs (miRNAs) are expressed in many different isoforms (isomiRs), whose biological relevance is often unclear. We found that mature miR-21, the most widely researched miRNA because of its importance in human disease, is produced in two prevalent isomiR forms that differ by 1 nt at their 3' end, and moreover that the 3' end of miR-21 is posttranscriptionally adenylated by the noncanonical poly(A) polymerase PAPD5. PAPD5 knockdown caused an increase in the miR-21 expression level, suggesting that PAPD5-mediated adenylation of miR-21 leads to its degradation. Exoribonuclease knockdown experiments followed by small-RNA sequencing suggested that PARN degrades miR-21 in the 3'-to-5' direction. In accordance with this model, microarray expression profiling demonstrated that PAPD5 knockdown results in a down-regulation of miR-21 target mRNAs. We found that disruption of the miR-21 adenylation and degradation pathway is a general feature in tumors across a wide range of tissues, as evidenced by data from The Cancer Genome Atlas, as well as in the noncancerous proliferative disease psoriasis. We conclude that PAPD5 and PARN mediate degradation of oncogenic miRNA miR-21 through a tailing and trimming process, and that this pathway is disrupted in cancer and other proliferative diseases.

DeOcesano-Pereira C, Amaral MS, Parreira KS, et al.
Long non-coding RNA INXS is a critical mediator of BCL-XS induced apoptosis.
Nucleic Acids Res. 2014; 42(13):8343-55 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
BCL-X mRNA alternative splicing generates pro-apoptotic BCL-XS or anti-apoptotic BCL-XL gene products and the mechanism that regulates splice shifting is incompletely understood. We identified and characterized a long non-coding RNA (lncRNA) named INXS, transcribed from the opposite genomic strand of BCL-X, that was 5- to 9-fold less abundant in tumor cell lines from kidney, liver, breast and prostate and in kidney tumor tissues compared with non-tumors. INXS is an unspliced 1903 nt-long RNA, is transcribed by RNA polymerase II, 5'-capped, nuclear enriched and binds Sam68 splicing-modulator. Three apoptosis-inducing agents increased INXS lncRNA endogenous expression in the 786-O kidney tumor cell line, increased BCL-XS/BCL-XL mRNA ratio and activated caspases 3, 7 and 9. These effects were abrogated in the presence of INXS knockdown. Similarly, ectopic INXS overexpression caused a shift in splicing toward BCL-XS and activation of caspases, thus leading to apoptosis. BCL-XS protein accumulation was detected upon INXS overexpression. In a mouse xenograft model, intra-tumor injections of an INXS-expressing plasmid caused a marked reduction in tumor weight, and an increase in BCL-XS isoform, as determined in the excised tumors. We revealed an endogenous lncRNA that induces apoptosis, suggesting that INXS is a possible target to be explored in cancer therapies.

Bae H, Lim W, Bae SM, et al.
Avian prostatic acid phosphatase: estrogen regulation in the oviduct and epithelial cell-derived ovarian carcinomas.
Biol Reprod. 2014; 91(1):3 [PubMed] Related Publications
Prostatic acid phosphatase (ACPP) is a glycoprotein that is mainly synthesized and secreted by glandular epithelial cells (GE) of the prostate, and it is well known as a biomarker for prostate cancer. Although ACPP was used as prognostic/diagnostic indicator and studied to elucidate regulatory mechanism(s) during several decades in humans, its role is not clearly understood. Gene profiling data using a chicken DNA microarray revealed that ACPP increased significantly during remodeling and recrudescence of the oviduct in response to estrogen. Thus, in this study, we investigated the expression and hormonal regulation of ACPP gene in the reproductive tracts of chickens. ACPP was specifically detected in the luminal cells (LE) and GE of chicken oviduct, and diethylstilbestrol (a synthetic nonsteroidal estrogen) stimulated its expression during development of the oviduct. In addition, ACPP mRNA and protein were localized to LE and GE during the regeneration phase of the oviduct of laying hens during induced molting. Furthermore, ACPP mRNA and protein were abundant in GE of ovarian carcinoma, but not in normal ovaries. Moreover, strong expression of ACPP protein was detected in epithelial cells of cancerous ovaries from women. Collectively, results of the present study are the first to show that ACPP is a novel estrogen-stimulated gene in the oviductal epithelial cells of the chicken and that its expression increases significantly in epithelial cells of ovarian carcinoma, which indicates that it may be a candidate biomarker for diagnosis of epithelia-derived ovarian cancer in women.

Schuler PJ, Saze Z, Hong CS, et al.
Human CD4+ CD39+ regulatory T cells produce adenosine upon co-expression of surface CD73 or contact with CD73+ exosomes or CD73+ cells.
Clin Exp Immunol. 2014; 177(2):531-43 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
While murine CD4(+) CD39(+) regulatory T cells (T(reg)) co-express CD73 and hydrolyze exogenous (e) adenosine triphosphate (ATP) to immunosuppressive adenosine (ADO), surface co-expression of CD73 on human circulating CD4(+) CD39(+) T(reg) is rare. Therefore, the ability of human T(reg) to produce and utilize ADO for suppression remains unclear. Using mass spectrometry, we measured nucleoside production by subsets of human CD4(+) CD39(+) and CD4(+) CD39(-)CD73(+) T cells or CD19(+) B cells isolated from blood of 30 volunteers and 14 cancer patients. CD39 and CD73 expression was evaluated by flow cytometry, Western blots, confocal microscopy or reverse transcription-polymerase chain reaction (RT-PCR). Circulating CD4(+) CD39(+) T(reg) which hydrolyzed eATP to 5'-AMP contained few intracytoplasmic granules and had low CD73 mRNA levels. Only ∼1% of these T(reg) were CD39(+) CD73(+) . In contrast, CD4(+) CD39(neg) CD73(+) T cells contained numerous CD73(+) granules in the cytoplasm and strongly expressed surface CD73. In vitro-generated T(reg) (Tr1) and most B cells were CD39(+) CD73(+) . All these CD73(+) T cell subsets and B cells hydrolyzed 5'-AMP to ADO. Exosomes isolated from plasma of normal control (NC) or cancer patients carried enzymatically active CD39 and CD73(+) and, when supplied with eATP, hydrolyzed it to ADO. Only CD4(+) CD39(+) T(reg) co-incubated with CD4(+) CD73(+) T cells, B cells or CD39(+) CD73(+) exosomes produced ADO. Thus, contact with membrane-tethered CD73 was sufficient for ADO production by CD4(+) CD39(+) T(reg). In microenvironments containing CD4(+) CD73(+) T cells, B cells or CD39(+) CD73(+) exosomes, CD73 is readily available to CD4(+) CD39(+) CD73(neg) T(reg) for the production of immunosuppressive ADO.

Aliagas E, Vidal A, Texidó L, et al.
High expression of ecto-nucleotidases CD39 and CD73 in human endometrial tumors.
Mediators Inflamm. 2014; 2014:509027 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
One of the strategies used by tumors to evade immunosurveillance is the accumulation of extracellular adenosine, which has immunosupressive and tumor promoting effects. The study of the mechanisms leading to adenosine formation at the tumor interstitium are therefore of great interest in oncology. The dominant pathway generating extracellular adenosine in tumors is the dephosphorylation of ATP by ecto-nucleotidases. Two of these enzymes acting sequentially, CD39 and CD73, efficiently hydrolyze extracellular ATP to adenosine. They have been found to play a crucial role in a variety of tumors, but there were no data concerning endometrial cancer, the most frequent of the invasive tumors of the female genital tract. The aim of the present work is to study the expression of CD39 and CD73 in human endometrial cancer. We have analyzed protein and gene expression, as well as enzyme activity, in type I endometrioid adenocarcinomas and type II serous adenocarcinomas and their nonpathological endometrial counterparts. High levels of both enzymes were found in tumor samples, with significantly increased expression of CD39 in type II serous tumors, which also coincided with the higher tumor grade. Our results reinforce the involvement of the adenosinergic system in cancer, emphasizing the relevance of ecto-nucleotidases as emerging therapeutic targets in oncology.

Beckenkamp A, Santana DB, Bruno AN, et al.
Ectonucleotidase expression profile and activity in human cervical cancer cell lines.
Biochem Cell Biol. 2014; 92(2):95-104 [PubMed] Related Publications
Cervical cancer is the third most frequent cancer in women worldwide. Adenine nucleotide signaling is modulated by the ectonucleotidases that act in sequence, forming an enzymatic cascade. Considering the relationship between the purinergic signaling and cancer, we studied the E-NTPDases, ecto-5'-nucleotidase, and E-NPPs in human cervical cancer cell lines and keratinocytes. We evaluated the expression profiles of these enzymes using RT-PCR and quantitative real-time PCR analysis. The activities of these enzymes were examined using ATP, ADP, AMP, and p-nitrophenyl-5'-thymidine monophosphate (p-Nph-5'-TMP) as substrate, in a colorimetric assay. The extracellular adenine nucleotide hydrolysis was estimated by HPLC analysis. The hydrolysis of all substrates exhibited a linear pattern and these activities were cation-dependent. An interesting difference in the degradation rate was observed between cervical cancer cell lines SiHa, HeLa, and C33A and normal imortalized keratinocytes, HaCaT cells. The mRNA of ecto-5'-nucleotidase, E-NTPDases 5 and 6 were detectable in all cell lines, and the dominant gene expressed was the Entpd 5 enzyme, in SiHa cell line (HPV16 positive). In accordance with this result, a higher hydrolysis activity for UDP and GDP nucleotides was observed in the supernatant of the SiHa cells. Both normal and cancer cells presented activity and mRNAs of members of the NPP family. Considering that these enzymes exert an important catalytic activity, controlling purinergic nucleotide concentrations in tumors, the presence of ectonucleotidases in cervical cancer cells can be important to regulate the levels of extracellular adenine nucleotides, limiting their effects.

Rouhigharabaei L, Finalet Ferreiro J, Tousseyn T, et al.
Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.
PLoS One. 2014; 9(1):e85851 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
The transcription factor FOXP1 is implicated in the pathogenesis of B-cell lymphomas through chromosomal translocations involving either immunoglobulin heavy chain (IGH) locus or non-IG sequences. The former translocation, t(3;14)(p13;q32), results in dysregulated expression of FOXP1 juxtaposed with strong regulatory elements of IGH. Thus far, molecular consequences of rare non-IG aberrations of FOXP1 remain undetermined. Here, using molecular cytogenetics and molecular biology studies, we comprehensively analyzed four lymphoma cases with non-IG rearrangements of FOXP1 and compared these with cases harboring t(3;14)(p13;q32)/IGH-FOXP1 and FOXP1-expressing lymphomas with no apparent structural aberrations of the gene. Our study revealed that non-IG rearrangements of FOXP1 are usually acquired during clinical course of various lymphoma subtypes, including diffuse large B cell lymphoma, marginal zone lymphoma and chronic lymphocytic leukemia, and correlate with a poor prognosis. Importantly, these aberrations constantly target the coding region of FOXP1, promiscuously fusing with coding and non-coding gene sequences at various reciprocal breakpoints (2q36, 10q24 and 3q11). The non-IG rearrangements of FOXP1, however, do not generate functional chimeric genes but commonly disrupt the full-length FOXP1 transcript leading to an aberrant expression of N-truncated FOXP1 isoforms (FOXP1(NT)), as shown by QRT-PCR and Western blot analysis. In contrast, t(3;14)(p13;q32)/IGH-FOXP1 affects the 5' untranslated region of FOXP1 and results in overexpress the full-length FOXP1 protein (FOXP1(FL)). RNA-sequencing of a few lymphoma cases expressing FOXP1(NT) and FOXP1(FL) detected neither FOXP1-related fusions nor FOXP1 mutations. Further bioinformatic analysis of RNA-sequencing data retrieved a set of genes, which may comprise direct or non-direct targets of FOXP1(NT), potentially implicated in disease progression. In summary, our findings point to a dual mechanism through which FOXP1 is implicated in B-cell lymphomagenesis. We hypothesize that the primary t(3;14)(p13;q32)/IGH-FOXP1 activates expression of the FOXP1(FL) protein with potent oncogenic activity, whereas the secondary non-IG rearrangements of FOXP1 promote expression of the FOXP1(NT) proteins, likely driving progression of disease.

Xiong L, Wen Y, Miao X, Yang Z
NT5E and FcGBP as key regulators of TGF-1-induced epithelial-mesenchymal transition (EMT) are associated with tumor progression and survival of patients with gallbladder cancer.
Cell Tissue Res. 2014; 355(2):365-74 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Epithelial-mesenchymal transitions (EMTs) are essential manifestations of epithelial cell plasticity during tumor progression. Transforming growth factor-β(TGF-β) modulates epithelial plasticity in tumor physiological contexts by inducing EMT, which is associated with the altered expression of genes. In the present study, we used DNA micro-array analysis to search for differentially expressed genes in the TGF-β1 induced gallbladder carcinoma cell line (GBC-SD cells), as compared with normal GBC-SD cells. We identified 225 differentially expressed genes, including 144 that were over-expressed and 81 that were under-expressed in the TGF-β1 induced GBC-SD cells. NT5E (CD73) is the most increased gene, while the Fc fragment of the IgG binding protein (FcGBP) is the most decreased gene. The expression patterns of these two genes in gallbladder adenocarcinoma and chronic cholecystitis tissue were consistent with the micro-array data. Immunochemistry and clinicopathological results showed that the expression of NT5E and FcGBP in gallbladder adenocarcinoma is an independent marker for evaluation of the disease progression, clinical biological behaviors and prognosis. The data from the current study indicate that differential NT5E and FcGBP expressions could be further evaluated as biomarkers for predicting survival of patients with gallbladder cancer and that NT5E and FcGBP could be promising targets in the control of gallbladder cancer progression.

Khatri A, Williams BW, Fisher J, et al.
SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours.
Br J Cancer. 2014; 110(2):304-12 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition.
METHODS: Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development.
RESULTS: The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m(-2) min(-1) and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP.
CONCLUSION: Prolonged dFdCTP systemic exposures (≥72 h) were commonly observed. Infusion rate <25 mg m(-2) min(-1) and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.

Pagnotta SM, Laudanna C, Pancione M, et al.
Ensemble of gene signatures identifies novel biomarkers in colorectal cancer activated through PPARγ and TNFα signaling.
PLoS One. 2013; 8(8):e72638 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
We describe a novel bioinformatic and translational pathology approach, gene Signature Finder Algorithm (gSFA) to identify biomarkers associated with Colorectal Cancer (CRC) survival. Here a robust set of CRC markers is selected by an ensemble method. By using a dataset of 232 gene expression profiles, gSFA discovers 16 highly significant small gene signatures. Analysis of dichotomies generated by the signatures results in a set of 133 samples stably classified in good prognosis group and 56 samples in poor prognosis group, whereas 43 remain unreliably classified. AKAP12, DCBLD2, NT5E and SPON1 are particularly represented in the signatures and selected for validation in vivo on two independent patients cohorts comprising 140 tumor tissues and 60 matched normal tissues. Their expression and regulatory programs are investigated in vitro. We show that the coupled expression of NT5E and DCBLD2 robustly stratifies our patients in two groups (one of which with 100% survival at five years). We show that NT5E is a target of the TNF-α signaling in vitro; the tumor suppressor PPARγ acts as a novel NT5E antagonist that positively and concomitantly regulates DCBLD2 in a cancer cell context-dependent manner.

Allard B, Pommey S, Smyth MJ, Stagg J
Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs.
Clin Cancer Res. 2013; 19(20):5626-35 [PubMed] Related Publications
PURPOSE: Monoclonal antibodies (mAb) that block programmed death (PD)-1 or cytotoxic T lymphocyte antigen (CTLA-4) receptors have been associated with durable clinical responses against a variety of cancer types and hold great potential as novel cancer therapeutics. Recent evidence suggest that targeted blockade of multiple immunosuppressive pathways can induce synergistic antitumor responses.
EXPERIMENTAL DESIGN: In this study, we investigated whether targeted blockade of CD73, an ectonucleotidase that catabolizes the hydrolysis of extracellular adenosine monophosphate (AMP) to adenosine, can enhance the antitumor activity of anti-CTLA-4 and anti-PD-1 mAbs against transplanted and chemically induced mouse tumors.
RESULTS: Anti-CD73 mAb significantly enhanced the activity of both anti-CTLA-4 and anti-PD-1 mAbs against MC38-OVA (colon) and RM-1 (prostate) subcutaneous tumors, and established metastatic 4T1.2 breast cancer. Anti-CD73 mAb also significantly enhanced the activity of anti-PD-1 mAb against 3-methylcholanthrene (MCA)-induced fibrosarcomas. Gene-targeted mice revealed that single-agent therapies and combinatorial treatments were dependent on host IFN-γ and CD8(+) T cells, but independent of perforin. Interestingly, anti-CD73 mAb preferentially synergized with anti-PD-1 mAb. We investigated the effect of extracellular adenosine on tumor-infiltrating T cells and showed that activation of A2A adenosine receptor enhances PD-1 expression, but not CTLA-4 expression, on tumor-specific CD8+ T cells and CD4+ Foxp3+ T regulatory cells.
CONCLUSIONS: Taken together, our study revealed that targeted blockade of CD73 can enhance the therapeutic activity of anti-PD-1 and anti-CTLA-4 mAbs and may thus potentiate therapeutic strategies targeting immune checkpoint inhibitors in general.

Allard B, Turcotte M, Spring K, et al.
Anti-CD73 therapy impairs tumor angiogenesis.
Int J Cancer. 2014; 134(6):1466-73 [PubMed] Related Publications
CD73 is an ecto-nucleotidase overexpressed in various types of tumors that catabolizes the generation of extracellular adenosine, a potent immunosuppressor. We and others have shown that targeted blockade of CD73 can rescue anti-tumor T cells from the immunosuppressive effects of extracellular adenosine. Another important function of extracellular adenosine is to regulate adaptive responses to hypoxia. However, the importance of CD73 for tumor angiogenesis and the effect of anti-CD73 therapy on tumor angiogenesis remain unknown. In this study, we demonstrated that CD73 expression on tumor cells and host cells contribute to tumor angiogenesis. Our data revealed that tumor-derived CD73 enhances the production of vascular endothelial growth factor (VEGF) by tumor cells that host-derived CD73 is required for in vivo angiogenic responses and that endothelial cells require CD73 expression for tube formation and migration. Notably, the pro-angiogeneic effects of CD73 relied on both enzymatic and non-enzymatic functions. Using a mouse model of breast cancer, we demonstrated that targeted blockade of CD73 with a monoclonal antibody significantly decreased tumor VEGF levels and suppressed tumor angiogenesis in vivo. Taken together, our study strongly suggests that targeted blockade of CD73 can significantly block tumor angiogenesis, and further supports its clinical development for cancer treatment.

Grozio A, Sociali G, Sturla L, et al.
CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells.
J Biol Chem. 2013; 288(36):25938-49 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
NAD(+) is mainly synthesized in human cells via the "salvage" pathways starting from nicotinamide, nicotinic acid, or nicotinamide riboside (NR). The inhibition with FK866 of the enzyme nicotinamide phosphoribosyltransferase (NAMPT), catalyzing the first reaction in the "salvage" pathway from nicotinamide, showed potent antitumor activity in several preclinical models of solid and hematologic cancers. In the clinical studies performed with FK866, however, no tumor remission was observed. Here we demonstrate that low micromolar concentrations of extracellular NAD(+) or NAD(+) precursors, nicotinamide mononucleotide (NMN) and NR, can reverse the FK866-induced cell death, this representing a plausible explanation for the failure of NAMPT inhibition as an anti-cancer therapy. NMN is a substrate of both ectoenzymes CD38 and CD73, with generation of NAM and NR, respectively. In this study, we investigated the roles of CD38 and CD73 in providing ectocellular NAD(+) precursors for NAD(+) biosynthesis and in modulating cell susceptibility to FK866. By specifically silencing or overexpressing CD38 and CD73, we demonstrated that endogenous CD73 enables, whereas CD38 impairs, the conversion of extracellular NMN to NR as a precursor for intracellular NAD(+) biosynthesis in human cells. Moreover, cell viability in FK866-treated cells supplemented with extracellular NMN was strongly reduced in tumor cells, upon pharmacological inhibition or specific down-regulation of CD73. Thus, our study suggests that genetic or pharmacologic interventions interfering with CD73 activity may prove useful to increase cancer cell sensitivity to NAMPT inhibitors.

Falk IJ, Fyrberg A, Paul E, et al.
Decreased survival in normal karyotype AML with single-nucleotide polymorphisms in genes encoding the AraC metabolizing enzymes cytidine deaminase and 5'-nucleotidase.
Am J Hematol. 2013; 88(12):1001-6 [PubMed] Related Publications
De novo acute myeloid leukemia with normal karyotype (NK-AML) comprises a large group of patients with no common cytogenetic alterations and with a large variation in treatment response. Single-nucleotide polymorphisms (SNPs) in genes related to the metabolism of the nucleoside analogue AraC, the backbone in AML treatment, might affect drug sensitivity and treatment outcome. Therefore, SNPs may serve as prognostic biomarkers aiding clinicians in individualized treatment decisions, with the aim of improving patient outcomes. We analyzed polymorphisms in genes encoding cytidine deaminase (CDA 79A>C rs2072671 and -451C>T rs532545), 5'-nucleotidase (cN-II 7A>G rs10883841), and deoxycytidine kinase (DCK 3'UTR 948T>C rs4643786) in 205 de novo NK-AML patients. In FLT3-internal tandem duplication (ITD)-positive patients, the CDA 79C/C and -451T/T genotypes were associated with shorter overall survival compared to other genotypes (5 vs. 24 months, P < 0.001 and 5 vs. 23 months, P = 0.015, respectively), and this was most pronounced in FLT3-ITD-positive/NPM1-positive patients. We observed altered in vitro sensitivity to topoisomerase inhibitory drugs, but not to nucleoside analogues, and a decrease in global DNA methylation in cells carrying both CDA variant alleles. A shorter survival was also observed for the cN-II variant allele, but only in FLT3-ITD-negative patients (25 vs. 31 months, P = 0.075). Our results indicate that polymorphisms in genes related to nucleoside analog drug metabolism may serve as prognostic markers in de novo NK-AML.

Li Y, Wang X, Ni T, et al.
Human papillomavirus type 58 genome variations and RNA expression in cervical lesions.
J Virol. 2013; 87(16):9313-22 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Human papillomavirus type 58 (HPV58) is relatively prevalent in China and other Asian countries. In this study, the HPV58 genome in cervical lesions was decoded from five grade 2 or 3 cervical intraepithelial neoplasia lesion (CIN2/3) samples and five cervical cancer tissues using rolling-circle amplification of total cell DNA and deep sequencing and verified by whole-genome cloning and sequencing. HPV58 isolates from China feature a total of 52 nucleotide substitutions (0.66%) from the reference HPV58 sequence, which appear mainly in two regions, with 12 from nucleotides (nt) 3430 to 4136 covering the E2/E4/E5 open reading frames (ORFs) and 13 from nt 4621 to 5540 covering the L2 ORF; these could be grouped as HPV58 Chinese Zhejiang-1, -2, and -3 (CNZJ-1, -2, and -3) according to their sequence similarities and restriction enzyme digestion. Phylogenetically, CNZJ-3 is similar to the reference HPV58 sublineage A1 sequence. The other two are close to sublineage A2. Analysis of cervical lesion-derived RNA revealed abundant HPV58 early transcripts spliced at the E6 and E1/E2 ORFs, where two 5' splice sites at nt 232 and nt 898 and two 3' splice sites at nt 510 and nt 3355 can be identified. Thus, our study represents the first genome-wide analysis of HPV58 and its expression in cervical lesions.

Swierniak M, Wojcicka A, Czetwertynska M, et al.
In-depth characterization of the microRNA transcriptome in normal thyroid and papillary thyroid carcinoma.
J Clin Endocrinol Metab. 2013; 98(8):E1401-9 [PubMed] Related Publications
CONTEXT: A single microRNA gene may give rise to several mature products that differ in length, called isomiRs. IsomiRs are known to be tissue specific and functionally relevant. The microRNA sequence heterogeneity of the thyroid gland has yet to be determined.
OBJECTIVE: The objective of the study was to provide a comprehensive view of the microRNA transcriptome in normal thyroid and papillary thyroid carcinoma (PTC).
DESIGN: We used next-generation deep sequencing to analyze microRNA length heterogeneity and expression profiles of PTC tumors (n = 14), unaffected tissue adjacent to tumors (n = 14), and control, noncancerous thyroid tissue (n = 14). The results were validated with a microarray on an additional set of 9 PTC tumor/normal tissue pairs.
RESULTS: Eighty-nine microRNAs were significantly deregulated in PTC compared with normal thyroid tissue (false discovery rate < 0.05, fold change 0.13-20.7). Top deregulated miRNAs included miR-146b-5p, miR-221-3p, miR-7-3p, miR-551b-3p, miR-486-3p, and miR-144-3p, confirming previous microarray profiling. The expression of miRNAs did not depend on the BRAF mutation status. Interestingly, 85% of the most abundant microRNAs consisted of isoforms that differed from the standard reference sequence deposited in miRBase. Moreover, the reference microRNAs were completely absent in 42.4% and 35.9% of the microRNAs expressed in normal thyroid and PTC tumors, respectively. Numerous isomiRs had altered seed sequences, which led to a different set of target genes. For highly deregulated miR-146b-5p, we detected 6 isoforms (tumor/normal fold change 14.4-28.7, false discovery rate < 0.002) that varied at their 5' ends with a 1-nt difference that created 2 alternative seeds. The target genes for those 2 seeds overlapped in only 13.1% of genes.
CONCLUSIONS: Almost all microRNAs exhibit isoforms of variable length and potentially distinct function in thyroid tumorigenesis.

Loi S, Pommey S, Haibe-Kains B, et al.
CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer.
Proc Natl Acad Sci U S A. 2013; 110(27):11091-6 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Using gene-expression data from over 6,000 breast cancer patients, we report herein that high CD73 expression is associated with a poor prognosis in triple-negative breast cancers (TNBC). Because anthracycline-based chemotherapy regimens are standard treatment for TNBC, we investigated the relationship between CD73 and anthracycline efficacy. In TNBC patients treated with anthracycline-only preoperative chemotherapy, high CD73 gene expression was significantly associated with a lower rate of pathological complete response or the disappearance of invasive tumor at surgery. Using mouse models of breast cancer, we demonstrated that CD73 overexpression in tumor cells conferred chemoresistance to doxorubicin, a commonly used anthracycline, by suppressing adaptive antitumor immune responses via activation of A2A adenosine receptors. Targeted blockade of CD73 enhanced doxorubicin-mediated antitumor immune responses and significantly prolonged the survival of mice with established metastatic breast cancer. Taken together, our data suggest that CD73 constitutes a therapeutic target in TNBC.

Fang ZQ, Zang WD, Chen R, et al.
Gene expression profile and enrichment pathways in different stages of bladder cancer.
Genet Mol Res. 2013; 12(2):1479-89 [PubMed] Related Publications
Bladder cancer is a highly heterogeneous neoplasm. We examined the gene expression profile in 3 bladder cancer stages (Ta, T1, T2) using expression microarray analysis of 40 bladder tumors. Differentially expressed genes were found by the t-test, with <0.005 as the significance threshold. KEGG pathway-enrichment analysis was used to study the signaling pathways of the genes. We found 36 genes that could be used as molecular markers for predicting the transition from Ta-T1 to T1-T2. Among these, 11 overlapped between Ta-T1 and T1-T2 stages. Six genes were down-regulated at the Ta-T1 stage, but were up-regulated at the T1-T2 stage (ANXA5, ATP6V1B2, CTGF, GEM, IL13RA1, and LCP1); 5 genes were up-regulated at the Ta-T1 stage, but down-regulated at the T1-T2 stage (ACPP, GNL1, RIPK1, RAPGEF3, and ZER1). Another 25 genes changed relative expression levels at the T1-T2 stage. These genes (including COL1A1, COL1A2, FN1, ITGA5, LGALS1, SPP1, VIM, POSTN, and COL18A1) may be involved in bladder cancer progression by affecting extracellular matrix-receptor interaction and focal adhesion. The cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and calcium-signaling pathway were associated with bladder cancer progression at both the Ta-T1 and T1-T2 stages.

Taniuchi F, Higai K, Tanaka T, et al.
Transcriptional regulation of fucosyltransferase 1 gene expression in colon cancer cells.
ScientificWorldJournal. 2013; 2013:105464 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
The α 1,2-fucosyltransferase I (FUT1) enzyme is important for the biosynthesis of H antigens, Lewis B, and Lewis Y. In this study, we clarified the transcriptional regulation of FUT1 in the DLD-1 colon cancer cell line, which has high expression of Lewis B and Lewis Y antigens, expresses the FUT1 gene, and shows α 1,2-fucosyltransferase (FUT) activity. 5'-rapid amplification of cDNA ends revealed a FUT1 transcriptional start site -10 nucleotides upstream of the site registered at NM_000148 in the DataBase of Human Transcription Start Sites (DBTSS). Using the dual luciferase assay, FUT1 gene expression was shown to be regulated at the region -91 to -81 nt to the transcriptional start site, which contains the Elk-1 binding site. Site-directed mutagenesis of this region revealed the Elk-1 binding site to be essential for FUT1 transcription. Furthermore, transfection of the dominant negative Elk-1 gene, and the chromatin immunoprecipitation (CHIp) assay, supported Elk-1-dependent transcriptional regulation of FUT1 gene expression in DLD-1 cells. These results suggest that a defined region in the 5'-flanking region of FUT1 is critical for FUT1 transcription and that constitutive gene expression of FUT1 is regulated by Elk-1 in DLD-1 cells.

Farazi TA, Hoell JI, Morozov P, Tuschl T
MicroRNAs in human cancer.
Adv Exp Med Biol. 2013; 774:1-20 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20-23-nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the translation and stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis, and invasion. miRNA targeting is initiated through specific base-pairing interactions between the 5' end ("seed" region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3' UTR lead to more effective mRNA destabilization. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. To provide a critical overview of miRNA dysregulation in cancer, we first discuss the methods currently available for studying the role of miRNAs in cancer and then review miRNA genomic organization, biogenesis, and mechanism of target recognition, examining how these processes are altered in tumorigenesis. Given the critical role miRNAs play in tumorigenesis processes and their disease specific expression, they hold potential as therapeutic targets and novel biomarkers.

Tzoneva G, Perez-Garcia A, Carpenter Z, et al.
Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL.
Nat Med. 2013; 19(3):368-71 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric patients and over 50% of adult patients with ALL do not achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most substantial challenge in the treatment of this disease. Using whole-exome sequencing, we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs, in 20/103 (19%) relapse T cell ALLs and 1/35 (3%) relapse B-precursor ALLs. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside-analog metabolism in disease progression and chemotherapy resistance in ALL.

Meyer JA, Wang J, Hogan LE, et al.
Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia.
Nat Genet. 2013; 45(3):290-4 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Relapsed childhood acute lymphoblastic leukemia (ALL) carries a poor prognosis, despite intensive retreatment, owing to intrinsic drug resistance. The biological pathways that mediate resistance are unknown. Here, we report the transcriptome profiles of matched diagnosis and relapse bone marrow specimens from ten individuals with pediatric B-lymphoblastic leukemia using RNA sequencing. Transcriptome sequencing identified 20 newly acquired, novel nonsynonymous mutations not present at initial diagnosis, with 2 individuals harboring relapse-specific mutations in the same gene, NT5C2, encoding a 5'-nucleotidase. Full-exon sequencing of NT5C2 was completed in 61 further relapse specimens, identifying additional mutations in 5 cases. Enzymatic analysis of mutant proteins showed that base substitutions conferred increased enzymatic activity and resistance to treatment with nucleoside analog therapies. Clinically, all individuals who harbored NT5C2 mutations relapsed early, within 36 months of initial diagnosis (P = 0.03). These results suggest that mutations in NT5C2 are associated with the outgrowth of drug-resistant clones in ALL.

Cappellari AR, Rockenbach L, Dietrich F, et al.
Characterization of ectonucleotidases in human medulloblastoma cell lines: ecto-5'NT/CD73 in metastasis as potential prognostic factor.
PLoS One. 2012; 7(10):e47468 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
Medulloblastoma (MB) is the most common malignant brain tumor in children and occurs mainly in the cerebellum. Important intracellular signaling molecules, such those present in the Sonic Hedgehog and Wnt pathways, are involved in its development and can also be employed to determine tumor grade and prognosis. Ectonucleotidases, particularly ecto-5'NT/CD73, are important enzymes in the malignant process of different tumor types regulating extracellular ATP and adenosine levels. Here, we investigated the activity of ectonucleotidases in three malignant human cell lines: Daoy and ONS76, being representative of primary MB, and the D283 cell line, derived from a metastatic MB. All cell lines secreted ATP into the extracellular medium while hydrolyze poorly this nucleotide, which is in agreement with the low expression and activity of pyrophosphate/phosphodiesterase, NTPDases and alkaline phosphatase. The analysis of AMP hydrolysis showed that Daoy and ONS76 completely hydrolyzed AMP, with parallel adenosine production (Daoy) and inosine accumulation (ONS76). On the other hand, D283 cell line did not hydrolyze AMP. Moreover, primary MB tumor cells, Daoy and ONS76 express the ecto-5'NT/CD73 while D283 representative of a metastatic tumor, revealed poor expression of this enzyme, while the ecto-adenosine deaminase showed higher expression in D283 compared to Daoy and ONS76 cells. Nuclear beta-catenin has been suggested as a marker for MB prognosis. Further it can promotes expression of ecto-5'NT/CD73 and suppression of adenosine deaminase. It was observed that Daoy and ONS76 showed greater nuclear beta-catenin immunoreactivity than D283, which presented mainly cytoplasmic immunoreactivity. In summary, the absence of ecto-5'NT/CD73 in the D283 cell line, a metastatic MB phenotype, suggests that high expression levels of this ectonucleotidase could be correlated with a poor prognosis in patients with MB.

Mustafa F, Al Amri D, Al Ali F, et al.
Sequences within both the 5' UTR and Gag are required for optimal in vivo packaging and propagation of mouse mammary tumor virus (MMTV) genomic RNA.
PLoS One. 2012; 7(10):e47088 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: This study mapped regions of genomic RNA (gRNA) important for packaging and propagation of mouse mammary tumor virus (MMTV). MMTV is a type B betaretrovirus which preassembles intracellularly, a phenomenon distinct from retroviruses that assemble the progeny virion at cell surface just before budding such as the type C human and feline immunodeficiency viruses (HIV and FIV). Studies of FIV and Mason-Pfizer monkey virus (MPMV), a type D betaretrovirus with similar intracellular virion assembly processes as MMTV, have shown that the 5' untranslated region (5' UTR) and 5' end of gag constitute important packaging determinants for gRNA.
METHODOLOGY: Three series of MMTV transfer vectors containing incremental amounts of gag or 5' UTR sequences, or incremental amounts of 5' UTR in the presence of 400 nucleotides (nt) of gag were constructed to delineate the extent of 5' sequences that may be involved in MMTV gRNA packaging. Real time PCR measured the packaging efficiency of these vector RNAs into MMTV particles generated by co-transfection of MMTV Gag/Pol, vesicular stomatitis virus envelope glycoprotein (VSV-G Env), and individual transfer vectors into human 293T cells. Transfer vector RNA propagation was monitored by measuring transduction of target HeLaT4 cells following infection with viral particles containing a hygromycin resistance gene expression cassette on the packaged RNA.
PRINCIPAL FINDINGS: MMTV requires the entire 5' UTR and a minimum of ~120 nucleotide (nt) at the 5' end of gag for not only efficient gRNA packaging but also propagation of MMTV-based transfer vector RNAs. Vector RNAs without the entire 5' UTR were defective for both efficient packaging and propagation into target cells.
CONCLUSIONS/SIGNIFICANCE: These results reveal that the 5' end of MMTV genome is critical for both gRNA packaging and propagation, unlike the recently delineated FIV and MPMV packaging determinants that have been shown to be of bipartite nature.

Galrão AL, Sodré AK, Camargo RY, et al.
Methylation levels of sodium-iodide symporter (NIS) promoter in benign and malignant thyroid tumors with reduced NIS expression.
Endocrine. 2013; 43(1):225-9 [PubMed] Related Publications
DNA methylation regulates gene expression. Aberrant methylation plays an important role in human tumorigenesis. We have previously detected reduced NIS mRNA expression in thyroid tumors as compared to non-tumor tissues. Thus, in this study we investigated whether the methylation of the CpG-island located in the NIS gene promoter was associated with reduced mRNA expression in thyroid tumors. Methylation levels of 30 pairs of samples from 10 benign and 20 malignant thyroid tumors (T) along with matched non-tumor (NT) areas were determined by semiquantitative methylation specific-PCR. NIS methylation was detected in all samples. Methylation levels and frequencies did not differ between the groups and were not associated with BRAF mutational status. Highest methylation levels and frequencies were detected in the 5' region of the CpG-island decreasing toward the 3' end. Intraindividual analysis (T versus NT) showed high tumor methylation levels in 40 % of the samples in the benign group and 30 % in the malignant group, associated with low NIS mRNA expression. No quantitative correlation was detected between methylation levels and mRNA expression in any the groups. The results of this study showed that methylation of NIS promoter is a very frequent event in both benign and malignant tumors as well as in their surrounding tissues, and characterized a non-homogeneous methylation pattern along the CpG island. Therefore, further investigations involving other sites that may be implicated in methylation regulation of NIS expression are warranted.

Røe OD, Szulkin A, Anderssen E, et al.
Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma.
PLoS One. 2012; 7(8):e40521 [PubMed] Article available free on PMC after 01/08/2015 Related Publications
BACKGROUND: Pemetrexed, a multi-folate inhibitor combined with a platinum compound is the first-line treatment of malignant mesothelioma, but median survival is still one year. Intrinsic and acquired resistance to pemetrexed is common, but its biological basis is obscure. Here we report for the first time a genome-wide profile of acquired resistance in the tumour from an exceptional case with advanced pleural mesothelioma and almost six years survival after 39 cycles of second-line pemetrexed/carboplatin treatment.
METHODOLOGY AND PRINCIPAL FINDINGS: Genome-wide analysis with Illumina BeadChip Kit of 25,000 genes was performed on mRNA from pre-treatment and post-resistance biopsies from this individual as well on case and control samples from our previously published study (in total 17 samples). Cell specific expression of proteins encoded by selected genes were analysed by immunohistochemistry. Serial serum levels of CA125, CYFRA21-1 and SMRP levels were examined. TS protein, the main target of pemetrexed was overexpressed. Proteins and genes related to DNA damage response, elongation and telomere extension and repair related directly and indirectly to platinum resistance were overexpressed, as the CHK1 protein and the genes CHEK2, LIG3, POLD1, POLA2, FANCD2, PRPF19, RECQ5 respectively, the last two not previously described in mesothelioma. We observed a down-regulation of leukocyte transendothelial migration and cell adhesion molecules pathways. Silencing of NT5C in two mesothelioma cell lines did not sensitize the cells to Pemetrexed. Proposed resistance markers are TS, KRT7/ CK7, TYMP/ thymidine phosphorylase and down-regulated SPARCL1 and CDKN1B. Moreover, comparison of the primary expression of the sensitive versus a primary resistant case showed multi-fold overexpressed DNA repair, cell cycle, cytokinesis, and spindle formation in the latter. Serum CA125 and SMRP reflected the clinical and radiological course and tumour burden.
CONCLUSIONS: Genome-wide microarray of mesothelioma pre- and post-resistance biopsies indicated a novel resistance signature to pemetrexed/carboplatin that deserve validation in a larger cohort.

Mitra AK, Kirstein MN, Khatri A, et al.
Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors.
Pharmacogenomics. 2012; 13(9):1009-21 [PubMed] Related Publications
AIM: The aim of this study was to evaluate the association of gemcitabine pathway SNPs with detailed pharmacokinetic measures obtained from solid tumor patients receiving gemcitabine-based therapy.
MATERIALS & METHODS: SNPs within nine gemcitabine pathway genes, namely CDA, CMPK, DCK, DCTD, NT5C2, NT5C3, SLC28A1, SLC28A3 and SLC29A1 were analyzed for association with gemcitabine pharmacokinetics.
RESULTS: Significant association of gemcitabine clearance with SNPs in NT5C2 was identified. Clearance of 2´,2´-difluorodeoxyuridine, a gemcitabine metabolite was significantly predicted by CDA, SLC29A1 and NT5C2 SNPs. This study reports an association of formation clearance of 2´,2´-difluoro-2´-deoxycytidine triphosphate, an active form of gemcitabine with SNPs within uptake transporters SLC28A1, SLC28A3 and SLC29A1.
CONCLUSION: Genetic variation in gemcitabine pathway genes is associated with its pharmacokinetics and hence could influence gemcitabine response. Our study identified pharmacogenetic markers that could be further tested in larger patient cohorts and could open up opportunities to individualize therapy in solid tumor patients.

Schnittger S, Bacher U, Haferlach C, et al.
Diversity of the juxtamembrane and TKD1 mutations (exons 13-15) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data.
Genes Chromosomes Cancer. 2012; 51(10):910-24 [PubMed] Related Publications
In acute myeloid leukemia (AML) mutations in the juxtamembrane and tyrosine kinase 1 domain (exons 13-15) of the FLT3 gene (FLT3-ITD/LM) are heterogeneous with respect to mutation load, size, and localization. We characterized length and structure of these mutations by fragment analysis and sequencing in 689 AML which were identified among 3,365 (20.5%) newly diagnosed AML (1,803 males, 1,562 females; 15.8-91.8 years). Mutations were heterogeneous in length (median: 63, range: 3-1,236 nucleotides; nt). Most frequent were sizes of 21 (8.4%) or 24 nt (6.0%). Ninety-one different insertion sites were observed (between nt 1,788 and 1,934, according to accession "FLT3 [Ensembl/Havana merge: ENSG00000122025]" with nt 1,856 (n = 41) and 1,863 (n = 35) being most frequent. In addition, 89 different insertion end points were observed between nt 1,790 and 1,994. FLT3-mutation/wild-type ratio was available in 615 patients (median, 0.80; range 0.03-181.73). 128 Patients (20.8%) had ratios <0.3, 334 (54.3%) had ratio ≥0.3 <1, 118 (19.2%) ≥1, and 35 (5.7%) showed complete loss of the FLT3-wild-type allele. Overall (OS) and event-free (EFS) survival were better for FLT3-negative than FLT3mut normal karyotype patients (P = 0.078 and P = 0.004, respectively) and patients with low level FLT3-mutations had significantly longer OS and EFS compared with high level mutations (FLT3-mutation/wild-type ratio ≥1) (P < 0.001 and P = 0.002, respectively). The length of the mutation had no prognostic impact. Mutations localized more 5' were associated with better outcome than more 3'mutations, but no strict association to certain functional domains was detected. In conclusion, FLT3-mutations are extremely heterogenous with mutation load being the most relevant parameter.

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