AKAP13

Gene Summary

Gene:AKAP13; A kinase (PRKA) anchor protein 13
Aliases: BRX, LBC, p47, HA-3, Ht31, c-lbc, PRKA13, AKAP-13, AKAP-Lbc, ARHGEF13, PROTO-LB, PROTO-LBC
Location:15q24-q25
Summary:The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms containing c-terminal dbl oncogene homology (DH) and pleckstrin homology (PH) domains. The DH domain is associated with guanine nucleotide exchange activation for the Rho/Rac family of small GTP binding proteins, resulting in the conversion of the inactive GTPase to the active form capable of transducing signals. The PH domain has multiple functions. Therefore, these isoforms function as scaffolding proteins to coordinate a Rho signaling pathway, function as protein kinase A-anchoring proteins and, in addition, enhance ligand-dependent activity of estrogen receptors alpha and beta. [provided by RefSeq, Jul 2012]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:A-kinase anchor protein 13
HPRD
Source:NCBIAccessed: 21 August, 2015

Ontology:

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

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 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.

  • Chromosome 15
  • Northern Blotting
  • Risk Factors
  • Breast Cancer
  • Oligonucleotide Array Sequence Analysis
  • Transfection
  • Valine
  • Antineoplastic Agents
  • Proto-Oncogene Proteins
  • Sequence Homology
  • Neoplastic Cell Transformation
  • RTPCR
  • Tumor Markers
  • Cancer DNA
  • Cancer Gene Expression Regulation
  • alpha Catenin
  • Young Adult
  • Two-Hybrid System Techniques
  • Neoplasm Invasiveness
  • Cell Movement
  • Neoplasm Recurrence, Local
  • Signal Transducing Adaptor Proteins
  • Quinolones
  • Immunoenzyme Techniques
  • rho GTP-Binding Proteins
  • Molecular Sequence Data
  • Immunohistochemistry
  • Drug Resistance
  • DNA Primers
  • Signal Transduction
  • Amino Acid Sequence
  • Base Sequence
  • GTP-Binding Proteins
  • Zinc Fingers
  • A Kinase Anchor Proteins
  • Gene Expression Profiling
  • Western Blotting
  • Genetic Predisposition
  • Neoplasm Metastasis
Tag cloud generated 21 August, 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: AKAP13 (cancer-related)

Visnovsky J, Kudela E, Farkasova A, et al.
Amplification of TERT and TERC genes in cervical intraepithelial neoplasia and cervical cancer.
Neuro Endocrinol Lett. 2014; 35(6):518-22 [PubMed] Related Publications
OBJECTIVES: Telomerase is activated in various stages of oncogenesis. For cervical cancer, telomerase is already active in precancerous lesions. In our study we focused on the analysis of the amplification patterns of telomerase genes TERT and TERC.
DESIGN AND SETTING: We included 39 patients in our study between January 2012 and April 2013. Each patient underwent a classical gynaecological examination and a colposcopy. During the colposcopic examination we collected material for a Pap smear, HPV DNA test (HC2) and LBC (LiquiPrep™), and performed punch biopsies for histopathological evaluation. Residual cytologic sample was hybridized with the FISH probe and telomerase genes were analysed.
RESULTS: The amplification of the TERT gene showed us a very similar amplification pattern as TERC and gradually corresponded with both histolopathological (p<0.001) and cytopathological findings (p<0.001). The specificity and sensitivity of TERC gene amplification for the detection of CIN2+ lesions (cut off value 2.3) was 88.2% and 95.5% respectively (PPV 91.3%, NPV 93.8%).
CONCLUSIONS: We identified increasing amplification pattern of telomerase genes in cervical lesions. According to our results telomerase genes could help in the future to determine the malignant potential of cervical lesions and could be tested together with cytology and HPV DNA in order to obtain the highest combined sensitivity and specificity for CIN2+ lesion detection.

Wu CY, Hou LK, Ren SX, et al.
High feasibility of liquid-based cytological samples for detection of EGFR mutations in Chinese patients with NSCLC.
Asian Pac J Cancer Prev. 2014; 15(18):7885-9 [PubMed] Related Publications
BACKGROUND: Activating mutations of epidermal growth factor receptor (EGFR) could predict response to tyrosine kinase inhibitor (TKI) treatment in patients with non-small cell lung cancer (NSCLC). However, the detection of EGFR mutation is frequently challenging in clinical practice for the lack of tumor tissue. The aim of this study was to investigate the feasibility of performing EGFR mutation testing on various types of liquid-based cytology (LBC) samples.
MATERIALS AND METHODS: A total of 434 liquid-based cytology samples were collected from March 2010 and November 2013. Among them, 101 with diagnosis of lung adenocarcinoma had paired surgically resected specimens. The ADx Amplification Refractory Mutation System (ADx-ARMS) was used to determine EGFR mutation status both in LBC and resected samples.
RESULTS: All liquid-based cytology samples were adequate for EGFR mutation analysis. The mutation rate was 50.5% in the 434 NSCLC patients with LBC samples and the incidence rates of EGFR mutation were consistent among different specimens. We also detected EGFR positives in 52.5% (53/101) patients with paired histologic specimens. The concordance rate of EGFR mutation between LBC samples and paired histologic specimens was 92.1%.
CONCLUSIONS: Our results suggest that liquid-based cytology samples are highly reliable for EGFR mutation testing in patients with NSCLC.

Rossi ED, Martini M, Straccia P, et al.
Thyroglossal duct cyst cancer most likely arises from a thyroid gland remnant.
Virchows Arch. 2014; 465(1):67-72 [PubMed] Related Publications
Thyroglossal duct cancer is a rare entity, occurring in 1.5 % of all thyroglossal duct cysts (TDC). A definitive consensus about its neoplastic origin has not been established as two contrasting theories exist, one proposing an origin in extra-thyroid remnants and the other a metastatic localization of a primary thyroid cancer. We compare morphological and molecular characteristics of both thyroglossal and thyroid carcinomas in a case series from our institute. We evaluated histology of 80 TDC. In 12 cases, prior cytological evaluation had been performed by liquid-based cytology (LBC). The BRAF gene was examined for mutations, and the histology of both thyroglossal duct and synchronous thyroid carcinoma was reevaluated. In 9 out of 80 (11 %) TDC cases, a papillary thyroid cancer (PTC) was diagnosed. In five out of nine (56 %) thyroglossal carcinomas, a synchronous thyroid cancer was diagnosed: 3 PTC and 2 follicular variant PTC (FVPC). In five thyroglossal carcinomas, mutated BRAF (V600E) was found, three in PTC and in thyroglossal as well as in the synchronous tumor in the thyroid. All the patients are in a disease-free status and still alive. Our results suggest that the majority of thyroglossal carcinomas most likely develop as a primary malignancy from a thyroid remnant. Neither the presence of V600E BRAF mutations nor that of a well-differentiated thyroid carcinoma changed the outcome or disease-free survival. We suggest that a diagnosis of thyroglossal carcinoma should be followed by a detailed evaluation of the thyroid gland. In the absence of clinical and radiological thyroid alterations, follow-up as for thyroid cancer is the correct management.

Watanabe Y, Maeda I, Oikawa R, et al.
Aberrant DNA methylation status of DNA repair genes in breast cancer treated with neoadjuvant chemotherapy.
Genes Cells. 2013; 18(12):1120-30 [PubMed] Related Publications
Dysregulation of homologous recombination (HR) DNA repair has been implicated in breast carcinogenesis and chemosensitivity. Here, we investigated the methylation status of sixteen HR genes and analyzed their association with tumor subtypes and responses to neoadjuvant chemotherapy. Core specimens were obtained before neoadjuvant chemotherapy from sixty cases of primary breast cancer of the following four subgroups: luminal breast cancer (LBC) with pathological complete response (pCR), LBC with stable disease, triple-negative breast cancer (TNBC) with pCR and TNBC with poor response. The aberrant DNA methylation status of the following HR related-genes was analyzed using bisulfite-pyrosequencing: BRCA1, BRCA2, BARD1, MDC1, RNF8, RNF168, UBC13, ABRA1, PALB2, RAD50, RAD51, RAD51C, MRE11, NBS1, CtIP and ATM. Among the genes analyzed, only the incidence of BRCA1 and RNF8 methylation was significantly higher in TNBC than that in LBC. Whereas the incidence of BRCA1 methylation was tended to be higher in pCR cases than in poor-response cases in TNBC, that of RNF8 was significantly lower in pCR cases than in poor-response cases. Our results indicate that the methylation status of HR genes was not generally associated with TNBC subtype or chemosensitivity although hypermethylation of BRCA1 is associated with TNBC subtype and may impact chemosensitivity.

Molinaro V, Pensotti V, Marabelli M, et al.
Complementary molecular approaches reveal heterogeneous CDH1 germline defects in Italian patients with hereditary diffuse gastric cancer (HDGC) syndrome.
Genes Chromosomes Cancer. 2014; 53(5):432-45 [PubMed] Related Publications
Germline inactivation of the E-cadherin gene (CDH1) is associated with hereditary diffuse gastric cancer (HDGC), a rare autosomal dominant syndrome predisposing to both diffuse gastric cancer (DGC) and lobular breast cancer (LBC). We searched for CDH1 germline defects in 32 HDGC Italian probands selected according to international consensus criteria and in 5 selected relatives. We used a series of molecular methods, including: DNA sequencing, multiplex ligation-dependent probe amplification, single-nucleotide primer extension, bisulfite sequencing, reverse-transcription PCR, and bioinformatics tools. We identified pathogenic mutations in 6 out of 32 probands (19%): one truncating and two missense mutations, one large deletion, one allelic expression imbalance and one splicing defect. Three out of six CDH1 constitutive alterations were novel. Our data support the need for a multimethod approach for CDH1 genetic testing, demonstrating that both DNA and RNA analyses are required to increase the detection rate of pathogenic mutations, thus reducing the number of patients without a clear molecular diagnosis. On the whole, our results indicate that not only DGC patients, but also subjects with personal or family history of LBC might benefit from CDH1 genetic testing. Moreover, our findings support the notion that prophylactic gastrectomy should be offered to asymptomatic CDH1 mutation carriers; indeed, while endoscopic analysis with histological examination of random gastric biopsies can miss cancer foci, gastrectomy performed in these subjects always revealed foci of cancer cells.

Jajoo S, Mukherjea D, Kaur T, et al.
Essential role of NADPH oxidase-dependent reactive oxygen species generation in regulating microRNA-21 expression and function in prostate cancer.
Antioxid Redox Signal. 2013; 19(16):1863-76 [PubMed] Free Access to Full Article Related Publications
AIMS: Oncogenic microRNAs (miRs) promote tumor growth and invasiveness. One of these, miR-21, contributes to carcinogenesis in prostate and other cancers. In the present study, we tested the hypothesis that NADPH oxidase-dependent reactive oxygen species (ROS) regulate the expression and function of miR-21 and its target proteins, maspin and programmed cell death 4 (PDCD4), in prostate cancer cells.
RESULTS: The highly aggressive androgen receptor negative PC-3M-MM2 prostate cancer cells demonstrated high expression of miR-21 and p47(phox) (an essential subunit of NADPH oxidase). Using loss-of-function strategy, we showed that transfection of PC-3M-MM2 cells with anti-miR-21- and p47(phox) siRNA (si-p47(phox)) led to reduced expression of miR-21 with concurrent increase in maspin and PDCD4, and decreased the invasiveness of the cells. Tail-vein injections of anti-miR-21- and si-p47(phox)-transfected PC-3M-MM2 cells in severe combined immunodeficient mice reduced lung metastases. Clinical samples from patients with advanced prostate cancer expressed high levels of miR-21 and p47(phox), and low expression of maspin and PDCD4. Finally, ROS activated Akt in these cells, the inhibition of which reduced miR-21 expression.
INNOVATION: The levels of NADPH oxidase-derived ROS are high in prostate cancer cells, which have been shown to be involved in their growth and migration. This study demonstrates that ROS produced by this pathway is essential for the expression and function of an onco-miR, miR-21, in androgen receptor-negative prostate cancer cells.
CONCLUSION: These data demonstrate that miR-21 is an important target of ROS, which contributes to the highly invasive and metastatic phenotype of prostate cancer cells.

Jensen HA, Styskal LE, Tasseff R, et al.
The Src-family kinase inhibitor PP2 rescues inducible differentiation events in emergent retinoic acid-resistant myeloblastic leukemia cells.
PLoS One. 2013; 8(3):e58621 [PubMed] Free Access to Full Article Related Publications
Retinoic acid is an embryonic morphogen and dietary factor that demonstrates chemotherapeutic efficacy in inducing maturation in leukemia cells. Using HL60 model human myeloid leukemia cells, where all-trans retinoic acid (RA) induces granulocytic differentiation, we developed two emergent RA-resistant HL60 cell lines which are characterized by loss of RA-inducible G1/G0 arrest, CD11b expression, inducible oxidative metabolism and p47(phox) expression. However, RA-treated RA-resistant HL60 continue to exhibit sustained MEK/ERK activation, and one of the two sequentially emergent resistant lines retains RA-inducible CD38 expression. Other signaling events that define the wild-type (WT) response are compromised, including c-Raf phosphorylation and increased expression of c-Cbl, Vav1, and the Src-family kinases (SFKs) Lyn and Fgr. As shown previously in WT HL60 cells, we found that the SFK inhibitor PP2 significantly increases G1/G0 cell cycle arrest, CD38 and CD11b expression, c-Raf phosphorylation and expression of the aforementioned regulators in RA-resistant HL60. The resistant cells were potentially incapable of developing inducible oxidative metabolism. These results motivate the concept that RA resistance can occur in steps, wherein growth arrest and other differentiation events may be recovered in both emergent lines. Investigating the mechanistic anomalies in resistant cell lines is of therapeutic significance and helps to mechanistically understand the response to retinoic acid's biological effects in WT HL60 cells.

Tan LH, Tan SY, Tang T, et al.
Relationship between atypical T- and B-cell size predicts survival in peripheral T-cell lymphomas with large B-cells.
Pathology. 2013; 45(1):28-37 [PubMed] Related Publications
BACKGROUND: Pathological prognostication for peripheral T-cell lymphomas (PTCLs) complicated by large B-cell (LBC) proliferations has not been previously devised.
METHODS: Forty-six cases of PTCL with LBCs were reviewed immunohistologically, by in situ hybridisation for Epstein-Barr virus encoded RNA and polymerase chain reaction analyses for T-cell receptor (TCR) clonality. Follow-up intervals ranged from 1 to 149 months (mean 40 months).
RESULTS: Cases with atypical T-cell size equal to or exceeding that of interspersed LBCs (ATEB+, n = 12, including an ALK negative anaplastic large cell lymphoma) had significantly inferior disease-specific survival compared to ATEB negative (ATEB-, n = 34) cases (p = 0.002 for all cases and p = 0.014 when restricted to TCR clonal cases, n = 30) [hazard ratio 11.2; 95% confidence interval (CI) 0.94-85.0, p = 0.019]. All recorded deaths amongst ATEB+ cases occurred in 26 months, while TCR polyclonal ATEB- cases (n = 9) had none; TCR clonal ATEB- cases (n = 22) had 62% 5-year survival (95% CI 33-91%, p = 0.001). There was no survival separation between angioimmunoblastic (n = 25) and unspecified (n = 20) subsets of PTCL (p = 0.957).
CONCLUSION: In PTCLs, cytological grading using harboured LBCs as internal yardsticks, as well as molecular genotypic measures of lymphoma cell burden, have prognostic value.

Rossi ED, Martini M, Capodimonti S, et al.
BRAF (V600E) mutation analysis on liquid-based cytology-processed aspiration biopsies predicts bilaterality and lymph node involvement in papillary thyroid microcarcinoma.
Cancer Cytopathol. 2013; 121(6):291-7 [PubMed] Related Publications
BACKGROUND: Activating mutations in the valine-to-glutamic acid substitution at position 600 of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF-1) gene are detected frequently in patients with papillary thyroid carcinoma (PTC). These mutations have been identified in approximately 29% to 69% of PTCs and in >80% of PTCs of the tall cell variant, whereas they have not been detected in benign lesions or in the majority of those (80%) with the follicular variant of PTC. The objective of the current study was to evaluate the role of liquid-based cytology (LBC) for the detection of BRAF mutations in the outcome of patients who have thyroid PTC measuring ≤ 1 cm and, hence, in guiding their clinical and surgical management.
METHODS: From October 2010 through June 2011, 230 consecutive cases were diagnosed as positive for malignancy on fine-needle aspiration cytology processed by LBC. Of these, 73 PTCs ≤ 1 cm underwent BRAF mutational analysis. The aspirated material was processed using an LBC technique. After DNA extraction of the residual material, BRAF mutation analysis was performed using a direct sequencing method.
RESULTS: Fifty of 73 patients (68.5%) underwent surgery, and 34 of those patients (68%) had tumors that expressed a BRAF mutation (31 PTCs, including 11 tall cell variants and 3 follicular-variant PTCs). A significant association between BRAF mutation and bilaterality of cancer was observed (odds ratio, 0.077; P = .0007). BRAF mutation was associated significantly with lymph node involvement (odds ratio, 19; P = .0007) but not with extracapsular infiltration (odds ratio, 0.298; P = .179).
CONCLUSIONS: The current results indicated that BRAF gene mutations can be identified successfully on LBC material and using other cytologic methods with high reproducibility, feasibility, and informative results. The presence of a BRAF mutation may preoperatively predict the behavior of microscopic PTC, suggesting a more aggressive surgical approach.

Carr HS, Morris CA, Menon S, et al.
Rac1 controls the subcellular localization of the Rho guanine nucleotide exchange factor Net1A to regulate focal adhesion formation and cell spreading.
Mol Cell Biol. 2013; 33(3):622-34 [PubMed] Free Access to Full Article Related Publications
RhoA is overexpressed in human cancer and contributes to aberrant cell motility and metastatic progression; however, regulatory mechanisms controlling RhoA activity in cancer are poorly understood. Neuroepithelial transforming gene 1 (Net1) is a RhoA guanine nucleotide exchange factor that is overexpressed in human cancer. It encodes two isoforms, Net1 and Net1A, which cycle between the nucleus and plasma membrane. Net1 proteins must leave the nucleus to activate RhoA, but mechanisms controlling the extranuclear localization of Net1 isoforms have not been described. Here, we show that Rac1 activation causes relocalization of Net1 isoforms outside the nucleus and stimulates Net1A catalytic activity. These effects do not require Net1A catalytic activity, its pleckstrin homology domain, or its regulatory C terminus. We also show that Rac1 activation protects Net1A from proteasome-mediated degradation. Replating cells on collagen stimulates endogenous Rac1 to relocalize Net1A, and inhibition of proteasome activity extends the duration and magnitude of Net1A relocalization. Importantly, we demonstrate that Net1A, but not Net1, is required for cell spreading on collagen, myosin light chain phosphorylation, and focal adhesion maturation. These data identify the first physiological mechanism controlling the extranuclear localization of Net1 isoforms. They also demonstrate a previously unrecognized role for Net1A in regulating cell adhesion.

Neumeister VM, Anagnostou V, Siddiqui S, et al.
Quantitative assessment of effect of preanalytic cold ischemic time on protein expression in breast cancer tissues.
J Natl Cancer Inst. 2012; 104(23):1815-24 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Companion diagnostic tests can depend on accurate measurement of protein expression in tissues. Preanalytic variables, especially cold ischemic time (time from tissue removal to fixation in formalin) can affect the measurement and may cause false-negative results. We examined 23 proteins, including four commonly used breast cancer biomarker proteins, to quantify their sensitivity to cold ischemia in breast cancer tissues.
METHODS: A series of 93 breast cancer specimens with known time-to-fixation represented in a tissue microarray and a second series of 25 matched pairs of core needle biopsies and breast cancer resections were used to evaluate changes in antigenicity as a function of cold ischemic time. Estrogen receptor (ER), progesterone receptor (PgR), HER2 or Ki67, and 19 other antigens were tested. Each antigen was measured using the AQUA method of quantitative immunofluorescence on at least one series. All statistical tests were two-sided.
RESULTS: We found no evidence for loss of antigenicity with time-to-fixation for ER, PgR, HER2, or Ki67 in a 4-hour time window. However, with a bootstrapping analysis, we observed a trend toward loss for ER and PgR, a statistically significant loss of antigenicity for phosphorylated tyrosine (P = .0048), and trends toward loss for other proteins. There was evidence of increased antigenicity in acetylated lysine, AKAP13 (P = .009), and HIF1A (P = .046), which are proteins known to be expressed in conditions of hypoxia. The loss of antigenicity for phosphorylated tyrosine and increase in expression of AKAP13, and HIF1A were confirmed in the biopsy/resection series.
CONCLUSIONS: Key breast cancer biomarkers show no evidence of loss of antigenicity, although this dataset assesses the relatively short time beyond the 1-hour limit in recent guidelines. Other proteins show changes in antigenicity in both directions. Future studies that extend the time range and normalize for heterogeneity will provide more comprehensive information on preanalytic variation due to cold ischemic time.

Di Lorito A, Rosini S, Falò E, et al.
Molecular alterations in endometrial archived liquid-based cytology.
Diagn Cytopathol. 2013; 41(6):492-6 [PubMed] Related Publications
Endometrial cancer is one of the most common gynecological malignancy worldwide and its prevalence is increasing. The introduction of liquid-based cytology (LBC) and endoflower dispositive in routine practice gives the possibility to examine endometrial cells by cytological diagnosis and may also release the opportunity to study molecular alterations, in endometrioid type cancer in which carcinogenesis is well known. We gathered 72 cases of endometrial LBC samples and corresponding formalin-fixed paraffin-embedded (FFPE) blocks, collected from 2004 to 2010. DNA was isolated from both samples using standard protocols. DNA quality and quantity were assessed using Nanodrop and BIOMED2 multiplex PCR. Mutations in exon 5 of PTEN and exon 20 of PI3K were studied using Sanger sequencing. DNA with good quality and amount was isolated from 67/72 FFPE cases. In these samples, two cases were found to harbor mutations in exon 5 of PTEN. No PI3K mutations were identified. LBC samples were then assessed to verify the concordance with the FFPE DNA results. The results obtained were concordant, that is the wild type cases in FFPE were also wild type in LBC and vice versa for the mutated case. Unfortunately, the second case of mutation in PTEN could not be confirmed in LBC due to low amount of DNA obtained. Detection of molecular alterations in LBC will open a new era for the detection in asymptomatic women of precursor lesions that could evolve into cancer and for endometrial cancer diagnosis and screening in selected high-risk women.

Cao C, Chen Y, Masood R, et al.
α-Catulin marks the invasion front of squamous cell carcinoma and is important for tumor cell metastasis.
Mol Cancer Res. 2012; 10(7):892-903 [PubMed] Free Access to Full Article Related Publications
Squamous cell carcinomas (SCC) comprise the most common types of human epithelial cancers. One subtype, head and neck squamous cell carcinoma (HNSCC), is a particularly aggressive cancer with poor prognosis due to late diagnosis and lymph node metastasis. Of all the processes involved in carcinogenesis, local invasion and distant metastasis are clinically the most relevant, but are the least well understood on a molecular level. Here, we find that in vivo, the α-catenin homologue-α-catulin, a protein originally reported to interact with Lbc Rho guanine nucleotide exchange factor, is highly expressed at the tumor invasion front and in the metastatic streams of cells in both malignant hHNSCCs and a mouse model of oral SCC. Knockdown of α-catulin in hHNSCC cell lines dramatically decrease the migratory and invasive potential of those cells in vitro and metastatic potential in xenotransplants in vivo. Analysis of tumors deficient in α-catulin showed that the tumor cells are unable to invade the surrounding stroma. Accordingly, transcriptional profiling of those tumors revealed that α-catulin ablation is accompanied by changes in genes involved in cell migration and invasion. Interestingly enough, in vitro experiments show that an upregulation of α-catulin expression correlates with the transition of tumor cells from an epithelial to a mesenchymal morphology, as well as an upregulation of epithelial-to-mesenchymal transition (EMT) markers vimentin and snail. Overall, these results strongly indicate that α-catulin contributes to the invasive behavior of metastatic cells and may be used as a prognostic marker and future therapeutic target for patients with cancer.

González F, Nair KS, Daniels JK, et al.
Hyperandrogenism sensitizes leukocytes to hyperglycemia to promote oxidative stress in lean reproductive-age women.
J Clin Endocrinol Metab. 2012; 97(8):2836-43 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Hyperandrogenism and oxidative stress are related in polycystic ovary syndrome (PCOS), but it is unknown whether hyperandrogenemia can activate oxidative stress.
OBJECTIVE: The purpose of this study was to determine the effect of oral androgen administration on fasting and glucose-stimulated leukocytic reactive oxygen species (ROS) generation, reduced nicotinamide adenine dinucleotide phosphate oxidase p47(phox) subunit gene expression, and plasma thiobarbituric acid-reactive substances (TBARS) in lean healthy reproductive-age women.
PARTICIPANTS, DESIGN, AND SETTING: Sixteen lean healthy ovulatory reproductive-age women were treated with 130 mg dehydroepiandrosterone (DHEA) or placebo (n = 8 each) for 5 d in this randomized, controlled, double-blind study that was performed at an an academic medical center.
MAIN OUTCOME MEASURES: Leukocytic ROS generation, p47(phox) gene expression, and plasma TBARS were quantified in the fasting state and 2 h after glucose ingestion, before and after treatment.
RESULTS: Before treatment, subjects receiving DHEA or placebo exhibited no differences in androgens or any prooxidant markers while fasting and after glucose ingestion. Compared with placebo, DHEA administration raised levels of testosterone, androstenedione, and DHEA-sulfate, increased the percent change in glucose-challenged p47(phox) RNA content, and increased the percent change in fasting and glucose-challenged ROS generation from mononuclear cells and polymorphonuclear cells, p47(phox) protein content, and plasma TBARS.
CONCLUSION: Elevation of circulating androgens comparable to what is present in PCOS increases leukocytic ROS generation, p47(phox) gene expression, and plasma TBARS to promote oxidative stress in lean healthy reproductive-age women. Thus, hyperandrogenemia activates and sensitizes leukocytes to glucose in this population.

Palka Bayard de Volo C, Alfonsi M, Gatta V, et al.
16q22.1 microdeletion detected by array-CGH in a family with mental retardation and lobular breast cancer.
Gene. 2012; 498(2):328-31 [PubMed] Related Publications
We describe the case of a boy with psychomotor delay and dysmorphic features, with a germline 16q22.1 microdeletion identified by array-CGH. The deletion spans 0.24Mb and encompasses three genes (ZFP90, CDH3 and CDH1). The deletion has been demonstrated to be inherited from his mother who was affected by lobular breast cancer (LBC) without any other apparently phenotypic features. We suppose that the microdeletion, in particular ZFP90 which is cerebrally expressed, is causative for the boy's phenotype. Mental retardation in the affected boy can recognize several mechanisms such as variable expressivity, non-penetrance, multifactorial/polygenic inheritance, recessive inheritance, a second rearrangement event and epigenetics. Furthermore, we suggest that the deletion of the CDH1, a tumor suppressor gene, involved in hereditary diffuse gastric cancer (HDGC) and LBC predisposed the mother to the carcinoma.

Fehér LZ, Pocsay G, Krenács L, et al.
Amplification of thymosin beta 10 and AKAP13 genes in metastatic and aggressive papillary thyroid carcinomas.
Pathol Oncol Res. 2012; 18(2):449-58 [PubMed] Related Publications
Papillary thyroid carcinoma (PTC) is the most common well-differentiated thyroid cancer. Although the great majority of the cases exhibit an indolent clinical course, some of them develop local invasion with distant metastasis, and a few cases transform into undifferentiated/anaplastic thyroid carcinoma with a rapidly lethal course. To identify gene copy number alterations predictive of metastatic potential or aggressive transformation, array-based comparative genomic hybridization (CGH-array) was performed in 43 PTC cases. Formalin-fixed and paraffin-embedded samples from primary tumours of 16 cases without metastasis, 14 cases with only regional lymph node metastasis, and 13 cases with distant metastasis, recurrence or extrathyroid extension were analysed. The CGH-array and confirmatory quantitative real-time PCR results identified the deletion of the EIF4EBP3 and TRAK2 gene loci, while amplification of thymosin beta 10 (TB10) and Tre-2 oncogene regions were observed as general markers for PTC. Although there have been several studies implicating TB10 as a specific marker based on gene expression data, our study is the first to report on genomic amplification. Although no significant difference could be detected between the good and bad prognosis cases in the A-kinase anchor protein 13 (AKAP13) gene region, it was discriminative markers for metastasis. Amplification in the AKAP13 region was demonstrated in 42.9% and 15.4% of the cases with local or with distant metastasis, respectively, while no amplification was detected in non-metastatic cases. AKAP13 and TB10 regions may represent potential new genomic markers for PTC and cancer progression.

Malapelle U, de Rosa N, Rocco D, et al.
EGFR and KRAS mutations detection on lung cancer liquid-based cytology: a pilot study.
J Clin Pathol. 2012; 65(1):87-91 [PubMed] Related Publications
In advanced non-small-cell lung carcinomas epidermal growth factor receptor (EGFR) and KRAS testing is often performed on cytology. Liquid-based cytology (LBC), which eliminates the need for slide preparation by clinicians, may be very useful. In 42 LBC DNA was extracted twice. One sample was obtained directly from CytoLyt solution, whereas the other DNA sample was derived after smear preparation and laser capture microdissection (LCM) of Papanicolaou-stained cells. EGFR and KRAS mutational analyses were performed by direct sequencing. On CytoLyt-derived DNA four EGFR (9%) and five KRAS (12%) gene mutations were found. When direct sequencing was performed after LCM, the rate of cases that displayed either EGFR or KRAS mutations increased from 21% to 40%. Although time-consuming, LCM makes direct sequencing highly sensitive even on LBC preparations containing only a few cells.

Wang X, Son YO, Chang Q, et al.
NADPH oxidase activation is required in reactive oxygen species generation and cell transformation induced by hexavalent chromium.
Toxicol Sci. 2011; 123(2):399-410 [PubMed] Free Access to Full Article Related Publications
Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Although overproduction of reactive oxygen species (ROS) has been suggested to play a major role in its carcinogenicity, the mechanisms of Cr(VI)-induced ROS production remain unclear. In this study, we investigated the role of NADPH oxidase (NOX), one of the major sources of cellular ROS, in Cr(VI)-induced oxidative stress and carcinogenesis. We found that short-term exposure to Cr(VI) (2μM) resulted in a rapid increase in ROS generation in Beas-2B cells, and concomitantly increased NOX activity and expression of NOX members (NOX1-3 and NOX5) and subunits (p22(phox), p47(phox), p40(phox), and p67(phox)). Cr(VI) also induced phosphorylation of p47(phox) and membrane translocation of p47(phox) and p67(phox), further confirming NOX activation. Knockdown of p47(phox) with a short hairpin RNA attenuated the ROS production induced by Cr(VI). Chronic exposure (up to 3 months) to low doses of Cr(VI) (0.125, 0.25, and 0.5μM) also promoted ROS generation and the expression of NOX subunits, such as p47(phox) and p67(phox), but inhibited the expression of main antioxidant enzymes, such as superoxidase dismutase (SOD) and glutathione peroxidase (GPx). Chronic Cr(VI) exposure resulted in transformation of Beas-2B cells, increasing cell proliferation, anchorage independent growth in soft agar, and forming aggressive tumors in nude mice. Stable knockdown of p47(phox) or overexpression of SOD1, SOD2, or catalase (CAT) eliminated Cr(VI)-induced malignant transformation. Our results suggest that NOX plays an important role in Cr(VI)-induced ROS generation and carcinogenesis.

Liu Z, Wu X, Duan Y, et al.
AID expression is correlated with Bcr-Abl expression in CML-LBC and can be down-regulated by As2O3 and/or imatinib.
Leuk Res. 2011; 35(10):1355-9 [PubMed] Related Publications
Activation-induced deaminase (AID), a cytidine deaminase, can accelerate the acquisition of BCR-ABL1 kinase domain mutations in human CML. In the present study, we investigated the expression of AID and Bcr-Abl in CML cells derived from 35 clinical patients. We found that both AID and Bcr-Abl were correlatively over-expressed in CML-LBC (lymphoid blast crisis) cells as compared with those in CML-CP (chronic phase) cells. AID expression was significantly decreased in CML-LBC cells after treated with arsenic trioxide, especially together with imatinib. We also observed satisfied therapy effects of As(2)O(3) and imatinib on patients with CML blast crisis. These data suggest that decreasing AID expression in CML-LBC by As(2)O(3) may be a promising approach to CML treatment.

Xiang L, Yang H, Li J, et al.
Different amplification patterns of the human telomerase RNA gene in invasive cervical carcinomas and cervical intraepithelial neoplasia grade III.
Diagn Cytopathol. 2012; 40(10):849-55 [PubMed] Related Publications
The aim of this study was to compare the amplification patterns of the human telomerase RNA gene (hTERC) in invasive cervical carcinomas (ICC) and cervical intraepithelial neoplasia grade III (CIN III) and to define their potential clinical implications. Cervical liquid-based cytological (LBC) specimens were collected from 53 squamous cell carcinomas (SCC), 14 CIN III, and 20 normal controls. Copy numbers of the hTERC gene were measured by fluorescence in situ hybridization (FISH) using a dual-color probe containing the hTERC probe and the control, chromosome 3 centromere-specific probe (CSP3). Nucleus with abnormal FISH pattern for hTERC was observed in 0.94-90.65% of SCC cells and in 0-85.59% of CIN III cells. Using the threshold of 5.89%, the occurrence of hTERC amplification in SCC and CIN III was similar (90.6% vs. 85.7%, P = 0.630). However, the median percentage of cells with extra gains of hTERC (hTERC:CSP3 > 1) in SCC was higher than in CIN III (64.3% vs. 31.7%, P = 0.001). Among those cells, the 3:2 signal pattern was the leading pattern for both SCC and CIN III; high-level amplification of hTERC was more common in SCC than in CIN III (60.9% vs. 48.9%, P = 0.002). In SCC, it was not found that extra gains of hTERC were associated with any clinicopathological parameters. Thus, hTERC amplification was common in cervical exfoliated cells from SCC and CIN III. More complex amplification patterns of hTERC were present in ICC. Clinical usefulness of hTERC amplification in LBC samples was limited in ICC.

Rossi ED, Larghi A, Verna EC, et al.
Endoscopic ultrasound-guided fine-needle aspiration with liquid-based cytologic preparation in the diagnosis of primary pancreatic lymphoma.
Pancreas. 2010; 39(8):1299-302 [PubMed] Related Publications
OBJECTIVES: The diagnosis subtyping of lymphoma on specimens collected by endoscopic ultrasound fine-needle aspiration (EUS-FNA) can be extremely difficult. When a cytopathologist is available for the on-site evaluation, the diagnosis may be achieved by applying flow cytometric techniques. We describe our experience with immunocytochemistry (ICC) and molecular biology studies applied on EUS-FNA specimens processed with a liquid-based cytologic (LBC) preparation for the diagnosis of primary pancreatic lymphoma (PPL).
METHODS: Three patients with a pancreatic mass underwent EUS-FNA. The collected specimens were processed with the ThinPrep method for the cytologic diagnosis and eventual additional investigations.
RESULTS: A morphologic picture consistent with PPL was found on the LBC specimens of the 3 patients. Subsequent ICC and molecular biology studies for immunoglobulin heavy chain gene rearrangement established the diagnosis of pancreatic large B-cell non-Hodgkin lymphoma in 2 patients and a non-Hodgkin lymphoma with plasmoblastic/immunoblastic differentiation in the remaining one.
CONCLUSIONS: An LBC preparation can be used to diagnose and subtype PPL by applying ICC and molecular biology techniques to specimens collected with EUS-FNA. This method can be an additional processing method for EUS-FNA specimens in centers where on-site cytopathologist expertise is not available.

Kumagai A, Motoi T, Tsuji K, et al.
Detection of SYT and EWS gene rearrangements by dual-color break-apart CISH in liquid-based cytology samples of synovial sarcoma and Ewing sarcoma/primitive neuroectodermal tumor.
Am J Clin Pathol. 2010; 134(2):323-31 [PubMed] Related Publications
To improve cytologic diagnostic accuracy for translocation-associated sarcomas, we explored dual-color break-apart (dc) chromogenic in situ hybridization (CISH) on liquid-based cytology (LBC) samples of 2 prototypic sarcomas: synovial sarcoma (SS) and Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET). LBC samples of 10 cases of SS and 9 cases of ES/PNET were subjected to dc-CISH using probes for the specifically rearranged genes in each tumor entity: SYT in SS and EWS in ES/PNET. Rearranged SYT was successfully detected in all SSs but not in any ES/PNETs. In contrast, EWS rearrangement was identified in all ES/PNETs but not in any SSs. These results were validated by dc-fluorescence in situ hybridization and reverse transcription-polymerase chain reaction. dc-CISH on LBC samples is a reliable modality to detect gene rearrangements in sarcomas. This system has a clear advantage over other methods, enabling simultaneous visualization of the genetic abnormality and well-preserved, nonoverlapping cytomorphologic features with clear background under bright-field microscope.

Guo G, Qiu X, Wang S, et al.
Oncogenic E17K mutation in the pleckstrin homology domain of AKT1 promotes v-Abl-mediated pre-B-cell transformation and survival of Pim-deficient cells.
Oncogene. 2010; 29(26):3845-53 [PubMed] Related Publications
Abl-mediated transformation requires the activation of multiple pathways involved in the cellular proliferation and survival, including PI3K/AKT and JAK/STAT-dependent Pim kinases. Recently, the E17K mutation in the AKT1 has been associated with multiple human malignancies and leukemia in mice. However, this mutation has not been identified in Abl-transformed cells. We investigated the presence of the AKT1(E17K) mutation in v-Abl-transformed cell clones. AKT1(E17K) was detected in 3 (2.6%) of 116 specimens examined. To show the involvement of AKT1(E17K) directly in v-Abl-mediated tumorigenesis, we infected bone marrow cells from mice with bicistronic retroviruses encoding v-Abl and either wild-type or the mutant AKT1. Interestingly, we found that E17K mutant greatly increased the v-Abl transformation efficiency as compared with wild-type AKT1. Ectopic expression of E17K mutant increased the expression levels of antiapoptotic protein BCL2 and phosphorylation levels of proapoptotic protein BAD. This correlated with an increased protection from imatinib-induced apoptosis in Abl transformants. Furthermore, AKT1(E17K) promotes survival of the Pim-deficient cells, indicating a functional link between AKT and Pim in v-Abl transformation. In addition, AKT1(E17K) delays loss of Pim-1 and Pim-2 protein levels on v-Abl inactivation, which suggests that there exists reciprocal signaling between AKT and Pim in v-Abl transformants.

Kikuchi H, Kuribayashi F, Kiwaki N, Nakayama T
Curcumin dramatically enhances retinoic acid-induced superoxide generating activity via accumulation of p47-phox and p67-phox proteins in U937 cells.
Biochem Biophys Res Commun. 2010; 395(1):61-5 [PubMed] Related Publications
The membrane bound cytochrome b558 composed of large gp91-phox and small p22-phox subunits, and cytosolic proteins p40-, p47- and p67-phox are important components of superoxide (O(2)(-))-generating system in phagocytes and B lymphocytes. A lack of this system in phagocytes is known to cause serious life-threatening infections. Here, we describe that curcumin, a polyphenol responsible for the yellow color of curry spice turmeric, dramatically activates the O(2)(-)-generating system during retinoic acid (RA)-induced differentiation of human monoblastic leukemia U937 cells to macrophage-like cells. When U937 cells were cultured in the presence of RA and curcumin, the O(2)(-)-generating activity increased more than 4-fold compared with that in the absence of the latter. Semiquantitative RT-PCR showed that co-treatment with RA and curcumin slightly enhanced gene expressions of the five components compared with those of the RA-treatment only. On the other hand, immunoblot analysis revealed that co-treatment with RA and curcumin caused remarkable accumulation of protein levels of p47-phox (to 7-fold) and p67-phox (to 4-fold) compared with those of the RA-treatment alone. These results suggested that curcumin dramatically enhances RA-induced O(2)(-)-generating activity via accumulation of cytosolic p47-phox and p67-phox proteins in U937 cells. Therefore, it should have the potential as an effective modifier in therapy of leukemia and/or as an immunopotentiator.

Rolland D, Ribrag V, Haioun C, et al.
Phase II trial and prediction of response of single agent tipifarnib in patients with relapsed/refractory mantle cell lymphoma: a Groupe d'Etude des Lymphomes de l'Adulte trial.
Cancer Chemother Pharmacol. 2010; 65(4):781-90 [PubMed] Related Publications
PURPOSE: Farnesyltransferase (Ftase) was identified by gene-expression profiling and by preclinical evaluation in in vitro and in vivo mantle cell lymphoma (MCL) models as a rational therapeutic target in MCL, one of the most refractory B-cell lymphomas. We conducted a multicenter phase II study of a potent Ftase inhibitor, tipifarnib, in patients with relapsed or refractory MCL.
METHODS: Tipifarnib was administered at 300 mg orally twice daily for the first 21 days of each 28-day cycle for 4 cycles, and in case of response for 6 cycles. Study endpoints were objective response at 4 and 6 cycles, progression free survival (PFS), overall survival, and toxicity. Prediction of response was retrospectively evaluated in the initial tumor biopsy by the RASGRP1/APTX gene expression ratio, and the AKAP13 expression level.
RESULTS: Eleven patients (median age, 71 years) were enrolled. Patients received a median number of three prior therapies (range 1-11). Nine patients completed at least 3 cycles of tipifarnib. No grade III-IV hematological toxicities were recorded. One patient presented a complete response (CR) after 4 and a persistent CR at 6 cycles (ORR = 9%). Median PFS was 3 months (range 0.7-14.2). The RASGRP1/APTX gene expression ratio was higher in the responder (n = 1) while the AKAP13 expression was higher in the non-responders (n = 2). This corresponds to the expected result for predicting response to tipifarnib.
CONCLUSION: Treatment with tipifarnib relapsed or refractory MCL is associated with low response rates. Limited gene expression studies suggest that response may be associated with molecular targets.

Boulet GA, Horvath CA, Depuydt CE, Bogers JJ
Biomarkers in cervical screening: quantitative reverse transcriptase PCR analysis of P16INK4a expression.
Eur J Cancer Prev. 2010; 19(1):35-41 [PubMed] Related Publications
Molecular insights into the human papillomavirus (HPV)-induced cervical carcinogenesis led to the discovery of biomarkers for cervical disease. The detection of cellular proteins that are overexpressed by HPV-infected cells, such as tumor suppressor protein p16(INK4a), might play an important role in future cervical cancer screening strategies. P16(INK4a) immunostaining correlates with the severity of cytological and histological abnormalities, but shows some methodological shortcomings such as the lack of standardized methodology and interobserver variability. This study evaluated quantitative reverse transcriptase PCR (RT-PCR) as an alternative tool to analyze p16(INK4a) overexpression as a biomarker for transforming HPV-infections in a liquid-based cervical cytology (LBC) setting. Sixty LBC samples, divided in three groups based on their cytological diagnosis, were subjected to HPV typing and analysis of p16 expression by immunocytochemistry and RT-PCR. The analytical sensitivity of the RT-PCR was determined by spiking HeLa and HaCaT cells. P16(INK4a) expression measured by RT-PCR did not correlate with the cytological diagnosis or HPV status (HPV-positivity, infection type and HPV16-positivity). The spiking experiment proved that, to detect increased biomarker expression by RT-PCR, about 1.0% dysplastic cells is required within a pool of normal keratinocytes. In conclusion, RT-PCR analysis of biomarker expression is not appropriate for cervical screening purposes. In typical LBC samples, the biomarker transcripts of the dysplastic cells are diluted by the RNA of the normal cells in such a manner that their overexpression cannot be detected by RT-PCR.

Andersson S, Sowjanya P, Wangsa D, et al.
Detection of genomic amplification of the human telomerase gene TERC, a potential marker for triage of women with HPV-positive, abnormal Pap smears.
Am J Pathol. 2009; 175(5):1831-47 [PubMed] Free Access to Full Article Related Publications
The vast majority of invasive cervical carcinomas harbor additional copies of the chromosome arm 3q, resulting in genomic amplification of the human telomerase gene TERC. Here, we evaluated TERC amplification in routinely collected liquid based cytology (LBC) samples with histologically confirmed diagnoses. A set of 78 LBC samples from a Swedish patient cohort were analyzed with a four-color fluorescence in situ hybridization probe panel that included TERC. Clinical follow-up included additional histological evaluation and Pap smears. Human papillomavirus status was available for all cases. The correlation of cytology, TERC amplification, human papillomavirus typing, and histological diagnosis showed that infection with high-risk human papillomavirus was detected in 64% of the LBC samples with normal histopathology, in 65% of the cervical intraepithelial neoplasia (CIN)1, 95% of the CIN2, 96% of the CIN3 lesions, and all carcinomas. Seven percent of the lesions with normal histopathology were positive for TERC amplification, 24% of the CIN1, 64% of the CIN2, 91% of the CIN3 lesions, and 100% of invasive carcinomas. This demonstrates that detection of genomic amplification of TERC in LBC samples can identify patients with histopathologically confirmed CIN3 or cancer. Indeed, the proportion of TERC-positive cases increases with the severity of dysplasia. Among the markers tested, detection of TERC amplification in cytological samples has the highest combined sensitivity and specificity for discernment of low-grade from high-grade dysplasia and cancer.

Cohen Y, Shalmon B, Korach J, et al.
AKT1 pleckstrin homology domain E17K activating mutation in endometrial carcinoma.
Gynecol Oncol. 2010; 116(1):88-91 [PubMed] Related Publications
OBJECTIVES: The PI3K/AKT pathway is frequently activated in endometrial carcinoma (EC) mainly due to mutations in the PIK3CA and PTEN genes. These events are common and believed to be the key to endometrial carcinogenesis. Recently, a somatic activating mutation in the AKT1 gene (E17K) was identified in several cancer types. In this study we explored the frequency of this AKT1 mutation in endometrial carcinoma.
METHODS: Tumor DNA, extracted from 73 EC was analyzed for AKT1 E17K mutation (G49A) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). In addition, the tumors were screened for coexisting common mutations in PTEN, PIK3CA and KRAS.
RESULTS: The AKT1 E17K mutation was detected in 4% of EC. One of the AKT1-mutated tumors showed coexisting PTEN loss-of-function mutation.
CONCLUSION: We identified the AKT1 E17K mutation in 4% of endometrial carcinomas. The presence of double AKT1/ PTEN mutants is in accord with the hypothesis that in EC more than one hit is required to completely activate the PI3K pathway. Furthermore, AKT1 mutations were limited to high grade, advanced stage tumors suggesting that this mutation confers a more aggressive tumor behavior.

Hu JK, Wang L, Li Y, et al.
The mRNA and protein expression of A-kinase anchor proteins 13 in human colorectal cancer.
Clin Exp Med. 2010; 10(1):41-9 [PubMed] Related Publications
There was no literature reporting the relationship between AKAP13 and colorectal carcinoma. This study is aim to investigate the expression and role of AKAP13 in human colorectal cancers. This study investigated 94 pair-matched human colorectal cancers and adjacent normal mucosa, as well as 36 adenomas, of which mRNA expression of AKAP13 was detected by relative Quantitative-Real-Time RT-PCR and protein expression by immunohistochemical staining. AKAP13 gene was upregulated in colorectal cancer group by 2.259 times compared to control group without significant difference (P = 0.081), and no expression was detected in adenoma by RT-PCR. The positive expression rate of AKAP13 protein in colorectal carcinoma (52.3%) was significantly higher than those in adenoma (9.1%) and normal tissue (34.7%) (P = 0.006) by immunohistochemical staining. Either the mRNA or protein expressions of AKAP13 were correlated with histological types and differentiation grade (P < 0.05). Our results suggest AKAP13 protein may be related to the carcinogenesis of human colorectal cancer. However, more deeply and larger scale research are required to prove the correlation.

Klemm L, Duy C, Iacobucci I, et al.
The B cell mutator AID promotes B lymphoid blast crisis and drug resistance in chronic myeloid leukemia.
Cancer Cell. 2009; 16(3):232-45 [PubMed] Free Access to Full Article Related Publications
Chronic myeloid leukemia (CML) is induced by BCR-ABL1 and can be effectively treated for many years with Imatinib until leukemia cells acquire drug resistance through BCR-ABL1 mutations and progress into fatal B lymphoid blast crisis (LBC). Despite its clinical significance, the mechanism of progression into LBC is unknown. Here, we show that LBC but not CML cells express the B cell-specific mutator enzyme AID. We demonstrate that AID expression in CML cells promotes overall genetic instability by hypermutation of tumor suppressor and DNA repair genes. Importantly, our data uncover a causative role of AID activity in the acquisition of BCR-ABL1 mutations leading to Imatinib resistance, thus providing a rationale for the rapid development of drug resistance and blast crisis progression.

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