PCM1

Gene Summary

Gene:PCM1; pericentriolar material 1
Aliases: PTC4, RET/PCM-1
Location:8p22
Summary:The protein encoded by this gene is a component of centriolar satellites, which are electron dense granules scattered around centrosomes. Inhibition studies show that this protein is essential for the correct localization of several centrosomal proteins, and for anchoring microtubules to the centrosome. Chromosomal aberrations involving this gene are associated with papillary thyroid carcinomas and a variety of hematological malignancies, including atypical chronic myeloid leukemia and T-cell lymphoma. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:pericentriolar material 1 protein
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: PCM1 (cancer-related)

Choi YY, Lee SY, Lee WK, et al.
RACK1 is a candidate gene associated with the prognosis of patients with early stage non-small cell lung cancer.
Oncotarget. 2015; 6(6):4451-66 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This study was conducted to identify genetic polymorphisms associated with the prognosis of patients with early stage NSCLC.
MATERIALS AND METHODS: We genotyped 1,969 potentially functional single nucleotide polymorphisms (SNPs) of 1,151 genes involved in carcinogenesis in 166 NSCLC patients who underwent curative surgery, using the Affymetrix custom-made GeneChip. A replication study was performed in an independent cohort of 626 patients.
RESULTS: Fifty six SNPs which were associated with both overall survival (OS) and disease-free survival (DFS) with log-rank P values < 0.05 in discovery set were selected for validation. Among those, five SNPs (RACK1 rs1279736C>A and rs3756585T>G, C3 rs2287845T>C, PCAF rs17006625A>G, and PCM1 rs17691523C>G) were found to be significantly associated with survival in the same direction as the discovery set. In combined analysis, the rs1279736C>A and rs3756585T>G were most significantly associated with OS and DFS in multivariate analysis (P for OS = 4 × 10⁻⁵ and 7 × 10⁻⁵, respectively; and P for DFS = 0.003, both; under codominant model). In vitro promoter assay and electrophoretic mobility shift assay revealed that the rs3756585 T-to-G change increased promoter activity and transcription factor binding of RACK1.
CONCLUSIONS: We identified five SNPs, especially RACK1 rs3756585T>G, as markers for prognosis of patients with surgically resected NSCLC.

Sandgren J, Holm S, Marino AM, et al.
Whole Exome- and mRNA-Sequencing of an AT/RT Case Reveals Few Somatic Mutations and Several Deregulated Signalling Pathways in the Context of SMARCB1 Deficiency.
Biomed Res Int. 2015; 2015:862039 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: AT/RTs are rare aggressive brain tumours, mainly affecting young children. Most cases present with genetic inactivation of SMARCB1, a core member of the SWI/SNF chromatin-remodeling complex. We have performed whole exome- and mRNA-sequencing on an early onset AT/RT case for detection of genetic events potentially contributing to the disease.
RESULTS: A de novo germline variant in SMARCB1, c.601C>T p.Arg201∗, in combination with somatic deletion of the healthy allele is likely the major tumour causing event. Only seven somatic small scale mutations were discovered (hitting SEPT03, H2BFM, ZIC4, HIST2H2AB, ZIK1, KRTAP6-3, and IFNA8). All were found with subclonal allele frequencies (range 5.7-17%) and none were expressed. However, besides SMARCB1, candidate genes affected by predicted damaging germline variants that were expressed were detected (KDM5C, NUMA1, and PCM1). Analysis of differently expressed genes revealed many dysregulated pathways in the tumour, such as cell cycle, CXCR4 pathway, GPCR-signalling, and neuronal system. FGFR1, CXCR4, and MDK were upregulated and may represent possible drug targets.
CONCLUSION: The loss of SMARCB1 function leads to AT/RT development and deregulated genes and pathways. Additional predisposing events may however contribute. Studies utilizing NGS technologies in larger cohorts will probably identify recurrent genetic and epigenetic alterations and molecular subgroups with implications for clinical practice and development of targeted therapies.

Schwaab J, Knut M, Haferlach C, et al.
Limited duration of complete remission on ruxolitinib in myeloid neoplasms with PCM1-JAK2 and BCR-JAK2 fusion genes.
Ann Hematol. 2015; 94(2):233-8 [PubMed] Related Publications
Rearrangements of chromosome band 9p24 are known to be associated with JAK2 fusion genes, e.g., t(8;9)(p22;p24) with a PCM1-JAK2 and t(9;22)(p24;q11) with a BCR-JAK2 fusion gene, respectively. In association with myeloid neoplasms, the clinical course is aggressive, and in absence of effective conventional treatment options, long-term remission is usually only observed after allogeneic stem cell transplantation (ASCT). With the discovery of inhibitors of the JAK2 tyrosine kinase and based on encouraging in vitro and in vivo data, we treated two male patients with myeloid neoplasms and a PCM1-JAK2 or a BCR-JAK2 fusion gene, respectively, with the JAK1/JAK2 inhibitor ruxolitinib. After 12 months of treatment, both patients achieved a complete clinical, hematologic, and cytogenetic response. Non-hematologic toxicity was only grade 1 while no hematologic toxicity was observed. However, remission in both patients was only short-term, with relapse occurring after 18 and 24 months, respectively, making ASCT indispensable in both cases. This data highlight (1) the ongoing importance of cytogenetic analysis for the diagnostic work-up of myeloid neoplasms as it may guide targeted therapy and (2) remission under ruxolitinib may only be short-termed in JAK2 fusion genes but it may be an important bridging therapy prior to ASCT.

Bain BJ, Ahmad S
Should myeloid and lymphoid neoplasms with PCM1-JAK2 and other rearrangements of JAK2 be recognized as specific entities?
Br J Haematol. 2014; 166(6):809-17 [PubMed] Related Publications
Since the publication of the 2001 and 2008 World Health Organization classifications of tumours of haematopoietic and lymphoid tissues, there has been an increasing move towards classification of haematological neoplasms on the basis of the underlying molecular genetic disorder. In recent decades there have been a significant number of reports of haematological neoplasms with rearrangement of JAK2. Published data on such cases have therefore been analysed to determine if any specific entities could be identified. On the basis of this analysis, it is suggested that lymphoid and myeloid neoplasms associated with t(8;9)(p22;p24); PCM1-JAK2 fusion should be recognized as an entity. Furthermore, lymphoid and myeloid neoplasms associated respectively with t(9;12)(p24;p13); ETV6-JAK2 and with t(9;22)(p24;q11·2); BCR-JAK2 should be documented carefully in order to define their features more clearly and assess whether they can be recognized as entities. Identification of all these conditions is important because of the possibility of response to JAK2 inhibitors.

Chen X, Paranjape T, Stahlhut C, et al.
Targeted resequencing of the microRNAome and 3'UTRome reveals functional germline DNA variants with altered prevalence in epithelial ovarian cancer.
Oncogene. 2015; 34(16):2125-37 [PubMed] Free Access to Full Article Related Publications
Ovarian cancer is a major cause of cancer deaths, yet there have been few known genetic risk factors identified, the best known of which are disruptions in protein coding sequences (BRCA1 and 2). Recent findings indicate that there are powerful genetic markers of cancer risk outside of these regions, in the noncoding mRNA control regions. To identify additional cancer-associated, functional non-protein-coding sequence germline variants associated with ovarian cancer risk, we captured DNA regions corresponding to all validated human microRNAs and the 3' untranslated regions (UTRs) of ~6000 cancer-associated genes from 31 ovarian cancer patients. Multiple single-nucleotide polymorphisms in the 3'UTR of the vascular endothelial growth factor receptor/FLT1, E2F2 and PCM1 oncogenes were highly enriched in ovarian cancer patients compared with the 1000 Genome Project. Sequenom validation in a case-control study (267 cases and 89 controls) confirmed a novel variant in the PCM1 3'UTR is significantly associated with ovarian cancer (P=0.0086). This work identifies a potential new ovarian cancer locus and further confirms that cancer resequencing efforts should not ignore the study of noncoding regions of cancer patients.

Hsu TI, Lin SC, Lu PS, et al.
MMP7-mediated cleavage of nucleolin at Asp255 induces MMP9 expression to promote tumor malignancy.
Oncogene. 2015; 34(7):826-37 [PubMed] Related Publications
Nucleolin (NCL) participates in DNA transcription, ribosomal biogenesis and the regulation of RNA stability. However, the contribution of NCL to tumor development is still not clear. Herein, we found that NCL expression correlated with poor prognosis in lung cancer patients. Overexpressed NCL was predominantly cleaved to C-terminal truncated NCL (TNCL). In lung cancer formation, activation of the epidermal growth factor receptor pathway induced NCL expression, and also the expression of matrix metalloproteinase (MMP) 7, which then cleaved NCL at Asp255 to generate TNCL of 55 kDa. TNCL increased the expression of several oncogenes, including MMP9, anaplastic lymphoma kinase (ALK), HIF1a and CBLB, and decreased the expression of tumor suppressors including BRD4, PCM1, TFG and KLF6 by modulating mRNA stability through binding to the 3'-untranslated regions of their transcripts, thus ultimately enhancing metastasis activity. In conclusion, this study identified a novel role of the cleavage form of NCL generated by MMP7 in stabilizing MMP9 mRNA. We also provide a new insight that MMP7 not only cleaves the extracellular matrix to promote tumor invasion but also cleaves NCL, which augment oncogenesis. Blocking NCL cleavage may provide a useful new strategy for lung cancer therapy.

Hopman S, Merks J, Eussen H, et al.
Structural genome variations in individuals with childhood cancer and tumour predisposition syndromes.
Eur J Cancer. 2013; 49(9):2170-8 [PubMed] Related Publications
BACKGROUND: Previous studies have shown a high prevalence of syndromes in children with cancer. We described four patterns of co-occurring morphological abnormalities indicating new tumour predisposition syndromes. These patterns were named after their key-abnormalities: blepharophimosis (BP), epicanthal folds (EF), asymmetric lower limbs (LLA) and Sydney creases (SC) pattern. The purpose of our study was to identify structural genomic variants possibly involved in these tumour predisposition syndromes.
PATIENTS AND METHODS: In 49 probands (13 from BP, nine from EF, 20 from LLA and seven from SC patterns respectively) karyotyping was performed. Copy number variation (CNV) in genomic DNA of the probands was analysed to detect microdeletions/-duplications using SNP array. FISH and quantitative-polymerase chain reaction (q-PCR) experiments were done to validate events identified by cytogenetic and CNV analysis.
RESULTS: Cytogenetic analysis showed an inherited inversion of chromosome 15, inv(15) (q25q26) in a proband with LLA-pattern. Evaluation of the genes at the breakpoints made it unlikely that these explained the phenotype and tumour in this patient. Eleven CNV events met our inclusion criteria; three inherited CNV events involved an oncogene. A duplication involving BCL9 was identified in a proband diagnosed with Burkitt lymphoma. A duplication involving PCM1 was identified in a proband diagnosed with pre-B-ALL. Both probands showed the EF-pattern of morphological abnormalities. A deletion involving TRA@ was identified in two probands from the BP-pattern diagnosed with rhabdomyosarcoma and pre-B-ALL respectively.
CONCLUSIONS: We report on structural genomic variants in paediatric cancer patients with newly recognised tumour predisposition syndromes. We identify three CNV events which we suggest to be susceptibility loci.

Patterer V, Schnittger S, Kern W, et al.
Hematologic malignancies with PCM1-JAK2 gene fusion share characteristics with myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1.
Ann Hematol. 2013; 92(6):759-69 [PubMed] Related Publications
The translocation t(8;9)(p22;p24) is a rare event that results in the fusion of JAK2 to PCM1 and thus leads to the activation of the Janus Kinase 2. In 2008, the WHO introduced a new entity called "Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1", which are characterized by the formation of a fusion gene encoding an aberrant tyrosine kinase. These disorders share characteristics with myeloproliferative neoplasms and typically show an eosinophilia. We here now report on 6 new cases with PCM1-JAK2 fusion. These patients show characteristics with respect to epidemiology, clinical presentation, and genetic changes that are very similar to patients with rearrangements of PDGFRA, PDGFRB, or FGFR1. Our data suggests the integration of cases with JAK2-PCM1 fusion in the respective WHO category of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1.

Ehrentraut S, Nagel S, Scherr ME, et al.
t(8;9)(p22;p24)/PCM1-JAK2 activates SOCS2 and SOCS3 via STAT5.
PLoS One. 2013; 8(1):e53767 [PubMed] Free Access to Full Article Related Publications
Fusions of the tyrosine kinase domain of JAK2 with multiple partners occur in leukemia/lymphoma where they reportedly promote JAK2-oligomerization and autonomous signalling, Affected entities are promising candidates for therapy with JAK2 signalling inhibitors. While JAK2-translocations occur in myeloid, B-cell and T-cell lymphoid neoplasms, our findings suggest their incidence among the last group is low. Here we describe the genomic, transcriptional and signalling characteristics of PCM1-JAK2 formed by t(8;9)(p22;p24) in a trio of cell lines established at indolent (MAC-1) and aggressive (MAC-2A/2B) phases of a cutaneous T-cell lymphoma (CTCL). To investigate signalling, PCM1-JAK2 was subjected to lentiviral knockdown which inhibited 7 top upregulated genes in t(8;9) cells, notably SOCS2/3. SOCS3, but not SOCS2, was also upregulated in a chronic eosinophilic leukemia bearing PCM1-JAK2, highlighting its role as a central signalling target of JAK2 translocation neoplasia. Conversely, expression of GATA3, a key T-cell developmental gene silenced in aggressive lymphoma cells, was partially restored by PCM1-JAK2 knockdown. Treatment with a selective JAK2 inhibitor (TG101348) to which MAC-1/2A/2B cells were conspicuously sensitive confirmed knockdown results and highlighted JAK2 as the active moiety. PCM1-JAK2 signalling required pSTAT5, supporting a general paradigm of STAT5 activation by JAK2 alterations in lymphoid malignancies. MAC-1/2A/2B--the first JAK2-translocation leukemia/lymphoma cell lines described--display conspicuous JAK/STAT signalling accompanied by T-cell developmental and autoimmune disease gene expression signatures, confirming their fitness as CTCL disease models. Our data support further investigation of SOCS2/3 as signalling effectors, prognostic indicators and potential therapeutic targets in cancers with JAK2 rearrangements.

Solyom S, Ewing AD, Rahrmann EP, et al.
Extensive somatic L1 retrotransposition in colorectal tumors.
Genome Res. 2012; 22(12):2328-38 [PubMed] Free Access to Full Article Related Publications
L1 retrotransposons comprise 17% of the human genome and are its only autonomous mobile elements. Although L1-induced insertional mutagenesis causes Mendelian disease, their mutagenic load in cancer has been elusive. Using L1-targeted resequencing of 16 colorectal tumor and matched normal DNAs, we found that certain cancers were excessively mutagenized by human-specific L1s, while no verifiable insertions were present in normal tissues. We confirmed de novo L1 insertions in malignancy by both validating and sequencing 69/107 tumor-specific insertions and retrieving both 5' and 3' junctions for 35. In contrast to germline polymorphic L1s, all insertions were severely 5' truncated. Validated insertion numbers varied from up to 17 in some tumors to none in three others, and correlated with the age of the patients. Numerous genes with a role in tumorigenesis were targeted, including ODZ3, ROBO2, PTPRM, PCM1, and CDH11. Thus, somatic retrotransposition may play an etiologic role in colorectal cancer.

Hoeller S, Walz C, Reiter A, et al.
PCM1-JAK2-fusion: a potential treatment target in myelodysplastic-myeloproliferative and other hemato-lymphoid neoplasms.
Expert Opin Ther Targets. 2011; 15(1):53-62 [PubMed] Related Publications
IMPORTANCE OF THE FIELD: Activating mutations of the JAK2 gene are of tumorigenic significance in myeloproliferative neoplasms. Translocations involving the JAK2 locus are of oncogenic importance in acute leukemias, myelodysplastic/myeloproliferative diseases and T-cell lymphomas. JAK2 locus gains, which are recurrent in Hodgkin's- and primary mediastinal B-cell lymphoma, are also efficient mechanisms of JAK2 activation. Recently, specific drugs blocking JAK2 have been developed and are currently in clinical trials.
AREAS COVERED IN THIS REVIEW: We discuss possible mechanisms of deregulation and the significance of pericentriolar material 1 (PCM)1-JAK2 fusion/t(8;9)(p21-23;p23-24) in hematolymphoid neoplasms. Such cases show morphological (myeloproliferaton, eosinophilia, myelofibrosis) and clinical (striking male predominance, aggressive course) similarities. Since increased JAK2 oligomerization and tyrosine kinase domain activation is the probable oncogenic mechanism in this instance, such patients are promising candidates for JAK2 inhibitor therapy.
WHAT THE READER WILL GAIN: The reader will gain important insights considering PCM1-JAK2 fusion in hematologic malignancies.
TAKE HOME MESSAGE: JAK2 is a tyrosine kinase with oncogenic potential in hematologic malignancies. It can be activated by point mutations, translocations and amplifications. Beyond malignancies associated with JAK2 point mutations, those associated with translocations might be suitable for tyrosine kinase inhibitors, which merits prospective evaluation.

Tabarés-Seisdedos R, Rubenstein JL
Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer.
Mol Psychiatry. 2009; 14(6):563-89 [PubMed] Related Publications
Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson's and Alzheimer's disease) and cancer. Furthermore, at least seven nonprotein-coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence.

Huang KP, Chase AJ, Cross NC, et al.
Evolutional change of karyotype with t(8;9)(p22;p24) and HLA-DR immunophenotype in relapsed acute myeloid leukemia.
Int J Hematol. 2008; 88(2):197-201 [PubMed] Related Publications
The rare recurrent translocation of (8;9)(p22;p24) with PCM1-JAK2 fusion was recently characterized in diverse hematological malignancies. Most of them are atypical chronic myeloid leukemia (CML) or other myeloproliferative disorders (MPD), and are predominantly in the male. We report a female patient with acute myeloid leukemia (AML) initially presenting with normal karyotype and negative HLA-DR expression who achieved complete remission after standard chemotherapy. The disease relapsed 7 months later with cytogenetic change of t(8;9)(p22;p24). Flow cytometry analysis showed evolutional change of immunophenotype from negative to positive HLA-DR expression and fluorescence in situ hybridization (FISH) analysis demonstrated a PCM1-JAK2 fusion gene. We speculate that the cytogenetic change of t(8;9)(p22;p24) may induce HLA-DR immunophenotypic switch and a coordination of the two evolutional changes may play a role in leukemic cell progression.

Walz C, Cross NC, Van Etten RA, Reiter A
Comparison of mutated ABL1 and JAK2 as oncogenes and drug targets in myeloproliferative disorders.
Leukemia. 2008; 22(7):1320-34 [PubMed] Free Access to Full Article Related Publications
Constitutively activated mutants of the non-receptor tyrosine kinases (TK) ABL1 (Abelson murine leukemia viral (v-abl) homolog (1) protein) and JAK2 (JAnus Kinase 2 or Just Another Kinase 2) play a central role in the pathogenesis of clinically and morphologically distinct chronic myeloproliferative disorders but are also found in some cases of de novo acute leukemia and lymphoma. Ligand-independent activation occurs as a consequence of point mutations or insertions/deletions within functionally relevant regulatory domains (JAK2) or the creation of TK fusion proteins by balanced reciprocal translocations, insertions or episomal amplification (ABL1 and JAK2). Specific abnormalities are correlated with clinical phenotype, although some are broad and encompass several World Health Organization-defined entities. TKs are excellent drug targets as exemplified by the activity of imatinib in BCR-ABL1-positive disease, particularly chronic myeloid leukemia. Resistance to imatinib is seen in a minority of cases and is often associated with the appearance of secondary point mutations within the TK domain of BCR-ABL1. These mutations are highly variable in their sensitivity to increased doses of imatinib or alternative TK inhibitors such as nilotinib or dasatinib. Selective and non-selective inhibitors of JAK2 are currently being developed, and encouraging data from pre-clinical experiments and initial phase-I studies regarding efficacy and potential toxicity of these compounds have already been reported.

Pils D, Horak P, Gleiss A, et al.
Five genes from chromosomal band 8p22 are significantly down-regulated in ovarian carcinoma: N33 and EFA6R have a potential impact on overall survival.
Cancer. 2005; 104(11):2417-29 [PubMed] Related Publications
BACKGROUND: Loss of heterozygosity on chromosomal band 8p22 is a common event in several epithelial tumors including ovarian carcinoma. So far, no clear evidence for a tumor suppressor gene (TSG) in this region has been found.
METHODS: On the basis of publicly available expression data in ovarian tissues, the authors selected the eight most noteworthy genes from 8p22 (DLC1, N33, ZDHHC2, FLJ32642, PDGFRL, MTSG1, PCM1, and EFA6R) for a detailed expression analysis in 58 primary ovarian carcinoma tissues and in 38 ovarian cancer cell lines by using quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR). Expression data were correlated to various clinicopathologic characteristics and survival.
RESULTS: Two genes showed a significantly (P< 0.05) lower expression in grade 3 tumors compared with tumors of lower grade (N33) or compared with normal controls and tumors with lower grade (EFA6R). Expression of N33 and EFA6R seems to have an impact on survival, in particular when the combined expression of both genes was used as predictive factor (P< 0.003). In addition, N33 and EFA6R showed a complete loss of expression in several ovarian cancer cell lines. Three genes (FLJ32642, MTSG1, and PCM1) had a significantly (P< 0.001, P< 0.004, and P< 0.001) lower expression in primary ovarian carcinoma compared with controls (ovarian tissues and cysts).
CONCLUSIONS: Two to five new potential tumor suppressor or antagonizing gene candidates (N33 and EFA6R with impact on survival, and potentially FLJ32642, MTSG1, and PCM1) for ovarian carcinoma, were identified from the chromosomal band 8p22 and are promising candidates for further functional analysis in ovarian carcinoma.

Bousquet M, Quelen C, De Mas V, et al.
The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene.
Oncogene. 2005; 24(48):7248-52 [PubMed] Related Publications
Several tyrosine kinase genes are involved in chromosomal translocations in chronic myeloproliferative disorders, but there are still uncharacterized translocations in some cases. We report two such cases corresponding to atypical chronic myeloid leukaemia with a t(8;9)(p22;p24) translocation. By fluorescence in situ hybridisation (FISH) on the corresponding metaphases with a bacterial artificial chromosome probe encompassing the janus kinase 2 (JAK2) gene at 9p24, we observed a split for both patients, suggesting that this gene was rearranged. The locus at 8p22 contains different candidate genes including the pericentriolar material 1 gene (PCM1), already implicated in reciprocal translocations. The rearrangement of the PCM1 gene was demonstrated by FISH, for both patients. By RT-PCR, we confirmed the fusion of 3' part of JAK2 with the 5' part of PCM1. Sequence analysis of the chimeric PCM1-JAK2 mRNA suggests that the putative protein displays the coiled-coil domains of PCM1 and the tyrosine kinase domain of JAK2. This new translocation identifies JAK2 as a possible therapeutic target for compounds with anti-tyrosine kinase activity.

Venter DJ, Ramus SJ, Hammet FM, et al.
Complex CGH alterations on chromosome arm 8p at candidate tumor suppressor gene loci in breast cancer cell lines.
Cancer Genet Cytogenet. 2005; 160(2):134-40 [PubMed] Related Publications
Loss of genetic material from chromosome arm 8p occurs frequently in human breast carcinomas, consistent with this region of the genome harboring one or more tumor suppressor genes (TSGs). We used the complementary techniques of microsatellite-based LOH, high-density FISH, and conventional CGH on 6 breast cancer cell lines (MCF7, SKBR3, T47D, MDA MB453, BT549, and BT474) to investigate the molecular cytogenetic changes occurring on chromosome 8 during tumorigenesis, with particular emphasis on 6 potential TSGs on 8p. We identified multiple alterations of chromosome 8, including partial or complete deletion of 8p or 8q, duplication of 8q, and isochromosome 8q. The detailed FISH analysis showed several complex rearrangements of 8p with differing breakpoints of varying proximity to the genes of interest. High rates of LOH were observed at markers adjacent to or within PCM1, DUSP4/MKP2, NKX3A, and DLC1, supporting their status as candidate TSGs. Due to the complex ploidy status of these cell lines, relative loss of 8p material detected by CGH did not always correlate with microsatellite-based LOH results. These results extend our understanding of the mechanisms accompanying the dysregulation of candidate tumor suppressor loci on chromosome arm 8p, and identify appropriate cellular systems for further investigation of their biological properties.

Reiter A, Walz C, Watmore A, et al.
The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2.
Cancer Res. 2005; 65(7):2662-7 [PubMed] Related Publications
We have identified a t(8;9)(p21-23;p23-24) in seven male patients (mean age 50, range 32-74) with diverse hematologic malignancies and clinical outcomes: atypical chronic myeloid leukemia/chronic eosinophilic leukemia (n = 5), secondary acute myeloid leukemia (n = 1), and pre-B-cell acute lymphoblastic leukemia (n = 1). Initial fluorescence in situ hybridization studies of one patient indicated that the nonreceptor tyrosine kinase Janus-activated kinase 2 (JAK2) at 9p24 was disrupted. Rapid amplification of cDNA ends-PCR identified the 8p22 partner gene as human autoantigen pericentriolar material (PCM1), a gene encoding a large centrosomal protein with multiple coiled-coil domains. Reverse transcription-PCR and fluorescence in situ hybridization confirmed the fusion in this case and also identified PCM1-JAK2 in the six other t(8;9) patients. The breakpoints were variable in both genes, but in all cases the chimeric mRNA is predicted to encode a protein that retains several of the predicted coiled-coil domains from PCM1 and the entire tyrosine kinase domain of JAK2. Reciprocal JAK2-PCM1 mRNA was not detected in any patient. We conclude that human autoantigen pericentriolar material (PCM1)-JAK2 is a novel, recurrent fusion gene in hematologic malignancies. Patients with PCM1-JAK2 disease are attractive candidates for targeted signal transduction therapy.

Armes JE, Hammet F, de Silva M, et al.
Candidate tumor-suppressor genes on chromosome arm 8p in early-onset and high-grade breast cancers.
Oncogene. 2004; 23(33):5697-702 [PubMed] Related Publications
Loss of genetic material from chromosome arm 8p occurs commonly in breast carcinomas, suggesting that this region is the site of one or more tumor-suppressor genes (TSGs). Comparative genomic hybridization analysis showed that 8p loss is more common in breast cancers from pre-menopausal compared with post-menopausal patients, as well as in high-grade breast cancers, regardless of the menopausal status. Subsequent high-resolution gene expression profiling of genes mapped to chromosome arm 8p, on an extended cohort of clinical tumor samples, indicated a similar dichotomy of breast cancer clinicopathologic types. Some of these genes showed differential downregulation in early-onset and later-onset, high-grade cancers compared with lower-grade, later-onset cancers. Three such genes were analysed further by in situ technologies, performed on tissue microarrays representing breast tumor and normal tissue samples. PCM1, which encodes a centrosomal protein, and DUSP4/MKP-2, which encodes a MAP kinase phosphatase, both showed frequent gene and protein loss in carcinomas. In contrast, there was an excess of cases showing loss of expression in the absence of reduced gene copy number of SFRP1, which encodes a dominant-negative receptor for Wnt-family ligands. These candidate TSGs may constitute some of the molecular drivers of chromosome arm 8p loss in breast carcinogenesis.

Dammermann A, Merdes A
Assembly of centrosomal proteins and microtubule organization depends on PCM-1.
J Cell Biol. 2002; 159(2):255-66 [PubMed] Free Access to Full Article Related Publications
The protein PCM-1 localizes to cytoplasmic granules known as "centriolar satellites" that are partly enriched around the centrosome. We inhibited PCM-1 function using a variety of approaches: microinjection of antibodies into cultured cells, overexpression of a PCM-1 deletion mutant, and specific depletion of PCM-1 by siRNA. All approaches led to reduced targeting of centrin, pericentrin, and ninein to the centrosome. Similar effects were seen upon inhibition of dynactin by dynamitin, and after prolonged treatment of cells with the microtubule inhibitor nocodazole. Inhibition or depletion of PCM-1 function further disrupted the radial organization of microtubules without affecting microtubule nucleation. Loss of microtubule organization was also observed after centrin or ninein depletion. Our data suggest that PCM-1-containing centriolar satellites are involved in the microtubule- and dynactin-dependent recruitment of proteins to the centrosome, of which centrin and ninein are required for interphase microtubule organization.

Nikiforova MN, Caudill CM, Biddinger P, Nikiforov YE
Prevalence of RET/PTC rearrangements in Hashimoto's thyroiditis and papillary thyroid carcinomas.
Int J Surg Pathol. 2002; 10(1):15-22 [PubMed] Related Publications
The relationship between Hashimoto's thyroiditis (HT) and follicular cell-derived thyroid cancer remains unclear. Recently, 2 studies reported a 95% prevalence of RET/PTC rearrangements in histologically benign tissue affected by HT, suggesting that multiple occult tumors exist in HT patients with high frequency. We tested the prevalence of RET/PTC rearrangements in 26 HT, in 6 papillary carcinomas arising in the background of HT, and in 27 papillary carcinomas not associated with HT. We detected no RET/PTC rearrangements in HT or papillary carcinomas arising in the background of HT, in contrast to a 33% prevalence among papillary carcinomas not associated with HT. However, the expression of wild-type RET was found in more than half of papillary carcinomas. These results suggest that, if the association between HT and thyroid cancer exists, its molecular basis is different from RET/PTC rearrangement.

Corvi R, Berger N, Balczon R, Romeo G
RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma.
Oncogene. 2000; 19(37):4236-42 [PubMed] Related Publications
The RET proto-oncogene is often activated through somatic rearrangements in papillary thyroid carcinomas (PTCs). Three main rearranged forms of RET have been described: RET/PTC1 and RET/PTC3, which arise from a paracentric inversion and RET/PTC2, which originates from a 10 : 17 translocation. We previously developed a dual-color FISH test to detect these RET rearrangements in interphase nuclei of thyroid lesions. This approach allowed us to detect a novel translocation involving the RET region, which was not detectable by RT - PCR with specific primers for known rearrangements. A combination of RT - PCR and RACE analyses finally led to the identification of the fusion gene, which involves the 5' portion of PCM-1, a gene coding for a centrosomal protein with distinct cell cycle distribution, and the RET tyrosine kinase (TK) domain. FISH analysis confirmed the chromosomal localization of PCM-1 on chromosome 8p21-22, a region commonly deleted in several tumors. Immunohistochemistry, using an antibody specific for the C-terminal portion of PCM-1 showed that the protein level is drastically decreased and its subcellular localization is altered in thyroid tumor tissue with respect to normal thyroid. However, heterozygosity is retained for seven microsatellite markers in the 8p21-22 region, suggesting that the non-rearranged PCM-1 allele is not lost and that the translocation is balanced. Oncogene (2000) 19, 4236 - 4242

Fugazzola L, Pierotti MA, Vigano E, et al.
Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer.
Oncogene. 1996; 13(5):1093-7 [PubMed] Related Publications
A post-Chernobyl papillary thyroid cancer, displaying a novel ELE1/RET oncogenic rearrangement with an anomalous fusion transcript, was molecularly characterized. In spite of the presence of a normal breakpoint in exon 5 of the activating ELE1 gene, the sequence of the rearranged genomic DNA showed a previously unreported intra-exonic breakpoint in the RET protooncogene. As a consequence, a cDNA sequence 93 nucleotides larger than the regular one, and with the exon 5 of ELE1 joined to exon 11 instead of exon 12 of RET, is formed. To characterize the product of this new oncogenic ELE1/RET rearrangement, here designated as RET/PTC4, we performed an immunoprecipitation and Western blot analysis on cell extracts from NIH3T3 transfectants. The results showed the presence of two isoforms of the chimeric protein, displaying a constitutive tyrosine phosphorylation. As expected, the molecular weight of this protein was higher than that of RET/ PTC3 protein (p80 and p85, instead of p76 and p81). Previous reports, from our and other laboratories, showed that post-Chernobyl papillary thyroid carcinomas are characterized by a high frequency (about 60%) of RET oncogenic rearrangements (Fugazzola et al., 1995; Klugbauer et al., 1995; Ito et al., 1994). These events predominantly involve ELE1 activating sequence, thus producing RET/PTC3 oncogene (Fugazzola et al., 1995; Klugbauer et al., 1995). Hence, this elevated frequency of RET rearrangements could increase the probability of selecting unusual events as that here described. Alternatively, targeted radiation effects could be responsible for the atypical RET rearrangement producing RET/PTC4 oncogene.

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