LPP

Gene Summary

Gene:LPP; LIM domain containing preferred translocation partner in lipoma
Location:3q28
Summary:This gene encodes a member of a subfamily of LIM domain proteins that are characterized by an N-terminal proline-rich region and three C-terminal LIM domains. The encoded protein localizes to the cell periphery in focal adhesions and may be involved in cell-cell adhesion and cell motility. This protein also shuttles through the nucleus and may function as a transcriptional co-activator. This gene is located at the junction of certain disease-related chromosomal translocations, which result in the expression of chimeric proteins that may promote tumor growth. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:lipoma-preferred partner
HPRD
Source:NCBIAccessed: 17 August, 2015

Ontology:

What does this gene/protein do?
Show (8)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 17 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.

  • HMGA Proteins
  • RNA Splice Sites
  • Genome-Wide Association Study
  • DNA-Binding Proteins
  • Hamartoma
  • Parapsoriasis
  • Base Sequence
  • Molecular Sequence Data
  • Skin Cancer
  • Chromosome 12
  • Tumor Markers
  • Transcription
  • Mycosis Fungoides
  • Translocation
  • Messenger RNA
  • Gene Fusion
  • Skin
  • Single Nucleotide Polymorphism
  • RNA
  • Chromosome Mapping
  • Lipoma
  • Genetic Predisposition
  • RTPCR
  • Karyotyping
  • Gene Rearrangement
  • Promoter Regions
  • Polymerase Chain Reaction
  • Chromosome Aberrations
  • Cancer Gene Expression Regulation
  • HMGA2
  • Proteins
  • Oncogene Fusion Proteins
  • LPP
  • High Mobility Group Proteins
  • LIM Domain Proteins
  • Receptors, CXCR
  • Cytoskeletal Proteins
  • Lung Cancer
  • Chromosome 3
  • FISH
Tag cloud generated 17 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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: LPP (cancer-related)

Severson PL, Vrba L, Stampfer MR, Futscher BW
Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells.
Mutat Res Genet Toxicol Environ Mutagen. 2014; 775-776:48-54 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Genetic mutations are known to drive cancer progression and certain tumors have mutation signatures that reflect exposures to environmental carcinogens. Benzo[a]pyrene (BaP) has a known mutation signature and has proven capable of inducing changes to DNA sequence that drives normal pre-stasis human mammary epithelial cells (HMEC) past a first tumor suppressor barrier (stasis) and toward immortality. We analyzed normal, pre-stasis HMEC, three independent BaP-derived post-stasis HMEC strains (184Aa, 184Be, 184Ce) and two of their immortal derivatives(184A1 and 184BE1) by whole exome sequencing. The independent post-stasis strains exhibited between 93 and 233 BaP-induced mutations in exons. Seventy percent of the mutations were C:G>A:T transversions, consistent with the known mutation spectrum of BaP. Mutations predicted to impact protein function occurred in several known and putative cancer drivers including p16, PLCG1, MED12, TAF1 in 184Aa; PIK3CG, HSP90AB1, WHSC1L1, LCP1 in 184Be and FANCA, LPP in 184Ce. Biological processes that typically harbor cancer driver mutations such as cell cycle, regulation of cell death and proliferation, RNA processing, chromatin modification and DNA repair were found to have mutations predicted to impact function in each of the post-stasis strains. Spontaneously immortalized HMEC lines derived from two of the BaP-derived post-stasis strains shared greater than 95% of their BaP-induced mutations with their precursor cells. These immortal HMEC had 10 or fewer additional point mutations relative to their post-stasis precursors, but acquired chromosomal anomalies during immortalization that arose independent of BaP. The results of this study indicate that acute exposures of HMEC to high dose BaP recapitulate mutation patterns of human tumors and can induce mutations in a number of cancer driver genes.

Skibola CF, Berndt SI, Vijai J, et al.
Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region.
Am J Hum Genet. 2014; 95(4):462-71 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

Girardot M, Pecquet C, Chachoua I, et al.
Persistent STAT5 activation in myeloid neoplasms recruits p53 into gene regulation.
Oncogene. 2015; 34(10):1323-32 [PubMed] Related Publications
STAT (Signal Transducer and Activator of Transcription) transcription factors are constitutively activated in most hematopoietic cancers. We previously identified a target gene, LPP/miR-28 (LIM domain containing preferred translocation partner in lipoma), induced by constitutive activation of STAT5, but not by transient cytokine-activated STAT5. miR-28 exerts negative effects on thrombopoietin receptor signaling and platelet formation. Here, we demonstrate that, in transformed hematopoietic cells, STAT5 and p53 must be synergistically bound to chromatin for induction of LPP/miR-28 transcription. Genome-wide association studies show that both STAT5 and p53 are co-localized on the chromatin at 463 genomic positions in proximal promoters. Chromatin binding of p53 is dependent on persistent STAT5 activation at these proximal promoters. The transcriptional activity of selected promoters bound by STAT5 and p53 was significantly changed upon STAT5 or p53 inhibition. Abnormal expression of several STAT5-p53 target genes (LEP, ATP5J, GTF2A2, VEGFC, NPY1R and NPY5R) is frequently detected in platelets of myeloproliferative neoplasm (MPN) patients, but not in platelets from healthy controls. In conclusion, persistently active STAT5 can recruit normal p53, like in the case of MPN cells, but also p53 mutants, such as p53 M133K in human erythroleukemia cells, leading to pathologic gene expression that differs from canonical STAT5 or p53 transcriptional programs.

Bidkhori G, Narimani Z, Hosseini Ashtiani S, et al.
Reconstruction of an integrated genome-scale co-expression network reveals key modules involved in lung adenocarcinoma.
PLoS One. 2013; 8(7):e67552 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Our goal of this study was to reconstruct a "genome-scale co-expression network" and find important modules in lung adenocarcinoma so that we could identify the genes involved in lung adenocarcinoma. We integrated gene mutation, GWAS, CGH, array-CGH and SNP array data in order to identify important genes and loci in genome-scale. Afterwards, on the basis of the identified genes a co-expression network was reconstructed from the co-expression data. The reconstructed network was named "genome-scale co-expression network". As the next step, 23 key modules were disclosed through clustering. In this study a number of genes have been identified for the first time to be implicated in lung adenocarcinoma by analyzing the modules. The genes EGFR, PIK3CA, TAF15, XIAP, VAPB, Appl1, Rab5a, ARF4, CLPTM1L, SP4, ZNF124, LPP, FOXP1, SOX18, MSX2, NFE2L2, SMARCC1, TRA2B, CBX3, PRPF6, ATP6V1C1, MYBBP1A, MACF1, GRM2, TBXA2R, PRKAR2A, PTK2, PGF and MYO10 are among the genes that belong to modules 1 and 22. All these genes, being implicated in at least one of the phenomena, namely cell survival, proliferation and metastasis, have an over-expression pattern similar to that of EGFR. In few modules, the genes such as CCNA2 (Cyclin A2), CCNB2 (Cyclin B2), CDK1, CDK5, CDC27, CDCA5, CDCA8, ASPM, BUB1, KIF15, KIF2C, NEK2, NUSAP1, PRC1, SMC4, SYCE2, TFDP1, CDC42 and ARHGEF9 are present that play a crucial role in cell cycle progression. In addition to the mentioned genes, there are some other genes (i.e. DLGAP5, BIRC5, PSMD2, Src, TTK, SENP2, PSMD2, DOK2, FUS and etc.) in the modules.

Ngan E, Northey JJ, Brown CM, et al.
A complex containing LPP and α-actinin mediates TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells.
J Cell Sci. 2013; 126(Pt 9):1981-91 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Transforming growth factor β (TGFβ) is a potent modifier of the malignant phenotype in ErbB2-expressing breast cancers. We demonstrate that epithelial-derived breast cancer cells, which undergo a TGFβ-induced epithelial-to-mesenchymal transition (EMT), engage signaling molecules that normally facilitate cellular migration and invasion of mesenchymal cells. We identify lipoma preferred partner (LPP) as an indispensable regulator of TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells. We show that LPP re-localizes to focal adhesion complexes upon TGFβ stimulation and is a critical determinant in TGFβ-mediated focal adhesion turnover. Finally, we have determined that the interaction between LPP and α-actinin, an actin cross-linking protein, is necessary for TGFβ-induced migration and invasion of ErbB2-expressing breast cancer cells. Thus, our data reveal that LPP, which is normally operative in cells of mesenchymal origin, can be co-opted by breast cancer cells during an EMT to promote their migration and invasion.

Strauss U, Bräuer AU
Current views on regulation and function of plasticity-related genes (PRGs/LPPRs) in the brain.
Biochim Biophys Acta. 2013; 1831(1):133-8 [PubMed] Related Publications
Plasticity-related genes (PRGs, Lipid phosphate phosphatase-related proteins LPPRs) are a defined as a subclass of the lipid phosphate phosphatase (LPP) superfamily, comprising so far five brain- and vertebrate-specific membrane-spanning proteins. LPPs interfere with lipid phosphate signaling and are thereby involved in mediating the extracellular concentration and signal transduction of lipid phosphate esters such as lysophosphatidate (LPA) and spingosine-1 phosphate (S1P). LPPs dephosphorylate their substrates through extracellular catalytic domains, thus making them ecto-phosphatases. PRGs/LPPRs are structurally similar to the other LPP family members in general. They are predominantly expressed in the CNS in a subtype specific pattern rather than having a wide tissue distribution. In contrast to LPPs, PRGs/LPPRs may act by modifying bioactive lipids and their signaling pathways, rather than possessing an ecto-phosphatase activity. However, the exact functional roles of PRGs/LPPRs have just begun to be explored. Here, we discuss new findings on the neuron-specific transcriptional regulation of PRG1/LPPR4 and new insights into protein-protein interaction and signaling pathway regulation. Further, we start to shed light on the subcellular localization and the resulting functional modulatory influence of PRG1/LPPR4 expression in excitatory synaptic transmission to the established neural effects such as promotion of filopodia formation, neurite extension, axonal sprouting and reorganization after lesion. This range of effects suggests an involvement in the pathogenesis and/or reparation attempts in disease. Therefore, we summarize available data on the association of PRGs/LPPRs with several neurological and other diseases in humans and experimental animals. Finally we highlight important open questions and emerging future directions of research. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

Yamamura M, Noguchi K, Nakano Y, et al.
Functional analysis of Zyxin in cell migration and invasive potential of oral squamous cell carcinoma cells.
Int J Oncol. 2013; 42(3):873-80 [PubMed] Related Publications
Zyxin is an evolutionarily conserved protein that has been implicated in the regulation of actin assembly and is mainly located at focal adhesions. However, the biological roles of Zyxin in cancer cells are incompletely understood. We analyzed the functions of Zyxin in cell migration and the invasive potential of OSCC. Zyxin expression was examined using eight OSCC cell lines with two different cell morphologies (6 epithelial type and 2 fibroblastic type). To knockdown Zyxin expression, OSCC cells were transfected with Zyxin siRNA and control siRNA. The cell lines were studied by western blot analysis, immunocytochemical analysis and cell migration and invasion assay. Epithelial type OSCC cells showed a high level of E-cadherin expression and a low level of Zyxin expression. N-cadherin as well as Zyxin were strongly expressed in fibroblastic type OSCC cells. Expression levels of LPP and TRIP6, members of the human Zyxin family, did not differ between epithelial type and fibroblastic type. Knockdown of Zyxin expression by siRNA in fibroblastic type OSCC cells was associated with cell morphological changes from spindle (fibroblastic) to polygonal (epithelial) shape and significantly inhibited cell growth as well as cell migration and invasion. Expression levels of Rac1 and Cdc42 were weaker in Zyxin siRNA-treated fibroblastic type OSCC cells than in control siRNA-treated cells, but the expression of RhoA did not differ significantly. Treatment of fibroblastic type OSCC cells with Rac1 inhibitor decreased the expression of Zyxin mRNA and protein. Zyxin is suggested to promote growth, migration and invasiveness of fibroblastic type OSCC cells by upregulating Rac1 and Cdc42.

Zhang B, Zhao H, Li T, et al.
Association study of gene LPP in women with polycystic ovary syndrome.
PLoS One. 2012; 7(10):e46370 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Previous genome-wide association study (GWAS) of polycystic ovary syndrome (PCOS) in Han Chinese population has found that SNPs in LPP gene were nominally significant in PCOS patients (P around 10E-05). Replication of the GWAS was applied to further confirm the relationship between LPP gene and PCOS.
METHODS: Three polymorphisms of LPP gene (rs715790, rs4449306, rs6782041) were selected and replicated in additional 1132 PCOS cases and 1142 controls. Genotyping of LPP gene was carried out by Taqman-MGB method.
RESULTS: In rs715790, the allele frequency is significantly different between the PCOS group and the control group. Meta-analysis showed that the allele frequencies of the three SNPs rs715790 (P(meta) =1.89E-05, OR=1.23), rs4449306 (P(meta) =3.0E-04, OR=1.10), rs6782041 (P(meta) = 2.0E-04, OR=1.09), were significantly different between PCOS cases and controls.
CONCLUSIONS: Our results suggest that LPP gene might be a novel candidate for PCOS.

Colas E, Muinelo-Romay L, Alonso-Alconada L, et al.
ETV5 cooperates with LPP as a sensor of extracellular signals and promotes EMT in endometrial carcinomas.
Oncogene. 2012; 31(45):4778-88 [PubMed] Related Publications
Endometrial carcinoma (EC) is the most frequent among infiltrating tumors of the female genital tract, with myometrial invasion representing an increase in the rate of recurrences and a decrease in survival. We have previously described ETV5 transcription factor associated with myometrial infiltration in human ECs. In this work, we further investigated ETV5 orchestrating downstream effects to confer the tumor the invasive capabilities needed to disseminate in the early stages of EC dissemination. Molecular profiling evidenced ETV5 having a direct role on epithelial-to-mesenchymal transition (EMT). In particular, ETV5 modulated Zeb1 expression and E-Cadherin repression leading to a complete reorganization of cell-cell and cell-substrate contacts. ETV5-promoted EMT resulted in the acquisition of migratory and invasive capabilities in endometrial cell lines. Furthermore, we identified the lipoma-preferred partner protein as a regulatory partner of ETV5, acting as a sensor for extracellular signals promoting tumor invasion. All together, we propose ETV5-transcriptional regulation of the EMT process through a crosstalk with the tumor surrounding microenvironment, as a principal event initiating EC invasion.

Amitay-Laish I, Sarid R, Ben-Amitai D, et al.
Human herpesvirus 8 is not detectable in lesions of large plaque parapsoriasis, and in early-stage sporadic, familial, and juvenile cases of mycosis fungoides.
J Am Acad Dermatol. 2012; 66(1):46-50 [PubMed] Related Publications
BACKGROUND: Human herpesvirus (HHV) 8, an essential etiologic agent of Kaposi sarcoma, is also associated with several lymphoproliferative disorders. The involvement of HHV 8 in mycosis fungoides (MF) and large plaque parapsoriasis (LPP) is controversial, with contradictory reports from various countries worldwide.
OBJECTIVE: We sought to investigate the presence of the HHV 8 genome in skin lesions of LPP and early-stage sporadic, familial, and juvenile MF in patients in Israel.
METHODS: Archival paraffin-embedded and frozen samples from skin biopsies of untreated patients with LPP and early-stage MF performed in 1990 through 2006 were randomly collected from the department of dermatology of a tertiary medical center in central Israel. DNA was extracted, and a TaqMan-based real-time polymerase chain reaction assay specific for the K6 gene region was used to detect the HHV 8 genome.
RESULTS: A total of 46 biopsies were sampled from 11 patients with LPP and 35 with early-stage MF (17 adults with sporadic MF, 10 children, and 8 patients with familial MF). In all, 44 samples were negative for HHV 8 DNA; two samples from adults with sporadic MF were positive.
LIMITATIONS: The presence of HHV 8 antibodies or virus sequences was not assessed in peripheral blood.
CONCLUSION: The results of this study, conducted in a region relatively endemic for HHV 8, support most earlier studies showing a lack of association of HHV 8 infection with LPP and sporadic adult-type MF. To our knowledge, the lack of association of HHV 8 infection with juvenile and familial MF has not been previously reported.

Jin Y, Birlea SA, Fain PR, et al.
Variant of TYR and autoimmunity susceptibility loci in generalized vitiligo.
N Engl J Med. 2010; 362(18):1686-97 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases.
METHODS: To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families.
RESULTS: We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05x10(-23)) and class II molecules (P=4.50x10(-34)), PTPN22 (P=1.31x10(-7)), LPP (P=1.01x10(-11)), IL2RA (P=2.78x10(-9)), UBASH3A (P=1.26x10(-9)), and C1QTNF6 (P=2.21x10(-16)). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase.
CONCLUSIONS: We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma.

Kubo T, Matsui Y, Naka N, et al.
Specificity of fusion genes in adipocytic tumors.
Anticancer Res. 2010; 30(2):661-4 [PubMed] Related Publications
BACKGROUND: In subsets of adipocytic tumors, specific chromosomal translocations lead to the generation of fusion genes. The high mobility group A2 (HMGA2)-lipoma preferred partner (LPP) and the reciprocal LPP-HMGA2 represent such fusion genes in lipoma, while the human translocation liposarcoma (TLS)-CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) and the Ewing sarcoma (EWS)-CHOP in liposarcoma. However, the specificity of these fusion genes has not been established in a variety of adipocytic tumors.
PATIENTS AND METHODS: One hundred and seventy-two cases of adipocytic tumors, comprising 98 cases of lipoma and 74 cases of liposarcoma, were analyzed for the possible expression of HMGA2-LPP, LPP-HMGA2, TLS-CHOP and EWS-CHOP fusion genes, using a reverse-transcription polymerase chain reaction method.
RESULTS: In lipoma, twenty-two cases (22.4%) were associated with either HMGA2-LPP or LPP-HMGA2, while neither TLS-CHOP nor EWS-CHOP transcript was detectable. On the contrary, in liposarcoma, neither HMGA2-LPP nor LPP-HMGA2 transcript was detectable, although twenty-five cases (33.8%) were related to either TLS-CHOP or EWS-CHOP.
CONCLUSION: HMGA2-LPP and LPP-HMGA2 were specific to lipoma, and TLS-CHOP and EWS-CHOP were specific to liposarcoma.

Wang X, Zamolyi RQ, Zhang H, et al.
Fusion of HMGA1 to the LPP/TPRG1 intergenic region in a lipoma identified by mapping paraffin-embedded tissues.
Cancer Genet Cytogenet. 2010; 196(1):64-7 [PubMed] Related Publications
Ordinary lipoma frequently harbors rearrangement of HMGA2. LPP is the most common partner gene to HMGA2, but has not been seen fused to HMGA1. We report the fusion of HMGA1 to the intergenic region between LPP and TPRG1 in a lipoma. Conventional cytogenetic analysis of an abdominal-wall lipoma diagnosed in a 60-year-old woman showed a t(3;6)(q27;p21). Molecular cytogenetic mapping of available paraffin-embedded tissues revealed the fusion of HMGA1 to a 139-kb genomic region between the LPP and TPRG1 loci. No rearrangement of HMGA2 was found. The biological function of this novel fusion could be similar to the role of HMGA2-LPP in tumorigenesis.

Pierron A, Fernandez C, Saada E, et al.
HMGA2-NFIB fusion in a pediatric intramuscular lipoma: a novel case of NFIB alteration in a large deep-seated adipocytic tumor.
Cancer Genet Cytogenet. 2009; 195(1):66-70 [PubMed] Related Publications
Lipomas are frequently characterized by aberrations of the 12q13 approximately q15 chromosomal region and often by rearrangements of the HMGA2 gene. These rearrangements include the formation of chimeric genes that fuse the 5' region of HMGA2 with a variety of partners, such as LPP (3q28) or NFIB (9p22). We describe here the fourth reported case of lipoma showing a HMGA2-NFIB fusion, and the first one in a child. We found a translocation t(9;12)(p22;q14) in a deep-seated intramuscular lipoma occurring in the buttock of a 5-year-old boy. By fluorescence in situ hybridization and reverse-transcription polymerase chain reaction, we have shown that the translocation t(9;12) resulted in an in-frame fusion of the first four exons of HMGA2 with the last exon of NFIB. Intramuscular lipomas are very rare in childhood. Our results confirm that lipomas containing NFIB rearrangements may be related to peculiar clinicohistologic features, including large size, deep situation, infiltration of surrounding muscles, or precocious occurrence. Both the truncation of HMGA2 and the nature of its fusion partner gene might be relevant in the adipose tissue tumorigenesis.

Kang JU, Koo SH, Kwon KC, et al.
Identification of novel candidate target genes, including EPHB3, MASP1 and SST at 3q26.2-q29 in squamous cell carcinoma of the lung.
BMC Cancer. 2009; 9:237 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
BACKGROUND: The underlying genetic alterations for squamous cell carcinoma (SCC) and adenocarcinoma (AC) carcinogenesis are largely unknown.
METHODS: High-resolution array- CGH was performed to identify the differences in the patterns of genomic imbalances between SCC and AC of non-small cell lung cancer (NSCLC).
RESULTS: On a genome-wide profile, SCCs showed higher frequency of gains than ACs (p = 0.067). More specifically, statistically significant differences were observed across the histologic subtypes for gains at 2q14.2, 3q26.2-q29, 12p13.2-p13.33, and 19p13.3, as well as losses at 3p26.2-p26.3, 16p13.11, and 17p11.2 in SCC, and gains at 7q22.1 and losses at 15q22.2-q25.2 occurred in AC (P < 0.05). The most striking difference between SCC and AC was gains at the 3q26.2-q29, occurring in 86% (19/22) of SCCs, but in only 21% (3/14) of ACs. Many significant genes at the 3q26.2-q29 regions previously linked to a specific histology, such as EVI1,MDS1, PIK3CA and TP73L, were observed in SCC (P < 0.05). In addition, we identified the following possible target genes (> 30% of patients) at 3q26.2-q29: LOC389174 (3q26.2),KCNMB3 (3q26.32),EPHB3 (3q27.1), MASP1 and SST (3q27.3), LPP and FGF12 (3q28), and OPA1,KIAA022,LOC220729, LOC440996,LOC440997, and LOC440998 (3q29), all of which were significantly targeted in SCC (P < 0.05). Among these same genes, high-level amplifications were detected for the gene, EPHB3, at 3q27.1, and MASP1 and SST, at 3q27.3 (18, 18, and 14%, respectively). Quantitative real time PCR demonstrated array CGH detected potential candidate genes that were over expressed in SCCs.
CONCLUSION: Using whole-genome array CGH, we have successfully identified significant differences and unique information of chromosomal signatures prevalent between the SCC and AC subtypes of NSCLC. The newly identified candidate target genes may prove to be highly attractive candidate molecular markers for the classification of NSCLC histologic subtypes, and could potentially contribute to the pathogenesis of the squamous cell carcinoma of the lung.

Kubo T, Matsui Y, Naka N, et al.
Expression of HMGA2-LPP and LPP-HMGA2 fusion genes in lipoma: identification of a novel type of LPP-HMGA2 transcript in four cases.
Anticancer Res. 2009; 29(6):2357-60 [PubMed] Related Publications
BACKGROUND: In a subset of lipoma, a specific t(3;12)(q27-28;q14-15) chromosomal translocation leads to the fusion of the high mobility group A2 (HMGA2) gene and the lipoma preferred partner (LPP) gene. Although the expression of HMGA2-LPP fusion gene has been reported in lipomas, the reciprocal LPP-HMGA2 fusion gene has rarely been described.
MATERIALS AND METHODS: Ninety-eight cases of lipoma were analyzed for the possible expression of HMGA2-LPP and LPP-HMGA2 fusion genes using a reverse-transcription polymerase chain reaction method.
RESULTS: Ten lipomas (10%) revealed both HMGA2-LPP and LPP-HMGA2 fusion transcripts, nine (9%) only HMGA2-LPP, and three (3%) only LPP-HMGA2. DNA sequencing analysis demonstrated that the HMGA2-LPP transcript in 19 lipomas consisted of exons 1-3 of HMGA2 and exons 9-11 of LPP, which was described previously. Out of 13 lipomas with LPP-HMGA2 transcript, 9 were associated with a previously reported LPP-HMGA2 fusion transcript, which fuses exon 8 of LPP to exon 4 of HMGA2, while 4 with a novel type of LPP-HMGA2 fusion transcript, which fuses exon 7 of LPP to exon 4 of HMGA2.
CONCLUSION: In addition to the HMGA2-LPP fusion gene, the LPP-HMGA2 fusion gene could have some specific roles for lipomagenesis. The biological implications of the expression and the variation of LPP-HMGA2 fusion transcripts need to be elucidated.

Jais JP, Haioun C, Molina TJ, et al.
The expression of 16 genes related to the cell of origin and immune response predicts survival in elderly patients with diffuse large B-cell lymphoma treated with CHOP and rituximab.
Leukemia. 2008; 22(10):1917-24 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
Gene expression profiles have been associated with clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated with anthracycline-containing chemotherapy. Using Affymetrix HU133A microarrays, we analyzed the lymphoma transcriptional profile of 30 patients treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and 23 patients treated with rituximab (R)-CHOP in the Groupe d'Etude des Lymphomes de l'Adulte clinical centers. We used this data set to select transcripts showing an association with progression-free survival in all patients or showing a differential effect in the two treatment groups. We performed real-time quantitative reverse transcription-PCR in the 23 R-CHOP samples of the screening set and an additional 44 R-CHOP samples set to evaluate the prognostic significance of these transcripts. In these 67 patients, the level of expression of 16 genes and the cell-of-origin classification were significantly associated with overall survival, independently of the International Prognostic Index. A multivariate model comprising four genes of the cell-of-origin signature (LMO2, MME, LPP and FOXP1) and two genes related to immune response, identified for their differential effects in R-CHOP patients (APOBEC3G and RAB33A), demonstrated a high predictive efficiency in this set of patients, suggesting that both features affect outcome in DLBCL patients receiving immunochemotherapy.

Ida CM, Wang X, Erickson-Johnson MR, et al.
Primary retroperitoneal lipoma: a soft tissue pathology heresy?: report of a case with classic histologic, cytogenetics, and molecular genetic features.
Am J Surg Pathol. 2008; 32(6):951-4 [PubMed] Related Publications
Adipose tissue tumors of the retroperitoneum showing no identifiable cytologic atypia are usually classified as lipomalike well-differentiated liposarcoma. Whether a subset of these tumors represents true examples of retroperitoneal lipoma remains a controversial subject, because the diagnostic liposarcoma cells may be of difficult identification, even after extensive sampling. Herein, we describe a large retroperitoneal lipoma with classic histopathologic, cytogenetic, molecular cytogenetic, and molecular genetic features. Extensive morphologic inspection showed no evidence of cytologic atypia. Cytogenetic analysis performed on fresh tissue material revealed the classic lipoma chromosome t(3;12)(q27;q14-15). Fluorescence in situ hybridization on multiple sections excluded the presence of MDM2 and CDK4 amplification, but showed HMGA2 balanced rearrangement in most cells. Reverse-transcriptase polymerase chain reaction followed by sequencing analysis confirmed the presence of the HMGA2-LPP fusion gene, a characteristic and the most common fusion product found in lipoma. The patient has been followed for 2.5 years without evidence of recurrence or metastasis. These results indicate that retroperitoneal lipomata do exist, but their diagnosis must rely on stringent histologic, cytogenetic, and molecular genetic analysis.

Hatano H, Morita T, Ogose A, et al.
Clinicopathological features of lipomas with gene fusions involving HMGA2.
Anticancer Res. 2008 Jan-Feb; 28(1B):535-8 [PubMed] Related Publications
BACKGROUND: Despite accumulating knowledge of chimeric genes derived from fusion of the HMGA2 gene with multiple partners in lipomas, the different clinicopathological features of lipomas depending on different gene aberrations have not been well documented. The purpose of this study was to examine the clinical significance of the expression of fusion genes in lipomas.
PATIENTS AND METHODS: The expressions of three previously reported gene fusion transcripts, including HMGA2/LPP, HMGA2/RDC1 and HMGA2/NFIB, were analyzed in 102 tumors from patients with lipomas.
RESULTS: There were 23 cases (22.5%) expressing HMGA2/LPP, 2 cases (1.9%) expressing HMGA2/RDC1 and no cases of HMGA2/NFIB expression (0%). There were no significant intergroup differences in age, gender, body mass index, tumor size or location. The magnetic resonance images and pathological features were also not different in regard to the status of fusion gene expression.
CONCLUSION: There were no significant differences of clinicopathological features in patients with lipoma with or without these fusion gene transcripts.

Kandolf Sekulović L, Cikota B, Stojadinović O, et al.
TCRgamma gene rearrangement analysis in skin samples and peripheral blood of mycosis fungoides patients.
Acta Dermatovenerol Alp Pannonica Adriat. 2007; 16(4):149-55 [PubMed] Related Publications
BACKGROUND: Diagnosing mycosis fungoides (MF) can be challenging in the early stage of the disease because histopathological features may simulate a variety of benign inflammatory skin diseases. Assessment of T-cell clonality was found to be useful in diagnosis and follow-up of patients.
OBJECTIVE: In this study, PCR-based TCRgamma gene rearrangement analysis was performed in skin and peripheral blood samples of patients with MF treated at the two largest referral centers in Serbia, and the results obtained were correlated with clinical and follow-up data.
METHODS: Skin and peripheral blood samples were obtained with informed consent from 37 patients treated at the Department of Dermatology of the Military Medical Academy and the Medical Center of Serbia from 2001 to 2006. The median time of follow-up was 4 years. Multiplex PCR was used for TCRgamma gene rearrangement analysis in skin and peripheral blood samples. Clonality results were correlated with the clinical data and disease course data.
RESULTS: Monoclonality was detected in skin samples of 30/37 patients (81%), in 2/5 patients with large-plaque parapsoriasis (LPP), in 28/32 (88%) patients with histologically proven MF, and in 1/16 (6%) patients with benign inflammatory dermatoses. A monoclonal pattern in both skin and peripheral blood was detected in 7/16 (44%) patients in the late stage of the disease, and in 1/7 (14%) patients in the early stage of the disease. A dominant clone was found in both skin and peripheral blood in 1/4 patients in remission, 2/5 with a stable disease, and 4/9 (44%) with disease progression.
CONCLUSION: TCR-gamma gene rearrangement analysis can be regarded as a useful adjunct to diagnosis of epidermotropic lymphoproliferative disorders. The presence of a dominant clone in both the skin and peripheral blood was more frequently detected in late stages and in patients with disease progression, confirming the usefulness of clonality detection by TCR-gamma gene rearrangement analysis in follow-up of patients with primary cutaneous T-cell lymphomas.

Plaza JA, Morrison C, Magro CM
Assessment of TCR-beta clonality in a diverse group of cutaneous T-Cell infiltrates.
J Cutan Pathol. 2008; 35(4):358-65 [PubMed] Related Publications
While some unequivocally benign infiltrates are easy to distinguish from cutaneous T-cell lymphoma (CTCL), drug-associated lymphomatoid hypersensitivity reaction and cutaneous lesions of collagen vascular disease can show cytologic atypia, clonality and an immunophenotypic profile that closely simulates CTCL and cause diagnostics difficulties. Similar immunophenotypic and molecular abnormalities to those of malignant lymphoma can also be observed in pityriasis lichenoides chronica (PLC), large plaque parapsoriasis (LPP), pigmented purpuric dermatosis (PPD) and atypical lymphocytic lobular panniculitis leading one to consider these entities as forms of cutaneous lymphoid dyscrasia. The purpose of our study was to evaluate the distinction of these various subcategories of cutaneous T-cell infiltrates by assessment of T-cell receptor (TCR)-beta gene rearrangement. Formalin-fixed paraffin-embedded skin biopsies from 80 patients containing a T-cell dominant lymphocytic infiltrate were analyzed for TCR-beta gene rearrangement. Our findings indicate that monoclonality is a reliable characteristic of CTCL with polyclonality being very infrequent. However, some cases of drug associated lymphomatoid hypersensitivity, collagen vascular disease and the various cutaneous lymphoid dyscrasias (i.e. PLC, PPD and atypical lymphocytic lobular panniculitis) could manifest restricted molecular profiles in the context of an oligoclonal process or frank monoclonality.

Choi YW, Choi JS, Zheng LT, et al.
Comparative genomic hybridization array analysis and real time PCR reveals genomic alterations in squamous cell carcinomas of the lung.
Lung Cancer. 2007; 55(1):43-51 [PubMed] Related Publications
Genomic alterations have been identified in lung cancer tissues and reported in numerous studies. To analyze genomic aberrations in lung cancer patients, we used array comparative genomic hybridization (array CGH) in 14 squamous cell lung carcinoma (SqC) tissues. Copy number gain and loss in chromosomal regions were detected, and the corresponding genes were confirmed by real time PCR. Several frequently altered loci, including gain of 3q (36% of samples), were found. The most frequently identified losses were found at 14q32.33 (21% of samples). The relative degree of chromosomal change was analyzed using log2 ratios. High-level DNA amplifications (>0.8 log2 ratio) were detected at 20 regions in 1p, 2q, 3q, 4q, 6q, 7p, 8q, 9p, 10q, 12q, 14q and 19p. We found that the fold change levels were highest at EVI1 (3q26.2), LPP (3q27-28) and FHF-1 (3q28) gene loci. Our results show that array CGH is a useful tool for identification of gene alteration in lung cancer, and that the above-mentioned genes might represent potential candidate genes for pathogenesis and diagnosis of lung cancer.

Hussenet T, Mallem N, Redon R, et al.
Overlapping 3q28 amplifications in the COMA cell line and undifferentiated primary sarcoma.
Cancer Genet Cytogenet. 2006; 169(2):102-13 [PubMed] Related Publications
Historically, amplicon mapping and characterization of double minute (dmin) chromosomes content have been the ways to pinpoint important oncogenes. The COMA cell line established from a sarcoma contains DMs, some of them composed of material of the long arm of chromosome 3. To identify putative oncogenes on 3q that may be included in these dmins, we have analyzed the COMA cell line by microarray-based comparative genomic hybridization (array-CGH). We have detected the amplification of 1-Mb segment at 3q28, which contains the genes LPP, FLJ42393, and hsa-mir-28. Fluorescence in situ hybridization experiments confirmed the presence of numerous copies of 3q28 segment included in dmins. Further screening of eight undifferentiated primary sarcomas with 3q gains previously detected by chromosome CGH disclosed, in two cases, amplifications at 3q28 overlapping the 1-Mb segment amplified in COMA. To isolate target genes upregulated by gene dosage effect, we measured the transcription levels of every gene (in the RefSeq collection) located in the common region of amplification, selected expressed sequence tags (ESTs) and the micro-RNA hsa-mir-28 in the COMA cell line compared to one MFH cell line without alteration at 3q28. Expression levels of all transcripts were almost similar in both cell lines, except for two ESTs (AI338598 and BX118304) showing a 20-fold increase. These two transcripts are poorly characterized and their contribution to MFH carcinogenesis is difficult to evaluate.

Schwindt H, Akasaka T, Zühlke-Jenisch R, et al.
Chromosomal translocations fusing the BCL6 gene to different partner loci are recurrent in primary central nervous system lymphoma and may be associated with aberrant somatic hypermutation or defective class switch recombination.
J Neuropathol Exp Neurol. 2006; 65(8):776-82 [PubMed] Related Publications
Primary central nervous system lymphomas (PCNSLs) are diffuse large B cell lymphomas confined to the brain. Only minimal data exist on chromosomal aberrations underlying PCNSLs. We studied 41 PCNSLs by fluorescence in situ hybridization for breakpoints affecting the BCL6 locus in chromosomal band 3q27. Of 37 cases evaluable, 14 (38%) carried a breakpoint in the BCL6 locus. Two of these showed juxtaposition of BCL6 to the IGH locus. In 4 cases, the BCL6 breakpoints were cloned using long-distance inverse polymerase chain reaction. All breakpoints were located within the BCL6 major translocation cluster. The translocation partners were the IGH gene in 14q32.33, the IGL gene in 22q11.22, and the histone 1 H4I gene in 6p22.1. In the fourth case, a deletion in 3q leads to loss of an 837-kb fragment extending from the first intron of BCL6 to the third intron of the lipoma-preferred partner (LPP) gene. This deletion may bring the BCL6 gene under the control of regulatory elements of the LPP gene or the miRNA-28 gene located in intron 4 of LPP. DNA sequence analysis of the junctional sequences provided evidence that aberrant class switch recombination or somatic hypermutation may be involved in the generation of BCL6 translocations.

Kubo T, Matsui Y, Goto T, et al.
MRI characteristics of parosteal lipomas associated with the HMGA2-LPP fusion gene.
Anticancer Res. 2006 May-Jun; 26(3B):2253-7 [PubMed] Related Publications
BACKGROUND: The magnetic resonance (MR) characteristics of parosteal lipomas with the HMGA2-LPP fusion transcripts are described.
PATIENTS AND METHODS: The expression of HMGA2-LPP fusion transcripts was determined using the reverse transcription-polymerase chain reaction method.
RESULTS: MR images of two cases with the fusion transcripts, a 56-year-old man and a 50-year-old woman, revealed heterogeneous high signal intensities on T1- and T2-weighted images, showing heterogeneous curvilinear enhancement on fat-suppressed T1-weighted images after Gd-DTPA injection, which resembled those of well-differentiated liposarcomas.
CONCLUSION: Since the HMGA2-LPP fusion transcripts are exclusively detectable in benign mesenchymal tumors, testing HMGA2-LPP expression may be useful for differential diagnosis in cases of radiologically-suspected well-differentiated liposarcomas.

Guo B, Sallis RE, Greenall A, et al.
The LIM domain protein LPP is a coactivator for the ETS domain transcription factor PEA3.
Mol Cell Biol. 2006; 26(12):4529-38 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
PEA3 is a member of a subfamily of ETS domain transcription factors which is regulated by a number of signaling cascades, including the mitogen-activated protein (MAP) kinase pathways. PEA3 activates gene expression and is thought to play an important role in promoting tumor metastasis and also in neuronal development. Here, we have identified the LIM domain protein LPP as a novel coregulatory binding partner for PEA3. LPP has intrinsic transactivation capacity, forms a complex with PEA3, and is found associated with PEA3-regulated promoters. By manipulating LPP levels, we show that it acts to upregulate the transactivation capacity of PEA3. LPP can also functionally interact in a similar manner with the related family member ER81. Thus, we have uncovered a novel nuclear function for the LIM domain protein LPP as a transcriptional coactivator. As LPP continually shuttles between the cell periphery and the nucleus, it represents a potential novel link between cell surface events and changes in gene expression.

Matsui Y, Hasegawa T, Kubo T, et al.
Intrapatellar tendon lipoma with chondro-osseous differentiation: detection of HMGA2-LPP fusion gene transcript.
J Clin Pathol. 2006; 59(4):434-6 [PubMed] Article available free on PMC after 01/12/2015 Related Publications
A 54 year old man developed an unusual lipoma in the patellar tendon, consisting of a fibro-adipose component and a chondro-osseous component. The fibro-adipose component contained mature adipocytes, lipoblasts, and fibroblasts; the chondro-osseous component showed typical endochondral bone formation. Molecular analysis showed that the identical HMGA2-LPP fusion transcript-characteristic of lipoma, parosteal lipoma, and pulmonary chondroid hamartoma-was detectable in the both components.

Kubo T, Matsui Y, Goto T, et al.
Overexpression of HMGA2-LPP fusion transcripts promotes expression of the alpha 2 type XI collagen gene.
Biochem Biophys Res Commun. 2006; 340(2):476-81 [PubMed] Related Publications
In a subset of human lipomas, a specific t(3;12) chromosome translocation gives rise to HMGA2-LPP fusion protein, containing the amino (N)-terminal DNA binding domains of HMGA2 fused to the carboxyl (C)-terminal LIM domains of LPP. In addition to its role in adipogenesis, several observations suggest that HMGA2-LPP is linked to chondrogenesis. Here, we analyzed whether HMGA2-LPP promotes chondrogenic differentiation, a marker of which is transactivation of the alpha 2 type XI collagen gene (Col11a2). Real-time PCR analysis showed that HMGA2-LPP and COL11A2 were co-expressed. Luciferase assay demonstrated that either of HMGA2-LPP, wild-type HMGA2 or the N-terminal HMGA2 transactivated the Col11a2 promoter in HeLa cells, while the C-terminal LPP did not. RT-PCR analysis revealed that HMGA2-LPP transcripts in lipomas with the fusion were 591-fold of full-length HMGA2 transcripts in lipomas without the fusion. These results indicate that in vivo overexpression of HMGA2-LPP promotes chondrogenesis by upregulating cartilage-specific collagen gene expression through the N-terminal DNA binding domains.

Nilsson M, Mertens F, Höglund M, et al.
Truncation and fusion of HMGA2 in lipomas with rearrangements of 5q32-->q33 and 12q14-->q15.
Cytogenet Genome Res. 2006; 112(1-2):60-6 [PubMed] Related Publications
Chromosome segment 12q13-->q15 recombines with many different chromosome bands in lipomas and at least ten recurrent translocations have been identified. The HMGA2 gene is often rearranged, but little is known about the molecular consequences at other breakpoints. Fusion genes between HMGA2 (12q14-->q15) and LPP (3q27-->q28), LHFP (13q12) and CMKOR1 (2q37) have been reported. In the present study, eight lipomas with rearrangements involving chromosome bands 12q14-->q15 and 5q32-->q33 were analyzed. In chromosome 5, five of the cases had a breakpoint in the 5' part of EBF in 5q33, while three cases had breakpoints located about 200 kb 3' of EBF. In chromosome 12, the breakpoints clustered to the region of HMGA2. Four cases had breaks within the gene and four had breaks 5' to HMGA2 where the gene BC058822 is located. Two versions of an HMGA2/EBF fusion transcript were detected in one case; one transcript was in frame and the other out of frame. Identical EBF/BC058822 fusion transcripts, seen in two cases, one of which also had the HMGA2/EBF transcript, were out of frame and resulted in truncation of EBF. Since EBF and HMGA2 have different orientations, the findings must be explained by complex aberrations including multiple breaks. The combined data indicate that the pathogenetically significant event is fusion, truncation or transcriptional activation of HMGA2, but it can not be excluded that EBF, which has been implicated in adipogenesis, contributes to the tumor development.

von Ahsen I, Rogalla P, Bullerdiek J
Expression patterns of the LPP-HMGA2 fusion transcript in pulmonary chondroid hamartomas with t(3;12)(q27 approximately 28;q14 approximately 15).
Cancer Genet Cytogenet. 2005; 163(1):68-70 [PubMed] Related Publications
The high frequency of the t(3;12)(q27 approximately 28; q14 approximately 15) in lipomas and pulmonary chondroid hamartomas (PCHs) makes the HMGA2-LPP fusion gene the most frequent fusion gene in human tumors. We analyzed 11 PCHs with a t(3;12)(q27 approximately 28;q14 approximately 15) for the expression of the LPP-HMGA2 fusion transcript. In a previous study, all of these tumors were shown to express the HMGA2-LPP fusion transcript, composed of exons 1-3 of HMGA2 and exons 9-11 of LPP. In the present study, reverse transcriptase-polymerase chain reaction revealed the expression of the reciprocal fusion transcript in 8 of 11 cases. In all positive tumors, the reciprocal fusion transcripts had the same structure, namely, exons 1-8 of LPP and exons 4-5 of HMGA2 encoding a protein composed of the proline-rich region and the first LIM-domain of LPP and the acidic tail of HMGA2. To our knowledge, this is the first report of the expression of the LPP-HMGA2 fusion transcript in a series of PCHs. Its frequent occurrence in PCHs indicates the absence of a larger deletion of the LPP locus accompanying the translocation, such as has been described in a lipoma. Thus, based on this one finding, a role of LPP-HMGA2 in PCH should be considered.

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