Clinicopathological Characterization and Genomic Aberrations in Subcutaneous Panniculitis-Like T-Cell Lymphoma

Department of Dermatology and Allergology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
Journal of Investigative Dermatology (Impact Factor: 6.37). 04/2008; 128(9):2304-9. DOI: 10.1038/jid.2008.6
Source: PubMed

ABSTRACT Subcutaneous panniculitis-like T-cell lymphomas (SPTLs) represent a rare, difficult-to-diagnose, and poorly characterized subtype of cutaneous T-cell lymphomas (CTCLs) affecting younger people more than the other CTCL forms. We performed a thorough clinical, immunohistological, and molecular analysis of nine Finnish SPTL patients. Specifically, we performed single-cell comparative genomic hybridization (CGH) from laser microdissected, morphologically malignant SPTL cells, as well as loss of heterozygosity (LOH) and fluorescence in situ hybridization (FISH) analysis for the NAV3 (neuron navigator 3) gene. CGH revealed large numbers of DNA copy number changes, the most common of which were losses of chromosomes 1pter, 2pter, 10qter, 11qter, 12qter, 16, 19, 20, and 22 and gains of chromosomes 2q and 4q. Some of the DNA copy number aberrations in SPTL, such as loss of 10q, 17p, and chromosome 19, overlap with those characteristic of common forms of CTCL (mycosis fungoides (MF) and Sezary syndrome (SS)), whereas 5q and 13q gains characterize SPTL. Allelic NAV3 aberrations (LOH or deletion by FISH), previously found in MF and SS, were identified in 44% of the SPTL samples. This study demonstrates that SPTL is also moleculocytogenetically a uniform entity of CTCL and supports the current World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification defining SPTL as a subgroup of its own.

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Available from: Bernhard Polzer, Jul 09, 2014
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    • "The NAV1 and NAV2 proteins have been reported to localize in the centrosomes and to be involved in the mitotic process (van Haren et al., 2009), nervous system development and regeneration , neural tumorigenesis (Coy et al., 2002), and cell migration events even beyond the nervous system (Klein et al., 2011). In tumors, NAV3 transcript expression is downregulated in 40% of primary neuroblastomas (Coy et al., 2002), and NAV3 is deleted or translocated in several subtypes of cutaneous T-cell lymphomas (Karenko et al., 2005; Vermeer et al., 2008; Hahtola et al., 2008a). We have identified NAV3 gene copy number changes (deletions/amplifications) also in cancers of epithelial origin, especially in colorectal cancers (Hahtola et al., 2008b; Carlsson et al., 2012). "
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    ABSTRACT: Copy number changes or reduced expression of the Neuron navigator 3 (NAV3) gene occurs in neuroblastomas and malignancies of epithelial or lymphoid origin. To elucidate whether NAV3 has a role in the tumorigenesis of nervous system tumors in general, we studied central and peripheral nervous system tumors for NAV3 copy number changes. In search for common tumorigenic denominators, we analyzed 113 central and peripheral nervous system tumors, including glial tumors (grades I-IV gliomas), medulloblastomas, and neuroblastomas. NAV3 copy number changes were studied by fluorescence in situ hybridization and correlated to survival analyses. To identify target genes of NAV3 deletion, NAV3 was silenced by siRNA in glioblastoma cell lines and gene expression profiles were analyzed by Agilent 4×44k dual-color microarrays. Selected upregulations were confirmed by immunohistochemistry and quantitative polymerase chain reaction. We found NAV3 amplifications to dominate in neuronally differentiated tumors, whereas glial tumors showed almost equal proportions of NAV3 deletion and amplification. However, Grade IV gliomas had more frequent NAV3 deletions than grades I-III gliomas. Silencing of NAV3 in glioma cell lines led to the upregulation of receptor genes associated with gonadotropin-releasing hormone and Jak-Stat signaling pathways. Kaplan-Meier analysis of the entire clinical tumor material showed association between NAV3 amplifications and favorable prognosis, as well as NAV3 deletions and unfavorable prognosis. With Cox regression model, a hazard ratio of 0.51 was observed for NAV3 amplifications and 1.36 for NAV3 deletions. We conclude that NAV3 may be a potential new prognostic biomarker and a potential therapeutic target. © 2012 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 02/2013; 52(2). DOI:10.1002/gcc.22019 · 3.84 Impact Factor
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    • "We have previously shown that chromosome 12q21 aberrations, specifically allelic loss of the neuron navigator 3 (NAV3) gene, are associated with several subtypes of cutaneous T-cell lymphoma (CTCL; Karenko et al, 2005; Hahtola et al, 2008a), CTCL-associated lung cancers (Hahtola et al, 2008b), and ca. 25% of cutaneous basal and squamous cell cancers (Maliniemi et al, 2011). "
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    ABSTRACT: The recently described navigator proteins have a multifaceted role in cytoskeletal dynamics. We report here on the relevance of one of them, navigator 3 (NAV3), in colorectal cancer (CRC). We analysed changes in chromosome 12 and NAV3 copy number in CRC/adenoma samples of 59 patients and in 6 CRC cell lines, using fluorescence in situ hybridisation, loss of heterozygosity, and array-CGH. NAV3 target genes were identified by siRNA depletion, expression arrays, and immunohistochemistry. NAV3 deletion and chromosome 12 polysomy were detected in 30 and 70% of microsatellite stability (MSS) carcinomas, in 23 and 30% of adenomas and in four of six CRC cell lines. NAV3 amplification was found in 25% of MSS samples. NAV3 alterations correlated with lymph node metastasis. In normal colon cells, NAV3 silencing induced upregulation of interleukin 23 receptor (IL23R) and gonadotropin releasing hormone receptor. In MSS and microsatellite instability tumours, IL23R immunoreactivity correlated with Dukes' staging and lymph node metastases, whereas nuclear beta-catenin correlated with lymph node metastases only. NAV3 copy number changes are frequent in CRC and in adenomas, and upregulation of IL23R, following NAV3 silencing, strongly correlates with Dukes' staging and lymph node metastases. This suggests that NAV3 has a role in linking tissue inflammation to cancer development in the colon.
    British Journal of Cancer 12/2011; 106(3):517-24. DOI:10.1038/bjc.2011.553 · 4.82 Impact Factor
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    • "Although some of the subsequent studies by other groups failed to confirm this finding (Carbone et al., 2008; Marty et al., 2008), the discrepancy might be explained by the different case series analyzed or by the different detection methods used in these studies (Karenko et al., 2005; Carbone et al., 2008; Marty et al., 2008; Vermeer et al., 2008). Allelic NAV3 deletion has also been shown to have a role in the oncogenesis of subcutaneous panniculitis-like T-cell lymphoma (Hahtola et al., 2008a) and other cancers (Hahtola et al., 2008b; Bleeker et al., 2009; Soon et al., 2009). Importantly, NAV3 gene deletion may be a relatively early event in the development of MF, because it was found in 50% of the early MF cases (Karenko et al., 2005). "
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    ABSTRACT: ATLL, adult T-cell leukemia/lymphoma; MF, mycosis fungoides
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