Genomic deletions at 1p and 14q are associated with an abnormal cDNA microarray gene expression pattern in meningiomas but not in schwannomas

The molecular pathology of meningiomas and shwannomas involve the inactivation of the NF2 gene to generate grade I tumors. Genomic losses at 1p and 14q are observed in both neoplasms, although more frequently in meningiomas. The inactivation of unidentified genes located in these regions appears associated with tumor progression in meningiomas, but no clues to its molecular/clinical meaning are available in schwannomas. Recent microarray gene expression studies have demonstrated the existence of molecular subgroups in both entities. In the present study, we correlated the presence of genomic deletions at 1p, 14q, and 22q with the expression patterns of 96 tumor-related genes obtained by cDNA low-density microarrays in a series of 65 tumors including 42 meningiomas and 23 schwannomas. Two expression pattern groups were identified by cDNA mycroarray analysis when compared to the expression pattern in normal control RNA in both meningiomas and schwannomas, each one with patterns similar and different from the normal control. Meningioma and schwannoma subgroups differed in the expression of 38 and 16 genes, respectively. Using MLPA and microsatellites, we identified genomic losses at 1p, 14q, and 22q at nonrandom frequencies (12.5-69%) in meningiomas and schwannomas. Losses at 22q were almost equally frequent in both molecular expression subgroups in both neoplasms. However, deletions at 1p and 14q accumulated in meningiomas with a gene expression pattern different from the normal pattern, whereas the inverse situation occurred in schwannomas. Those anomalies characterized the schwannomas with expression pattern similar to the normal control. These findings suggest that deletions at 1p and 14q enhance the development of an abnormal tumor-related gene expression pattern in meningiomas, but this fact is not corroborated in schwannomas. (C) 2010 Elsevier Inc. All rights reserved.

Distinct patterns of somatic alterations in a lymphoblastoid and a tumor genome derived from the same individual

Although patterns of somatic alterations have been reported for tumor genomes, little is known on how they compare with alterations present in non-tumor genomes. A comparison of the two would be crucial to better characterize the genetic alterations driving tumorigenesis. We sequenced the genomes of a lymphoblastoid (HCC1954BL) and a breast tumor (HCC1954) cell line derived from the same patient and compared the somatic alterations present in both. The lymphoblastoid genome presents a comparable number and similar spectrum of nucleotide substitutions to that found in the tumor genome. However, a significant difference in the ratio of non-synonymous to synonymous substitutions was observed between both genomes (P = 0.031). Protein-protein interaction analysis revealed that mutations in the tumor genome preferentially affect hub-genes (P = 0.0017) and are co-selected to present synergistic functions (P < 0.0001). KEGG analysis showed that in the tumor genome most mutated genes were organized into signaling pathways related to tumorigenesis. No such organization or synergy was observed in the lymphoblastoid genome. Our results indicate that endogenous mutagens and replication errors can generate the overall number of mutations required to drive tumorigenesis and that it is the combination rather than the frequency of mutations that is crucial to complete tumorigenic transformation.

Allelic status of 1p and 19q in oligodendrogliomas and glioblastomas: multiplex ligation-dependent probe amplification versus loss of heterozygosity

Identification of the 1p/19q allelic status in gliomas, primarily those with a major oligodendroglial component, has become an excellent molecular complement to tumor histology in order to identify those cases sensitive to chemotherapy. In addition to loss of heterozygosity (LOH), fluorescence in situ hybridization (FISH), or comparative genomic hybridization (CGH), multiplex ligation-dependent probe amplification (MLPA) has been shown to be an alternative methodology to identify deletions of those chromosome arms. We used MLPA to explore the 1p and 19q glioblastomas, and a series of 76 gliomas: 41 tumors with a major oligodendroglial component, 34 glioblastomas, and one low-grade astrocytoma. We compared the MLPA findings of the oligodendroglial cases with those previously obtained using LOH in the same samples. Thirty-eight of 41 oligodendrogliomas displayed identical findings by both LOH and MLPA, and losses at either 1p and/or 19q were identified in 12 of 35 (34%) astrocytic tumors. These findings agree with data previously reported comparing MLPA versus FISH or CGH in gliomas and suggest that MLPA can be used in the identification 1p/19q allelic deletions on these brain neoplams. (c) 2009 Elsevier Inc. All rights reserved. reserved.

The role of tumor hypoxia in MUC1-positive breast carcinomas

Mucin 1 (MUC1) is a glycoprotein that is expressed on apical cell membranes in a variety of normal tissues. MUC1 is involved in cell signaling, inhibition of cell-cell and cell matrix adhesion, apoptosis, proliferation, and transcription. Hypoxia is an important factor that promotes cancer metastasis and stimulates angiogenesis and tumor progression. Hypoxia inducible factor 1 (HIF-1 alpha) and carbonic anhydrase IX (CAIX) are two molecules that are involved in this process. The role of hypoxia in MUC1+ invasive ductal breast carcinomas is not well established. In this study, the expression of MUC1 was correlated with the hypoxia-associated markers HIF-1 alpha and CAIX, as well as several immunohistochemical markers and clinicopathologic features of prognostic significance in 243 invasive ductal carcinomas. MUC1 was overexpressed in 37.0% of patients and correlated with the expression of estrogen receptor (p = 0.0001), progesterone receptor (p = 0.0001), HIF-1 alpha (p = 0.006), VEGF (p = 0.024), and p53 (p = 0.025). In breast cancer, MUC1 expression has been associated with increased degradation of inhibitor of NF-kappa B (I kappa B alpha), driving NF-kappa B to the nucleus and blocking apoptosis and promoting cell survival. We analyzed NF-kappa B expression in MUC1+ breast carcinoma and found a very significant relationship between these proteins (p = 0.0001). Our findings indicate that MUC1 may play a role in the regulation of hormone receptors by increasing the inactivation of p53 and targeting NF-kappa B to the nucleus. Our data also support the notion that activation of HIF-1 alpha in MUC1+ breast carcinomas may modulate VEGF expression, allowing a metabolic adaptation to hypoxia.

Fungal infection by Paracoccidioides brasiliensis mimicking bone tumor

Paracoccidioides brasiliensis infection causes a systemic mycosis originally described in Latin America but with Current reports of worldwide distribution. The clinical presentation of paracoccidiodomycosis as an isolated long-bone lesion in children is quite unusual. This article describes a 10-year-old male with a lytic femoral bone lesion caused by P. brasiliensis infection that was first suspected of being of neoplasic etiology. The text also emphasizes the importance of including endemic fungal infections in the differential diagnosis of bone lesions.

Pitfalls in the Differential Diagnosis of Renal Tumor in an Adolescent

The differential diagnosis of renal tumors, particularly in adolescents, may be challenging. We describe an 11-year-old female with a primary intra-renal mass. Initial differential diagnoses included primitive neuroectodermal tumor (PNET), desmoplastic small round cell tumor (DSRCT), and Wilms Turner (WT). Extensive pathologic and molecular analysis on initial and relapsed tumor samples confirmed WT. The EWS-WTI and EWS-FL11 rearrange-merits, distinctive of DSRCT and PNET were negative. The differential diagnosis on monophasic blastemal WT may be complex. Primary renal DSRCT and MET have been rarely described. Nevertheless, molecular confirmation for these rare conditions may be necessary in selected cases. Pediatr Blood Cancer 2010;54:3 19-321. (C) 2009 Wiley-Liss, Inc.

Tumor necrosis factor region polymorphisms are associated with AIDS and with cytomegalovirus retinitis

Background: The tumor necrosis factor (TNF) gene is located within the highly polymorphic major histocompatibility complex region, exhibiting the -308 CA promoter region polymorphism and six microsatellites (TNFa-f) spanning the region nearby the TNF locus. Objective: In the present Study, we evaluated the frequency of -308 CA and TNFa-e polymorphisms and respective haplotypes (in chromosomal sequence: TNFd-TNFe-308GA-TNFc-TNFa-TNFb), in 222 patients with AIDS, 52 of whom exhibited cytomegalovirus retinitis, and in 202 healthy HIV-negative individuals. Method: TNF microsatellite and single nucleotide polymorphism typings were performed by PCR followed by polyacrylamide gel electrophoresis. Results: The TNF-308A allele and the 4-3-C-2-7-1 haplotype were associated with susceptibility to AIDS, whereas the TNFb4 allele and the 3-3-C-1-11-4 haplotype were associated with protection against AIDS development. The TNFc2 allele and the 4-1-G-2-2-1 haplotype, which contains the TNFc2 allele, were associated with cytomegalovirus retinitis. Conclusion: This study highlights that polymorphic sites spanning the region nearby the TNF locus are associated with AIDS per se and with cytomegalovirus retinitis in AIDS patients. (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

Distinct tumor suppressor mechanisms evolve in rodent species that differ in size and lifespan

Large, long-lived species experience more lifetime cell divisions and hence a greater risk of spontaneous tumor formation than smaller, short-lived species. Large, long-lived species are thus expected to evolve more elaborate tumor suppressor systems. In previous work, we showed that telomerase activity coevolves with body mass, but not lifespan, in rodents: telomerase activity is repressed in the somatic tissues of large rodent species but remains active in small ones. Without telomerase activity, the telomeres of replicating cells become progressively shorter until, at some critical length, cells stop dividing. Our findings therefore suggested that repression of telomerase activity mitigates the increased risk of cancer in larger-bodied species but not necessarily longer-lived ones. These findings imply that other tumor suppressor mechanisms must mitigate increased cancer risk in long-lived species. Here, we examined the proliferation of fibroblasts from 15 rodent species with diverse body sizes and lifespans. We show that, consistent with repressed telomerase activity, fibroblasts from large rodents undergo replicative senescence accompanied by telomere shortening and overexpression of p16(Ink4a) and p21(Cip1/Waf1) cycline-dependent kinase inhibitors. Interestingly, small rodents with different lifespans show a striking difference: cells from small shorter-lived species display continuous rapid proliferation, whereas cells from small long-lived species display continuous slow proliferation. We hypothesize that cells of small long-lived rodents, lacking replicative senescence, have evolved alternative tumor-suppressor mechanisms that prevent inappropriate cell division in vivo and slow cell growth in vitro. Thus, large-bodied species and small but long-lived species have evolved distinct tumor suppressor mechanisms.

Odor cues from tumor-bearing mice induces neuroimmune changes

Cohabitation for 14 days with an Ehrlich tumor-bearing mice was shown, among others, to increase locomotor activity, and hypothalamic noradrenaline levels and turnover, to decrease the innate immune responses and animal resistance to tumor growth. The present experiment was designed to access the relevance of tactile, olfactory, and visual communication to the neuroimmune changes induced by cohabitation with a tumor-bearing partner. Mice that were not allowed to perceive odor cues from their sick partners presented no alterations in neutrophil activity, a fact not observed after visual deprivation and physical isolation. Mice use scents for intraspecies communication in many social contexts. Tumors produce volatile organic compounds released into the atmosphere through breath, sweat, and urine. The present results strongly suggest that volatile compounds released by Ehrlich tumor-injected mice are perceived by their conspecifics, inducing the neuroimmune changes reported for cohabitation with a sick companion. (C) 2010 Published by Elsevier B.V.

Effects of individual housing on behavior and resistance to Ehrlich tumor growth in mice

This study analyzed in Balb/C mice the effects of individual housing on behavior, serum corticosterone and resistance to Ehrlich tumor growth. Mice (60 days old) were individually (IH) or grouped housed (G) (10-12 animals/cage) for 14-21 days. The 1st day of the housing condition was considered experimental day 1 (ED1). Results showed that on ED21, IH mice, when compared to G mice, presented no differences on corticosterone serum levels when kept undisturbed; however, an increased level of this hormone was observed in IH mice after an immobilization stress challenge. An increased time spent in the plus-maze closed arms and a decreased time in the open arms were also observed in IH mice. When compared to G animals, after inoculation with 105 Ehrlich tumor cells on ED1, IH mice presented an increase in volume of ascitic fluid and number of tumor cells. The survival time of IH mice was also shorter than that measured in G animals. Furthermore, IH mice injected with a different number of tumor cells on ED1 always presented increased Ehrlich tumor cells than G group. Interestingly. these effects were not observed when the tumor cells injection was done on ED4. These results suggest that individual-housing conditions induce an altered immune-endocrine response and, at the same time, decrease animals` resistance to Ehrlich tumor growth. It is proposed that the neural link between the behavioral and immunological changes observed after the stress of individual housing might involve the activation of the HPA axis. (C) 2008 Elsevier Inc. All rights reserved.

Cohabitation with a sick cage mate: Effects on ascitic form of Ehrlich tumor growth and macrophage activity

The present study was designed to evaluate the effects of mice cohabitation with a sick conspecific cage mate on peritoneal macrophage activity and on resistance to Ehrlich tumor growth. Female mice housed in pairs were divided into control and experimental groups. One mouse of each control pair was inoculated with NaCl (0.1 ml/10 g) intraperitoneally and the other, called `companion of healthy partner` (CHP), was kept undisturbed. One animal of each experimental pair of mice was inoculated with 5.0 x 10(6) Ehrlich tumor cells intraperitoneally and the other, the subject of this study, was called `companion of sick partner` (CSP). Peritoneal macrophages were removed from CSP and CHP mice to analyze resident macrophage activity (experiment 1), macrophage activity after Mycobacterium bovis (experiment 2) or Ehrlich tumor cells (experiment 3) in vivo inoculations. The resistance of CSP and CHP mice to Ehrlich tumor growth was also analyzed (experiment 4). Differences between groups were not found on resident macrophage activity. However, Onco-BCG- and Ehrlich tumor-activated macrophages from CSP mice presented a decreased intensity and percentage of phagocytosis and an increased respiratory burst in the presence of Staphylococcus aureus stimulation in vitro. CSP animals at the same time displayed a decreased resistance to Ehrlich tumor growth. These data were discussed in light of a possible psychological stress effect imposed by the housing condition on mice`s peritoneal macrophage activity and, as a consequence, on their resistance to Ehrlich tumor growth. Copyright (c) 2008 S. Karger AG, Basel.

Immunoprofile of Kuttner tumor (chronic sclerosing sialadenitis)

In the present study, the immunoprofile of chronic sclerosing sialadenitis, also known as Kuttner tumor, was analyzed. Two,cases that occurred in the submandibular gland of male patients were submitted to immunohistochemical reactions to different antibodies. Histological examinations showed a submandibular gland exhibiting various degrees of atrophy with destruction of acini, infiltration by inflammatory cells, and periductal fibrosis. Reactions to cytokeratins (CKs) showed acini and duct remnants positive to CKs 7, 8, 19, and 13. CK14 stained myoepithelial cells around preserved acini and intercalated duct, and also basal cell of excretory ducts, but was negative in proliferating and branching ducts. Smooth muscle actin (SMA) was expressed by myofibroblasts in periductal fibrosis, and an intense expression of extracellular components was also seen. Lymphocyte markers showed, besides mature follicles, a higher presence of CD45RO positive cells. Thus, the immunoprofile of Kuttner is much more in keeping with an inflammatory-induced degenerative disease than with a preneoplastic lesion.