Recurrent focal copy-number changes and loss of heterozygosity implicate two noncoding RNAs and one tumor suppressor gene at chromosome 3q13.31 in osteosarcoma.

Osteosarcomas are copy number alteration (CNA)-rich malignant bone tumors. Using microarrays, fluorescence in situ hybridization, and quantitative PCR, we characterize a focal region of chr3q13.31 (osteo3q13.

Copy number variations and cancer susceptibility.

Purpose Of Review: DNA copy number variations (CNVs) comprise a recently discovered element of genetic variation that affects a greater cumulative fraction of the genome than single-nucleotide polymorphisms (SNPs). This review discusses current understanding of the characteristics of CNVs in the human genome and explores the emerging discoveries of both constitutional and somatic CNVs in an ever-expanding variety of human cancers.

Recent Findings: The advent of high-resolution SNP arrays has made it possible to identify CNVs.

Oncogenic ILK, tumor suppression and all that JNK.

In neoplastic cells, proteins exert either pro or anti-tumorigenic functions. However, some proteins exhibit both properties, commonly dependent on specific aberrations occurring in a tumor-specific context. Recently, we demonstrated that the integrin-linked kinase (ILK), generally characterized as an oncogenic protein kinase, functions as a tumor suppressor protein in vitro and in vivo in the aggressive pediatric tumor, rhabdomyosarcoma (RMS).

IGF2 is highly expressed in pediatric undifferentiated sarcomas and reveals two distinct cytoplasmic trafficking patterns.

Pediatric undifferentiated soft tissue sarcomas (USTSs) are tumors composed of primitive mesenchymal cells. As such, they form an attractive model for studying the early events in sarcoma development. In an effort to better understand the critical molecular aberrations leading to sarcoma development, gene expression array analysis and post-array validation techniques were applied to several USTSs; the results were consistent with upregulation of the excitatory components of the insulin-like growth factor (IGF) pathway.

Copy number variations and cancer.

DNA copy number variations (CNVs) are an important component of genetic variation, affecting a greater fraction of the genome than single nucleotide polymorphisms (SNPs). The advent of high-resolution SNP arrays has made it possible to identify CNVs. Characterization of widespread constitutional (germline) CNVs has provided insight into their role in susceptibility to a wide spectrum of diseases, and somatic CNVs can be used to identify regions of the genome involved in disease phenotypes.

Postoperative fevers in pediatric solid tumor patients: how should they be managed?

Unlabelled: It is unclear how aggressively postoperative fevers should be managed in immunosuppressed pediatric oncology patients after major surgery. Little data exists on this subject. Therefore, a retrospective study of patients treated at our center was undertaken to examine this.

High frequency of de novo mutations in Li-Fraumeni syndrome.

Background: Li-Fraumeni syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in the TP53 gene. The frequency of germline de novo TP53 mutations is largely unknown; few unequivocal de novo mutations have been reported.

Methods And Results: Of 341 patients with early onset cancer sent for clinical testing to a national reference laboratory, 75 patients had TP53 germline mutations.

JNK1 determines the oncogenic or tumor-suppressive activity of the integrin-linked kinase in human rhabdomyosarcoma.

Although most reports describe the protein kinase integrin-linked kinase (ILK) as a proto-oncogene, occasional studies detail opposing functions in the regulation of normal and transformed cell proliferation, differentiation, and apoptosis. Here, we demonstrated that ILK functions as an oncogene in the highly aggressive pediatric sarcoma alveolar rhabdomyosarcoma (ARMS) and as a tumor suppressor in the related embryonal rhabdomyosarcoma (ERMS). These opposing functions hinge on signaling through a noncanonical ILK target, JNK1, to the proto-oncogene c-Jun.

The cycle of genome-directed medicine.

The genome era in medicine is upon us. Questions that arise from patient and family care are a watershed for research and technology, which in turn fuel the cycle of opportunity for impact through delivery of health services, which feeds back to families. Medical infrastructure needs to adapt to the dramatic pace of technology development in the wake of the Human Genome Project, in order for genome data to be delivered as information and applied as knowledge to benefit health.

Floral morphogenesis: stochastic explorations of a gene network epigenetic landscape.

In contrast to the classical view of development as a preprogrammed and deterministic process, recent studies have demonstrated that stochastic perturbations of highly non-linear systems may underlie the emergence and stability of biological patterns. Herein, we address the question of whether noise contributes to the generation of the stereotypical temporal pattern in gene expression during flower development. We modeled the regulatory network of organ identity genes in the Arabidopsis thaliana flower as a stochastic system.

Squalene selectively protects mouse bone marrow progenitors against cisplatin and carboplatin-induced cytotoxicity in vivo without protecting tumor growth.

Squalene, an isoprenoid antioxidant is a potential cytoprotective agent against chemotherapy-induced toxicity. We have previously published that squalene protects light-density bone marrow cells against cis-diamminedichloroplatinum( II) (cisplatin)-induced toxicity without protecting tumor cells in vitro. Here, we developed an in vivo mouse model of cisplatin and cis-diammine (cyclobutane-1,1-dicarboxylato) platinum(II) (carboplatin)-induced toxicity to further investigate squalene-mediated LD-BM cytoprotection including the molecular mechanism behind selective cytoprotection.

Telomere maintenance and dysfunction predict recurrence in paediatric ependymoma.

We have recently described the enzymatic subunit of telomerase (hTERT) as an important prognostic marker for paediatric ependymoma. Because of the lack of good, representative pre-clinical models for ependymoma, we took advantage of our large cohort of ependymoma patients, some with multiple recurrences, to investigate telomere biology in these tumours. Our cohort consisted of 133 ependymomas from 83 paediatric patients and included 31 patients with recurrences.

Expression of insulin-like growth factor pathway proteins in rhabdomyosarcoma: IGF-2 expression is associated with translocation-negative tumors.

Recent studies have shown a significant involvement of insulin-like growth factor (IGF) signaling components in the pathogenesis of rhabdomyosarcoma (RMS). Furthermore, there has been some evidence to indicate that differential expression of IGF pathway genes can distinguish RMS subtypes. The present study utilized immunohistochemistry to determine the expression patterns of IGF1, IGF2, IGF binding protein 2 (IGFBP2), IGF receptor 1 (IGF1R), and IGF receptor 2 (IGF2R) in 24 embryonal RMS (ERMS) and 8 alveolar RMS (ARMS).

Excessive genomic DNA copy number variation in the Li-Fraumeni cancer predisposition syndrome.

DNA copy number variations (CNVs) are a significant and ubiquitous source of inherited human genetic variation. However, the importance of CNVs to cancer susceptibility and tumor progression has not yet been explored. Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited disorder characterized by a strikingly increased risk of early-onset breast cancer, sarcomas, brain tumors and other neoplasms in individuals harboring germline TP53 mutations.

Fatal peri-operative acute tumour lysis syndrome precipitated by dexamethasone.

A 3-year-old patient presented for elective adenotonsillectomy to treat symptomatic obstructive sleep apnoea. The patient had not been assessed at a pre-operative anaesthesia clinic but had undergone uneventful general anaesthesia twice in the previous two years. An uneventful operative course was complicated by the development of clinical instability over the first 6 h postoperatively culminating in cardiorespiratory arrest.

Hypoxia enhances tumor stemness by increasing the invasive and tumorigenic side population fraction.

Although advances have been made in understanding the role of hypoxia in the stem cell niche, almost nothing is known about a potentially similar role of hypoxia in maintaining the tumor stem cell (TSC) niche. Here we show that a highly tumorigenic fraction of side population (SP) cells is localized in the hypoxic zones of solid tumors in vivo. We first identified a highly migratory, invasive, and tumorigenic fraction of post-hypoxic side population cells (SPm([hox]) fraction) in a diverse group of solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, and small-cell lung carcinoma.

The estrogen receptor pathway in rhabdomyosarcoma: a role for estrogen receptor-beta in proliferation and response to the antiestrogen 4'OH-tamoxifen.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Highly malignant, RMS frequently fails to respond to conventional aggressive multimodal radiation, surgery, and chemotherapy treatment protocols that also cause significant sequelae in the growing child. Other tumors of mesenchymal origin, such as locally aggressive fibromatoses and desmoid tumors, have been successfully treated with a selective estrogen receptor (ER) modulator, tamoxifen.

Risk stratification in cancer predisposition syndromes: lessons learned from novel molecular developments in Li-Fraumeni syndrome.

Germ-line mutations in specific genes predispose family members to cancer. Prediction of the exact tumor type and timing of cancer initiation is fundamental to the development of management strategies for these individuals. Recent advances in our understanding of the general processes that control cancer initiation may enable us to tailor more precise risk stratification.

Cisplatin treatment increases survival and expansion of a highly tumorigenic side-population fraction by upregulating VEGF/Flt1 autocrine signaling.

The cellular and molecular mechanisms of tumor progression following chemotherapy are largely unknown. Here, we demonstrate that cisplatin (CDDP) treatment upregulates VEGF and Flt1 expression leading to the survival and expansion of a highly tumorigenic fraction of side-population (SP) cells in osteosarcoma (HOS), neuroblastoma (SK-N-BE2) and rhabdomyosarcoma (RH-4) cell lines. In all three lines, we show that CDDP treatment increases levels of VEGF and Flt1 expression, and induces enhanced clonogenic capacity and increased expression of the 'stemness'-associated genes Nanog, Bmi-1 and Oct-4 in the SP fraction.

The CXCR4-SDF1alpha axis is a critical mediator of rhabdomyosarcoma metastatic signaling induced by bone marrow stroma.

Rhabdomyosarcoma (RMS) is the most common malignant soft-tissue tumor of childhood. Nearly 15% of children present with metastatic disease, frequently involving the lungs and bone marrow. The prognosis for patients with metastatic RMS is dismal, with an estimated 3-year overall survival of 30%.

High-density single nucleotide polymorphism array analysis in patients with germline deletions of 22q11.2 and malignant rhabdoid tumor.

Malignant rhabdoid tumors are highly aggressive neoplasms found primarily in infants and young children. The majority of rhabdoid tumors arise as a result of homozygous inactivating deletions or mutations of the INI1 gene located in chromosome band 22q11.2.

Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome frequently associated with germ line TP53 mutations. Unpredictable and disparate age of cancer onset is a major challenge in the management of LFS. Genetic modifiers, including the MDM2-SNP309 polymorphism, and genetic anticipation have been suggested as plausible explanations for young age of tumor onset, but the molecular mechanisms for these observations are unknown.

Toxicity and outcome of children with treatment related acute myeloid leukemia.

Background: The aim of this study was to evaluate the clinical course and outcome of children with treatment related acute myeloid leukemia (tAML) and compare them to children with primary AML (pAML).

Procedure: We retrospectively reviewed the demographic, treatment, toxicity, and outcome data of children with tAML and treatment related myelodysplastic syndrome (tMDS), treated at our institution between 1975 and 2005. We compared these parameters with matched controlled children with pAML.