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Simple Summary: Neuroblastoma (NB) is the most frequent solid extracranial tumor in children and the most frequently diagnosed cancer during infancy. A genetic modification, a gain of 17q chromosome arm, is the most common modification in neuroblastoma. Substantial research has been performed on 17q's role in neuroblastoma development and its clinical significance. This paper aims to make a comprehensive review of this evidence. The main findings of the review are: (1) current knowledge supports that 17q gain is involved in the development of neuroblastoma and (2) 17q gain is an important clinical marker independently and in association with other genetic modifications. Neuroblastoma (NB) is the most frequent extracranial solid childhood tumor. Despite advances in the understanding and treatment of this disease, the prognosis in cases of high-risk NB is still poor. 17q gain has been shown to be the most frequent genomic alteration in NB. However, the significance of this remains unclear because of its high frequency and association with other genetic modifications, particularly segmental chromosomal aberrations, 1p and 11q deletions, and MYCN amplification, all of which are also associated with a poor clinical prognosis. This work reviewed the evidence on the clinical and biological significance of 17q gain. It strongly supports the significance of 17q gain in the development of NB and its importance as a clinically relevant marker. However, it is crucial to distinguish between whole and partial chromosome 17q gains. The most important breakpoints appear to be at 17q12 and 17q21. The former distinguishes between whole and partial chromosome 17q gain; the latter is a site of IGF2BP1 and NME1 genes that appear to be the main oncogenes responsible for the functional effects of 17q gain. [ABSTRACT FROM AUTHOR]

Asthma-associated single nucleotide polymorphisms from large genome-wide association studies only explain a fraction of genetic heritability. Likely causes of the missing heritability include broad phenotype definitions and gene-environment interactions (GxE). The mechanisms underlying GxE in asthma are poorly understood. Previous GxE studies on pet ownership showed discordant results. We sought to study the GxE between the 17q12-21 locus and pet ownership in infancy in relation to wheeze. Wheezing classes derived from 5 UK-based birth cohorts (latent class analysis) were used to study GxE between the 17q12-21 asthma-risk variant rs2305480 and dog and cat ownership in infancy, using multinomial logistic regression. A total of 9149 children had both pet ownership and genotype data available. Summary statistics from individual analyses were meta-analyzed. rs2305480 G allele was associated with increased risk of persistent wheeze (additive model odds ratio, 1.37; 95% CI, 1.25-1.51). There was no evidence of an association between dog or cat ownership and wheeze. We found significant evidence of a GxE interaction between rs2305480 and dog ownership (P = 8.3 × 10−4) on persistent wheeze; among dog owners, the G allele was no longer associated with an increased risk of persistent wheeze (additive model odds ratio, 0.95; 95% CI, 0.73-1.24). For those without pets, G allele was associated with increased risk of persistent wheeze (odds ratio, 1.61; 95% CI, 1.40-1.86). Among cat owners, no such dampening of the genetic effect was observed. Among dog owners, rs2305480 G was no longer associated with an increased risk of persistent wheeze (or asthma). Early-life environmental exposures may therefore attenuate likelihood of asthma in those carrying 17q12-21 risk alleles. [ABSTRACT FROM AUTHOR]

Abstract: Neuroblastoma is the most common extracranial solid tumour of childhood and is characterized by a remarkable heterogeneity in histology and molecular biology that is reflected in its clinical outcome. Unlike many paediatric malignancies, molecular genetic results are used for prognosis rather than diagnosis. The molecular genetic changes in neuroblastoma are reviewed and summarized. Some genetic changes (ploidy, MYCN copy number, 11q deletion) are used for risk stratification that determines patient treatment. Other genetic changes (e.g 1p deletion, 17q gain) are strong prognostic indicators for an unfavourable outcome. Mutations in individual genes (e.g ALK) are becoming important in personalizing therapy as more agents become available for ‘druggable’ targets. Newer genetic data related to miRNA expression and genome-wide association screening offer the promise of new avenues to pursue to improve the dismal outcome in high risk patients with neuroblastoma. [Copyright &y& Elsevier]

Purpose: To assess the utility of fine needle aspiration cytology (FNAC) samples for molecular genetic analysis of neuroblastoma. Methods: The case files from the pediatric solid tumor clinic were reviewed to identify 20 neuroblastoma patients whose pre-treatment FNAC slides were preserved in the cytology laboratory. The FNAC slides were destained, air dried and hybridisation with fluorescence in situ hybridisation (FISH) probes was performed as per protocol. All slides were screened and analyzed carefully under the fluorescent microscope. Over four-fold increase of the N-myc signal numbers was defined as N-myc amplification. Focal occurrence of cells (at least 50) showing N-myc amplification surrounded by non-amplified tumor cells was defined as focal N-myc amplification. Presence of three or more signals for the long arm of chromosome 17 was defined as 17q gain. Results: FISH analysis gave informative results for all the FNAC smears in our study. FISH analysis of FNAC smears showed N-myc amplification in 5 (25 %) out of 20 patients and 15 (75 %) showed normal N-myc copy number. Three out of these five patients had homogenous amplification and two patients had focal N-myc amplification, indicating tumor heterogeneity. On investigation of chromosome 17q status, 5 (25 %) out of 20 patients demonstrated gain of 17q and 15 (75 %) patients showed normal 17q status. Four out of the five patients with 17q gain also showed N-myc amplification. Conclusions: The current study indicates that FNAC is a rapid and atraumatic diagnostic method for neuroblastoma which provides sufficient material for molecular genetic analyses by means of FISH. [ABSTRACT FROM AUTHOR]

The human epidermal growth factor receptor 2 gene (HER2) is amplified in approximately 15%-20% of all breast cancers. This results in overexpression of the HER2 protein, which is associated with worse clinical outcomes in breast cancer patients. Several studies have shown that trastuzumab, a monoclonal antibody that interferes with the HER2/neu receptor, can improve overall survival in patients with HER2-positive breast cancer. Immunohistochemistry (IHC), combined with different methods for in situ hybridization, is currently used for routine assessment of HER2 status. The aim of the present study was to determine whether real-time polymerase chain reaction (PCR) can serve as a supplementary method for evaluation of HER2 status in primary breast cancer. For this purpose, 145 formalin-fixed parafin-embedded primary breast cancer samples were tested by real-time PCR amplification of HER2, using amyloid precursor protein as a reference. The results were compared with HER2 status determined by fluorescence in situ hybridization (FISH) and IHC. The specificity, sensitivity, and reproducibility of real-time PCR were evaluated, and a comparison of formalin-fixed and fresh-frozen samples was performed. This showed concordance of 93% between real-time PCR and FISH, and 86% between real-time PCR and IHC. Therefore, we suggest that real-time PCR can be a useful supplementary method for assessment of HER2 status. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine whether the cumulative effects of five prostate cancer risk alleles (three single-nucleotide polymorphisms [SNPs] on chromosome 8Q24 and two SNPs on chromosome 17a) could help to identify possibly 'insignificant' disease. MATERIALS AND METHODS We genotyped 629 men of European ancestry who underwent radical prostatectomy at our institution between 2002 and 2007. Possibly 'insignificant' CaP was defined using the Ohori criteria (organ- confined, tumour volume < 0.5 mL, Gleason pattern ≤ 4). Statistical analysis was used to compare patients with 'insignificant' and all other 'significant' cancer based upon genotype. Carrier status for the 5 SNPs were compared between patients with 'insignificant' disease and a separate population of 801 controls without CaP. RESULTS Overall, 38 (6.0%) patients with CaP met the Ohori criteria for 'insignificant' disease. Men with 'significant' cancer had a greater frequency of any of the five risk alleles than either patients with 'insignificant' disease or controls. None of the individual alleles genotyped on chromosomes 8 or 17 distinguished between 'significant' and 'insignificant' CaP. However, carriers of two or more risk alleles were more likely to have 'significant' disease. CONCLUSIONS Although no single risk allele distinguished 'insignificant' CaP, 'insignificant' disease was nearly three times as likely among carriers of ≤ one risk allele. Future studies are needed to further elucidate the cumulative relationship between CaP risk alleles and CaP aggressiveness. [ABSTRACT FROM AUTHOR]

Abstract: We describe a 6-year-old boy with a de novo 12 Mb interstitial duplication of chromosome 17q11.1q12, identified by oligo array-CGH. The patient shows psychomotor developmental and language delay, dolicocephaly, minor facial anomalies, hypotonia and renal megacalicosis. The duplication involves the neurofibromatosis type I (NF1) gene and overlaps with long-range unusual deletions of the NF1 region, extending over 17q12 region and associated with renal cysts and diabetes (RCDA). To our knowledge this is the first case of a patient carrying a large-sized duplication involving the 17q11.2q12 region. In the duplicated chromosomal segment there are about 130 annotated genes. Among them, several genes which have been already proposed as candidate for mental retardation (MR) in patients with partially overlapping deletions may be responsible for neurological impairment in our patient. In addition, other genes within the duplicated region are of interest for possible correlation with a few clinical features of the patient. [ABSTRACT FROM AUTHOR]

Age at diagnosis is an important risk factor in neuroblastoma (NB) with worse prognosis in children older than 18 months. A more indolent course with long-term relapses and fatal outcome has been described in small series of adolescents. Our objective was to describe biological factors that contribute to this particular behaviour and could be helpful in their treatment. NB cases older than 10 years of age at diagnosis registered in the files of the Neuroblastoma Group of SEOP from 1992 to 2007 were included. Disease extension was classified according to the International Neuroblastoma Staging System (INSS). Tumour samples were studied according to the International Neuroblastoma Pathology Classification (INPC). Biological studies included MNA, 1p, 11q and 17q status and ploidy. Twenty-two patients, from 10.1 to 24.6 years old, were included. Advanced stages predominated. 14/17 patients presented unfavourable histology. None had NMA or 1p del. However, 11q del was found in 8/13 cases and 17q gain in 7/11. Overall survival (OS) and event-free survival (EFS) for the entire series at 5 years were 0.45 and 0.32, respectively. Moreover, 5-year OS and EFS for stage 4 patients were 0.33 and 0.15. NB in adolescents is a special subgroup characterised by high-risk prognostic features which differ from those seen in younger patients, especially in relation to genetic abnormalities. The outcome in stage 4 was worse than in younger metastatic children, outlining the need for new therapeutic approaches in this subgroup of patients. The exact cut-off to separate older patients has not yet been established and will probably be based on biology. [ABSTRACT FROM AUTHOR]

Vesicle-associated membrane proteins 2 and 3 (VAMP2 and VAMP3) are required for the release of D-serine, a competitive agonist of the neurotransmitter glycine at the glutamatergic N-methyl-D-aspartate receptors. Several lines of evidence point to an involvement of altered D-serine levels in the central nervous system in the aetiology of bipolar affective disorder (BPAD). Strong association findings between BPAD and two genes, G72 and DAAO, which are involved in the enzymatic degradation of D-serine, are reported. Based on the functional evidence and on the hypothesis that further genes, which are involved in the regulation of D-serine, could be involved in the disease aetiology, we considered VAMP2 and VAMP3 as candidate genes for BPAD.We analyzed three and four single nucleotide polymorphism (SNP) markers covering VAMP2 and VAMP3, respectively, in an initial BPAD case-control sample of German descent (409 cases, 407 controls). For replication, we analyzed three SNP markers covering VAMP2 in a second sample of the same ethnicity (378 cases, 384 controls).Although no association was found for VAMP3 markers, we observed evidence of association with SNPs at the VAMP2 locus in the initial sample (P values between 0.005 and 0.033). To validate these findings, we analyzed a second BPAD sample and failed to replicate the initial findings at the single-marker and haplotypic level.In conclusion, our results do not suggest that a common genetic variant at VAMP2 or VAMP3 contributes to the development of BPAD in German patients. [ABSTRACT FROM AUTHOR]

Conventional cytogenetic, molecular cytogenic and genetic methods disclosed a broad spectrum of genetic abnormalities leading to gain and loss of chromosomal segments in advanced stage neuroblastoma (NBL). Specific correlation between the genetic findings could delineate distinct genetic pathways, of which the biology and prognostic significance is as yet undetermined. Using spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH) on metaphases from 16 patients with advanced stage NBL, it was possible to explore the whole spectrum of rearrangement within complex karyotypes and to detect hidden recurrent translocations. All translocations were unbalanced. The most prevalent recurrent unbalanced translocations resulted in 17q gain in 12 patients (75%), 11q loss in nine patients (56%), and 1p deletion/imbalance in eight patients (50%). The most frequent recurrent translocation was der(11)t(11;17) in six patients. Three cytogenetic pathways could be delineated. The first, with six patients, was characterized by the unbalanced translocation der(11)t(11;17), detected only by SKY, resulting in the concomitant 17q gain and 11q loss. No MYCN amplification or 1p deletion (except one patient with 1p imbalance) were found, while 3p deletion, and complex karyotypes were common. The second subgroup, with four patients, had 17q gain and 1p deletion, and in two patients 11q loss, that was apparent only by FISH. 1p deletion occurred through der(1)t(1;17) or del(1p). The third subgroup of four patients was characterized by MYCN amplification with 17q gain and 1p deletion, very rarely with 11q loss (one patient) through a translocation with a non-17q partner. The SKY subclassifications were in accordance with the findings reported by molecular genetic techniques, and may indicate that distinct oncogenes and suppressor genes are involved in the der(11)t(11;17) pathway of advanced stage NBL. [Copyright &y& Elsevier]

Neuroblastoma is one of the most common solid tumors of childhood. Despite the most recent advances in combined therapy, the overall survival of patients with disseminated disease has not improved in the last 20 years. On the contrary, the increased knowledge of the genetic and molecular abnormalities that characterize neuroblastoma allowed the identification of several important prognostic factors and possible pathways of neuroblastoma development. Moreover, several other structural and numerical non-random chromosome abnormalities were recognized by comparative genomic hybridization and their role is actively investigated. More recently, it has become evident also that epigenetic factors may alter the pattern of expression of multiple genes whose role in neuroblastoma begins to be understood. It is thus likely that a combination of events that include gene translocation and rearrangement and the altered methylation of crucial genes, contribute to neuroblastoma development and progression and are likely responsible for the clinical heterogeneity of this tumor. [Copyright &y& Elsevier]

Thyroid hormone (triiodothyronine, T3) is a pleiotropic regulator of growth, differentiation and tissue homeostasis in higher organisms that acts through the control of target gene expression. Most, if not all, major T3 actions are mediated by specific high affinity nuclear receptors (TR) which are encoded by two genes, THRA and THRB. Several TRα and TRβ receptor isoforms are expressed. Abundant and contradictory literature exists on the relationship between circulating thyroid hormone levels, thyroid diseases and human cancer. In 1986, a connection between TR and cancer became evident when the chicken TRα1 was characterized as the c-erbA proto-oncogene, the cellular counterpart of the retroviral v-erbA oncogene. V-erbA causes erythroleukemias and sarcomas in birds, and hepatocellular carcinomas in transgenic mice. In recent years, many studies have analyzed the presence of quantitative (abnormal levels) or qualitative (mutations) alterations in the expression of THR genes in different types of human neoplasias. While their role in tumor generation or progression is currently unclear, both gross chromosomal and minor mutations (deletions, aberrant splicing, point mutations) and changes in the level of expression of THRA and THRB genes have been found. Together with other in vitro data indicating connections between TR and p53, Rb, cyclin D and other cell cycle regulators and oncogenes, these results suggest that THRA and THRB may be involved in human cancer. [Copyright &y& Elsevier]

Neuroblastoma is a malignant childhood tumor of migrating neuroectodermal cells derived from the neural crest and destined for the adrenal medulla and the sympathetic nervous system. The biological behavior of neuroblastomas is extremely variable and in some respects unique. Neuroblastomas tend to regress spontaneously in a portion of infants or to differentiate into a benign ganglioneuroma in some older patients. Unfortunately, in the majority of patients neuroblastoma is metastatic at the time of diagnosis, and it usually undergoes rapid progression with a fatal outcome. The mechanisms leading to this diverse clinical behavior of neuroblastomas are largely unclear. From the analysis of tumors at the cytogenetic and molecular level non-random genetic changes have been identified, including ploidy changes, amplification of the oncogene MYCN, deletions of chromosome 1p, gains of chromosome arm 17q, and deletions of 11q as well as of other genomic regions that allow tumors to be classified into subsets with distinct biological features and clinical behavior. MYCN status is widely accepted for therapy stratification. Additional genetic parameters are currently under investigation to refine risk assessment, but so far the molecular monitoring tools for prediction of therapy response and disease outcome are still incomplete. This should lead to more risk-adapted therapies according to the clinical-genetic parameters by which individual tumors are characterized. This review aims at discussing the role of genomic changes in neuroblastomas of diverse biological and clinical types. [Copyright &y& Elsevier]