Aggressive neuroblastoma remains a significant cause of childhood cancer death despite current intensive multimodal treatment protocols. The purpose of the present work was to characterize the genetic and clinical diversity of such tumors by high resolution arrayCGH profiling.
Based on a 32K BAC whole-genome tiling path array and using 50-250K Affymetrix SNP array platforms for verification, DNA copy number profiles were generated for 34 consecutive high-risk or lethal outcome neuroblastomas. In addition, age and MYCN amplification (MNA) status were retrieved for 112 unfavorable neuroblastomas of the Swedish Childhood Cancer Registry, representing a 25-year neuroblastoma cohort of Sweden, here used for validation of the findings. Statistical tests used were: Fisher's exact test, Bayes moderated t-test, independent samples t-test, and correlation analysis.
MNA or segmental 11q loss (11q-) was found in 28/34 tumors. With two exceptions, these aberrations were mutually exclusive. Children with MNA tumors were diagnosed at significantly younger ages than those with 11q- tumors (mean: 27.4 vs. 69.5 months; p=0.008; n=14/12), and MNA tumors had significantly fewer segmental chromosomal aberrations (mean: 5.5 vs. 12.0; p
Cites: Nucleic Acids Res. 2002 Feb 15;30(4):e1511842121
Primary tumours from 100 Norwegian node-negative breast carcinoma patients were examined for c-erbB-2, int-2, and c-myc proto-oncogene amplification. c-erbB-2, int-2, and c-myc amplification was found in 12.1% (12 of 99), 8.6% (8 of 93), and 1.1% (1 of 89) of the samples respectively. All the c-erbB-2 amplified tumours were of the ductal type, and all the int-2 amplified tumours were oestrogen receptor positive. No other significant or borderline significant associations between gene amplification and clinical or histopathological parameters were found. Relapse occurred more frequently in patients with c-erbB-2 gene amplification (relapse in 33.3% of the patients with c-erbB-2 amplification compared to 20.7% in the non-amplified group), but the difference was not statistically significant, int-2 amplification was not associated with increased risk of relapse, whereas the prognostic value of the c-myc amplification could not be evaluated.
Amplification of HER-2(erbB-2/neu) oncogene was detected in 36 of 142 (25%) breast carcinomas (BC) RNA expression was examined in 42 carcinomas, in 10 of them overexpression was revealed. Amplification was matched by overexpression. No association was found between the increased number of HER-2(erbB-2/neu) copies and tumor size, lymph node involvement, stage of disease, age of onset, and estrogen and progesterone receptor level. HER-2(erbB-2/neu) amplification was shown to be of independent prognostic significance in the group of 32 BC patients with sufficient follow-up (more than 40 months). Six of 7 HER-2(erbB-2/neu) amplification-positive patients and only 2 of 25 HER-2(erbB-2/neu) amplification-negative ones relapsed (p
Cancer is known to be a genetic disease that is both polygenic and heterogeneous, in most cases involving changes in several genes in a stepwise fashion. The spectrum of individual genes involved in the initiation and progression of cancer is greatly influenced by genetic factors unique to each patient. A study of complex diseases such as cancer is complicated by the genetic heterogeneous background and environmental factors in the human population. Endometrial cancer (EC) is ranked fourth among invasive tumors in women. In Sweden, approximately 1300 women (27/100,000 women) are diagnosed annually. To be able to study the genetic alterations in cancer, the use of an animal model is very convenient. Females of the BDII strain are genetically predisposed to EC and 90% of female BDII rats develop EC during their lifetime. Thus, BDII rats have been used to model human EC with respect to the genetics of susceptibility and of tumor development. A set of rat EC tumors was analyzed using conventional cytogenetics and comparative genome hybridization (CGH). Chromosomal aberrations, i.e., gains, were found on rat chromosome 4 (RNO4). Using FISH analysis, we concluded that the Met oncogene and Cdk6 (cyclin-dependent kinase 6) were amplified in this set of EC tumors. The data from this investigation were used to analyze a set of human endometrial tumors for amplification of Cdk6 and Met. Our preliminary data are indicative for a good correlation between our findings in the BDII rat model for EAC and the situation in human EC. These data provide strong support for the use of animal model systems for better understanding and scrutinizing of human complex disease of cancer.
In this study, we investigated recent sheep pox outbreaks that occurred in Ononsky and Borzunsky regions of Zabajkalskij kray of Russia. The outbreaks involved in 2756 animals of which 112 were infected and 3 were slaughtered. Samples of injured skin of infected sheep were analysed by electron microscopy and CaPV-specific P32 gene amplification. Following sequence analysis of entire P32 gene showed that both specimens were identical to the sequence of several sheep poxvirus isolates from China and India. The close location of China to the last decade's Russian outbreaks suggest that possible future outbreaks in Russia could occur along the border regions with countries where sheep and goat pox are not controlled.
BACKGROUND: Rickettsia helvetica is the only non-imported rickettsia found in Scandinavia. It was first detected in Ixodes ricinus ticks, but has never been linked to human disease. We studied two young Swedish men who died of sudden cardiac failure during exercise, and who showed signs of perimyocarditis similar to those described in rickettsial disease. METHODS: Samples from the heart and other organs were analysed by PCR and DNA sequencing. May-Gr?nwald-Giemsa, Grocott, and acridine-orange stains were used for histopathological examinations. Staining of R. helvetica grown on shell-vials in vero cells, and the early descriptions of R. rickettsii by H T Ricketts and S B Wohlbach served as controls. Immunohistochemistry was done with Proteus OX-19 rabbit antisera as the primary antibody. The structure of rickettsia-like organisms was investigated by transmission electron microscopy. Serological analyses were carried out by indirect immunofluorescence with R. helvetica as the antigen. FINDINGS: By use of a semi-nested PCR, with primers specific for the 16S rRNA and 17-kDa outer-membrane-protein genes, and sequence analysis of the amplified products, genetic material from R. helvetica was detected in the pericardium and in a lymph node from the pulmonary hilum in case 1, and in a coronary artery and the heart muscle in case 2. A serological response in case 1 revealed an endpoint titre for R. helvetica of 1/320 (1/256 with R. rickettsii as the antigen). Examination of PCR-positive tissue showed chronic interstitial inflammation and the presence of rickettsia-like organisms predominantly located in the endothelium. These organisms reacted with Proteus OX-19 antisera, and their size and form were consistent with rickettsia. Electron microscopy confirmed that the appearance of the organisms was similar to that described for spotted-fever rickettsia. INTERPRETATION: R. helvetica, transmitted by I. ricinus ticks, may be an important pathogen in the aetiology of perimyocarditis, which can result in sudden unexpected cardiac death in young people.
Potential interaction of Aurora-A amplification and BRCA2 mutation was examined in breast tumours from BRCA2 999del5 mutation carriers (n=20) and non-carriers (n=41). Aurora-A amplification studied by FISH was significantly more common in breast tumours from BRCA2 mutation carriers (p=0.0005). Extensive Aurora-A amplification was also detected on metaphase chromosomes in three breast epithelial cell lines with the same BRCA2 mutation. In addition, significant association was found between Aurora-A amplification and TP53 mutations in non-BRCA2 mutation carrier tumours (p=0.007). These results suggest that breast tumours with mutations in BRCA2 or TP53 could be promising candidates for Aurora-A targeted treatment.
Breakthrough Breast Cancer Research Unit, School of Cancer, Enabling Sciences and Technology, University of Manchester, Manchester Academic Health Science Centre, Paterson Institute for Cancer Research, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK.
The emergence of automated image analysis algorithms has aided the enumeration, quantification, and immunohistochemical analyses of tumor cells in both whole section and tissue microarray samples. To date, the focus of such algorithms in the breast cancer setting has been on traditional markers in the common invasive ductal carcinoma subtype. Here, we aimed to optimize and validate an automated analysis of the cell cycle regulator cyclin D1 in a large collection of invasive lobular carcinoma and relate its expression to clinicopathologic data. The image analysis algorithm was trained to optimally match manual scoring of cyclin D1 protein expression in a subset of invasive lobular carcinoma tissue microarray cores. The algorithm was capable of distinguishing cyclin D1-positive cells and illustrated high correlation with traditional manual scoring (?=0.63). It was then applied to our entire cohort of 483 patients, with subsequent statistical comparisons to clinical data. We found no correlation between cyclin D1 expression and tumor size, grade, and lymph node status. However, overexpression of the protein was associated with reduced recurrence-free survival (P=.029), as was positive nodal status (P
Neuroblastoma has several characteristics that suggest that preclinical diagnosis might improve outcome. Therefore, the Quebec Neuroblastoma Screening Project was undertaken from 1989 to 1994 to examine infants at 3 weeks and 6 months by measuring urinary catecholamine metabolites.
Over the 5-yr period, 45 tumors were detected by screening, 20 were identified clinically prior to the third week, and 64 were identified clinically at a later time. We analyzed available tumors for Shimada histopathology, tumor ploidy, MYCN copy number and serum ferritin.
Of the tumors detected by screening, only 2 of 45 tested had unfavorable histology, 2 of 45 had diploid or tetraploid DNA content, 0 of 43 had MYCN amplification, and 4 of 44 had elevated serum ferritin. All of these patients are alive and well. The 20 patients detected prior to the 3-week screen had similar biological characteristics. In contrast, of the patients detected clinically after 3 weeks of age, 19 of 51 testedhad unfavorable histology, 25 of 66 had diploid or tetraploid tumors, 12 of 56 had MYCN amplification, and 14 of 54 had elevated ferritin.
The difference between the screened and clinically detected cases was highly significant for each biological variable. Preliminary data on other biological variables, such as neurotrophin expression and allelic loss on 1 p in these patients are consistent with the above findings. These data suggest that mass screening for neuroblastoma at or before 6 months of age detects almost exclusively tumors that have favorable biological characteristics, many of which might have regressed spontaneously. Thus, continued mass screening for neuroblastoma at 6 months is unlikely to accomplish its intended goal, and should probably be discontinued.