Characterization of adolescent and pediatric renal cell carcinoma: A report from the Children's Oncology Group study AREN03B2

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111918/1/cncr29368.pd

Results of Treatment for Patients With Multicentric or Bilaterally Predisposed Unilateral Wilms Tumor (AREN0534): A report from the Children’s Oncology Group

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156248/2/cncr32958_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156248/1/cncr32958.pd

DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma

The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and ‘hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma

Highly Precise and Developmentally Programmed Genome Assembly in Paramecium Requires Ligase IV–Dependent End Joining

During the sexual cycle of the ciliate Paramecium, assembly of the somatic genome includes the precise excision of tens of thousands of short, non-coding germline sequences (Internal Eliminated Sequences or IESs), each one flanked by two TA dinucleotides. It has been reported previously that these genome rearrangements are initiated by the introduction of developmentally programmed DNA double-strand breaks (DSBs), which depend on the domesticated transposase PiggyMac. These DSBs all exhibit a characteristic geometry, with 4-base 5′ overhangs centered on the conserved TA, and may readily align and undergo ligation with minimal processing. However, the molecular steps and actors involved in the final and precise assembly of somatic genes have remained unknown. We demonstrate here that Ligase IV and Xrcc4p, core components of the non-homologous end-joining pathway (NHEJ), are required both for the repair of IES excision sites and for the circularization of excised IESs. The transcription of LIG4 and XRCC4 is induced early during the sexual cycle and a Lig4p-GFP fusion protein accumulates in the developing somatic nucleus by the time IES excision takes place. RNAi–mediated silencing of either gene results in the persistence of free broken DNA ends, apparently protected against extensive resection. At the nucleotide level, controlled removal of the 5′-terminal nucleotide occurs normally in LIG4-silenced cells, while nucleotide addition to the 3′ ends of the breaks is blocked, together with the final joining step, indicative of a coupling between NHEJ polymerase and ligase activities. Taken together, our data indicate that IES excision is a “cut-and-close” mechanism, which involves the introduction of initiating double-strand cleavages at both ends of each IES, followed by DSB repair via highly precise end joining. This work broadens our current view on how the cellular NHEJ pathway has cooperated with domesticated transposases for the emergence of new mechanisms involved in genome dynamics

Gene expression in a paleopolyploid: a transcriptome resource for the ciliate Paramecium tetraurelia

International audienceBACKGROUND: The genome of Paramecium tetraurelia, a unicellular model that belongs to the ciliate phylum, has been shaped by at least 3 successive whole genome duplications (WGD). These dramatic events, which have also been documented in plants, animals and fungi, are resolved over evolutionary time by the loss of one duplicate for the majority of genes. Thanks to a low rate of large scale genome rearrangement in Paramecium, an unprecedented large number of gene duplicates of different ages have been identified, making this organism an outstanding model to investigate the evolutionary consequences of polyploidization. The most recent WGD, with 51% of pre-duplication genes still in 2 copies, provides a snapshot of a phase of rapid gene loss that is not accessible in more ancient polyploids such as yeast. RESULTS: We designed a custom oligonucleotide microarray platform for P. tetraurelia genome-wide expression profiling and used the platform to measure gene expression during 1) the sexual cycle of autogamy, 2) growth of new cilia in response to deciliation and 3) biogenesis of secretory granules after massive exocytosis. Genes that are differentially expressed during these time course experiments have expression patterns consistent with a very low rate of subfunctionalization (partition of ancestral functions between duplicated genes) in particular since the most recent polyploidization event. CONCLUSIONS: A public transcriptome resource is now available for Paramecium tetraurelia. The resource has been integrated into the ParameciumDB model organism database, providing searchable access to the data. The microarray platform, freely available through NimbleGen Systems, provides a robust, cost-effective approach for genome-wide expression profiling in P. tetraurelia. The expression data support previous studies showing that at short evolutionary times after a whole genome duplication, gene dosage balance constraints and not functional change are the major determinants of gene retention

The household economics of rubber intercropping during the immature period in northeast thailand

International audienceIn order to alleviate poverty in Northeast Thailand, the Thai government has promoted rubber farming, which has expanded at the expense of annual crops. Because of a long immature period, planting rubber represents a loss of income for poor farmers in the very first years. This paper analyzed how rubber intercropping during the immature period helps farmers to compensate for this loss of income. Economic performances of the most widespread rubber farming systems were analyzed using information collected from a questionnaire addressed to 35 farmers in Buriram province. A sub-sample of 22 farmers was further interviewed to estimate the contribution of rubber intercropping in the formation of the total annual income during the immature period. The results showed that interest in rubber intercropping has grown, with cassava and rice as the main associated crops. With additional costs of about 14,169 B/ha/year over monospecific rubber plantations, rubber-cassava intercropping systems generated a gross margin estimated at 11,340 B/ha/year for a 3-year period. Compared to a monospecific rubber plantation, rubber-cassava intercropping systems reduced management costs by 59% over the 6-year period of rubber immaturity. The cashincome drawn from intercropping ranged from 0 to 26.8% of the household's total annual income, which can be of considerable importance for low-income farmers

Gain of 1q is associated with inferior event-free and overall survival in patients with favorable histology Wilms tumor: A report from the Children\u27s Oncology Group

BACKGROUND: Wilms tumor is the most common childhood renal tumor. While the majority of patients with favorable histology Wilms Tumor (FHWT) have good outcomes, some patients still experience recurrence and death from disease. This study’s goal was to determine if tumor-specific chromosome 1q gain is associated with event-free (EFS) and overall survival (OS) in FHWT. METHODS: Unilateral FHWT samples were obtained from patients enrolled on National Wilms Tumor Study-4 and Pediatric Oncology Group 9046, “A Molecular Genetic analysis of Wilms Tumor.” 1q gain, 1p loss, and 16q loss were determined using multiplex ligation-dependent probe amplification (MLPA). RESULTS: The eight-year EFS was 87% (95% CI 82%, 91%) for the entire cohort of 212 patients. Tumors of 58/212 patients (27%) displayed 1q gain. A strong relationship between 1q gain and 1p/16q loss was observed. The eight-year EFS was 76% (95% CI 63%, 85%) for those with 1q gain and 93% (95% CI 87%, 96%) for those lacking 1q gain (p=0.0024). The eight-year OS was 89% (95% CI 78%, 95%) for those with 1q gain, and 98% (95% CI 94%, 99%) for those lacking 1q gain (p=0.0075). Gain of 1q did not correlate with disease stage (p=0.16). After stratification for stage, 1q gain was associated with significantly increased risk of recurrence (risk ratio estimate: 2.72, p=0.0089). CONCLUSIONS: Gain of 1q may provide a valuable prognostic marker to stratify therapy for patients with FHWT. A confirmatory study is necessary before this biomarker is incorporated into risk stratification schema of future therapeutic studies

Association of Chromosome 1q Gain With Inferior Survival in Favorable-Histology Wilms Tumor: A Report From the Children\u27s Oncology Group.

PURPOSE: The goal of this study was to analyze the association of copy number gain of 1q in favorable-histology Wilms tumors (FHWTs) with event-free survival (EFS) and overall survival (OS) within each tumor stage and with 1p and 16q copy number loss and/or loss of heterozygosity. METHODS: Unilateral FHWTs from 1,114 patients enrolled in National Wilms Tumor Study-5 that were informative for 1p and 16q microsatellite markers (previously determined) and informative for 1q gain, 1p loss, and 16q loss using multiplex ligation-dependent probe amplification were analyzed. RESULTS: Eight-year EFS was 86% (95% CI, 84% to 88%) for the entire cohort. Of 1,114 patients, 317 tumors (28%) displayed 1q gain. Eight-year EFS was 77% for those with 1q gain and 90% for those lacking 1q gain (P < .001). Eight-year OS was 88% for those with 1q gain and 96% for those lacking 1q gain (P < .001). Within each disease stage, 1q gain was associated with inferior EFS (stage I, 85% v 95%; P = .0052; stage II, 81% v 87%; P = .0775; stage III, 79% v 89%; P = .01; stage IV, 64% v 91%; P = .001). OS was significantly inferior in patients with stage I (P < .0015) and stage IV disease (P = .011). With multivariable analysis, 1q gain was associated with an increased relative risk of relapse of 2.4 (P < .001), whereas 1p loss was not, despite significance on univariable analysis. CONCLUSION: Gain of 1q is associated with inferior survival in unilateral FHWTs and may be used to guide risk stratification in future studies

Comparison of diagnostic performance of CT and MRI for abdominal staging of pediatric renal tumors: a report from the Children\u27s Oncology Group

BACKGROUND: CT and MRI are both used for abdominal staging of pediatric renal tumors. The diagnostic performance of the two modalities for local and regional staging of renal tumors has not been systematically evaluated. OBJECTIVE: To compare the diagnostic performance of CT and MRI for local staging of pediatric renal tumors. MATERIALS AND METHODS: The study population was derived from the AREN03B2 study of the Children\u27s Oncology Group. Baseline abdominal imaging performed with both CT and MRI within 30 days of nephrectomy was available for retrospective review in 82 renal tumor cases. Each case was evaluated for capsular penetration, lymph node metastasis, tumor thrombus, preoperative tumor rupture, and synchronous contralateral lesions. The surgical and pathological findings at central review were the reference standard. RESULTS: The sensitivity of CT and MRI for detecting capsular penetration was 68.6% and 62.9%, respectively (P = 0.73), while specificity was 86.5% and 83.8% (P = 1.0). The sensitivity of CT and MRI for detecting lymph node metastasis was 76.5% and 52.9% (P = 0.22), and specificity was 90.4% and 92.3% (P = 1.0). Synchronous contralateral lesions were identified by CT in 4/9 cases and by MRI in 7/9 cases. CONCLUSION: CT and MRI have similar diagnostic performance for detection of lymph node metastasis and capsular penetration. MR detected more contralateral synchronous lesions; however these were present in a very small number of cases. Either modality can be used for initial loco-regional staging of pediatric renal tumors