Genomic and Cytogenetic Characterization of a Balanced Translocation Disrupting NUP98.

A 41-year-old Asian woman with bilateral renal angiomyolipomas (AML) was incidentally identified to have a balanced translocation, 46,XX,t(11;12)(p15.4;q15). She had no other features or family history to suggest a diagnosis of tuberous sclerosis. Her healthy daughter had the same translocation and no renal AML at the age of 3 years. Whole-genome sequencing was performed on genomic maternal DNA isolated from blood. A targeted de novo assembly was then conducted with ABySS for chromosomes 11 and 12. Sanger sequencing was used to validate the translocation breakpoints. As a result, genomic characterization of chromosomes 11 and 12 revealed that the 11p breakpoint disrupted the NUP98 gene in intron 1, causing a separation of the promoter and transcription start site from the rest of the gene. The translocation breakpoint on chromosome 12q was located in a gene desert. NUP98 has not yet been associated with renal AML pathogenesis, but somatic NUP98 alterations are recurrently implicated in hematological malignancies, most often following a gene fusion event. We also found evidence for complex structural events involving chromosome 12, which appear to disrupt the TDG gene. We identified a TDGP1 partially processed pseudogene at 12p12.1, which adds complexity to the de novo assembly. In conclusion, this is the first report of a germline constitutional structural chromosome rearrangement disrupting NUP98 that occurred in a generally healthy woman with bilateral renal AML.

Catalyzing community action within a national campaign: VERB community and national partnerships.

The VERB campaign used a social marketing approach to deliver its message through the mass media, school and community promotions, and partnerships to encourage children aged 9-13 years (tweens) to be physically active every day. This paper presents the VERB campaign's community and national partnership strategy, highlights three successful partnerships, and discusses challenges associated with the efforts. The national advertising generated awareness of and affinity for the product's brand and motivated the primary audience to seek out the product. The campaign's national and community partners were engaged to facilitate a product-distribution channel. The campaign developed a three-pronged partnership strategy to integrate the promotion with the placement of the campaign's product (physical activity): (1) reframe the way physical activity is positioned and delivered; (2) connect the brand to the point-of-purchase; and (3) refer (or drive) the audience to the action outlets, opportunities, places, spaces and programs to purchase the product. The VERB campaign provided partners with marketing training and resources to assist them as they leveraged tweens' brand awareness and supported regular physical activity among tweens. The method of technical assistance and the types of marketing tools were provided in relationship to four characteristics of the partner: (1) partner's network, (2) leaders and champions in the network, (3) partner's financial resources for community campaigns; and (4) partner's understanding of the marketing mindset. Coordinated, collaborative, and strong mass-media and community-based interventions within a national social marketing campaign can sustain the immediate effects of such campaigns.

VERB - a social marketing campaign to increase physical activity among youth.

The VERB campaign is a multiethnic media campaign with a goal to increase and maintain physical activity among tweens, or children aged nine to 13 years. Parents, especially mothers aged 29 to 46, and other sources of influence on tweens (e.g., teachers, youth program leaders) are the secondary audiences of the VERB initiative. VERB applies sophisticated commercial marketing techniques to address the public health problem of sedentary lifestyles of American children, using the social marketing principles of product, price, place, and promotion. In this paper, we describe how these four principles were applied to formulate the strategies and tactics of the VERB campaign, and we provide examples of the multimedia materials (e.g., posters, print advertising, television, radio spots) that were created.

GDF6, a novel locus for a spectrum of ocular developmental anomalies.

Colobomata represent visually impairing ocular closure defects that are associated with a diverse range of developmental anomalies. Characterization of a chromosome 8q21.2-q22.1 segmental deletion in a patient with chorioretinal coloboma revealed elements of nonallelic homologous recombination and nonhomologous end joining. This genomic architecture extends the range of chromosomal rearrangements associated with human disease and indicates that a broader spectrum of human chromosomal rearrangements may use coupled homologous and nonhomologous mechanisms. We also demonstrate that the segmental deletion encompasses GDF6, encoding a member of the bone-morphogenetic protein family, and that inhibition of gdf6a in a model organism accurately recapitulates the proband's phenotype. The spectrum of disorders generated by morpholino inhibition and the more severe defects (microphthalmia and anophthalmia) observed at higher doses illustrate the key role of GDF6 in ocular development. These results underscore the value of integrated clinical and molecular investigation of patients with chromosomal anomalies.

Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples.

Recent clinical trials have suggested that patients whose breast tumors overexpress HER2 may derive particular benefit from anthracycline-containing chemotherapy compared to that without anthracycline. It has been proposed that the HER2 gene amplification reported in these tumors might mask an underlying TOP2A gene amplification that occurs frequently and concurrently with HER2 amplification. Topoisomerase II alpha, encoded by TOP2A, is a direct molecular target of anthracycline drug action and is potentially useful as a predictive marker of response to anthracycline therapy for breast cancer. In this study, we examined whether TOP2A gene amplification is an appropriate marker for identifying breast tumors expressing high levels of topoisomerase II alpha. We determined topoisomerase II alpha protein expression by immunohistochemistry in 81 human breast tumors in relation to HER2 and TOP2A gene copy numbers analyzed by fluorescence in situ hybridization, histologic grade, cell proliferation fraction measured by MIB-1 expression, and HER2 protein expression determined by immunohistochemistry. The results showed no correlation between TOP2A gene copy number and topoisomerase II alpha protein expression levels in breast tumors, in contrast to the analogous situation for HER2 gene amplification and HER2 immunohistochemistry. Our results suggest that TOP2A gene amplification in breast tumors does not predict high expression of topoisomerase II alpha protein.