Population based allele frequencies of disease associated polymorphisms in the Personalized Medicine Research Project

<p>Abstract</p> <p>Background</p> <p>There is a lack of knowledge regarding the frequency of disease associated polymorphisms in populations and population attributable risk for many populations remains unknown. Factors that could affect the association of the allele with disease, either positively or negatively, such as race, ethnicity, and gender, may not be possible to determine without population based allele frequencies.</p> <p>Here we used a panel of 51 polymorphisms previously associated with at least one disease and determined the allele frequencies within the entire Personalized Medicine Research Project population based cohort. We compared these allele frequencies to those in dbSNP and other data sources stratified by race. Differences in allele frequencies between self reported race, region of origin, and sex were determined.</p> <p>Results</p> <p>There were 19544 individuals who self reported a single racial category, 19027 or (97.4%) self reported white Caucasian, and 11205 (57.3%) individuals were female. Of the 11,208 (57%) individuals with an identifiable region of origin 8337 or (74.4%) were German.</p> <p>41 polymorphisms were significantly different between self reported race at the 0.05 level. Stratification of our Caucasian population by self reported region of origin revealed 19 polymorphisms that were significantly different (p = 0.05) between individuals of different origins. Further stratification of the population by gender revealed few significant differences in allele frequencies between the genders.</p> <p>Conclusions</p> <p>This represents one of the largest population based allele frequency studies to date. Stratification by self reported race and region of origin revealed wide differences in allele frequencies not only by race but also by region of origin within a single racial group. We report allele frequencies for our Asian/Hmong and American Indian populations; these two minority groups are not typically selected for population allele frequency detection. Population wide allele frequencies are important for the design and implementation of studies and for determining the relevance of a disease associated polymorphism for a given population.</p

Novel Fusion of MYST/Esa1-Associated Factor 6 and PHF1 in Endometrial Stromal Sarcoma

Rearrangement of chromosome band 6p21 is recurrent in endometrial stromal sarcoma (ESS) and targets the PHF1 gene. So far, PHF1 was found to be the 3′ partner in the JAZF1-PHF1 and EPC1-PHF1 chimeras but since the 6p21 rearrangements involve also other chromosomal translocation partners, other PHF1-fusions seem likely. Here, we show that PHF1 is recombined with a novel fusion partner, MEAF6 from 1p34, in an ESS carrying a t(1;6)(p34;p21) translocation as the sole karyotypic anomaly. 5′-RACE, RT-PCR, and sequencing showed the presence of an MEAF6-PHF1 chimera in the tumor with exon 5 of MEAF6 being fused in-frame to exon 2 of PHF1 so that the entire PHF1 coding region becomes the 3′ terminal part of the MEAF6-PHF1 fusion. The predicted fusion protein is composed of 750 amino acids and contains the histone acetyltransferase subunit NuA4 domain of MEAF6 and the tudor, PHD zinc finger, and MTF2 domains of PHF1. Although the specific functions of the MEAF6 and PHF1 proteins and why they are targeted by a neoplasia-specific gene fusion are not directly apparent, it seems that rearrangement of genes involved in acetylation (EPC1, MEAF6) and methylation (PHF1), resulting in aberrant gene expression, is a common theme in ESS pathogenesis

The Polycomb Repressive Complex 2 Is a Potential Target of SUMO Modifications

The Polycomb Repressive Complex 2 (PRC2) functions as a transcriptional repressor through a mechanism that involves methylation of Histone H3 at lysine 27. The PRC2 complex activity is essential for cellular proliferation, development, and cell fate decisions. PRC2 target genes include important regulators of development and proliferation as well as tumor suppressor genes. Consistent with this, the activity of several Polycomb group (PcG) proteins is deregulated in human cancer suggesting an important role for PcGs in tumor development. Whereas the downstream functions of PcGs are well characterized, the mechanisms of their recruitment to target genes and the regulation of their activity are not fully understood.Here we show that the two PRC2 components SUZ12 and EZH2 are sumoylated in vitro and in vivo. Among several putative sumoylation sites we have mapped the major site of SUZ12 sumoylation. Furthermore, we show that SUZ12 interacts with the E2-conjugating enzyme UBC9 both in vitro and in vivo and that mutation of the SUZ12 sumoylation site does not abolish this binding. Finally, we provide evidence that the E3-ligase PIASXbeta interacts and enhances the sumoylation of SUZ12 in vivo suggesting that PIASXbeta could function as an E3-ligase for SUZ12.Taken together, our data identify sumoylation as a novel post-translational modification of components of the PRC2 complex, which could suggest a potential new mechanism to modulate PRC2 repressive activity. Further work aimed to identify the physiological conditions for these modifications will be required to understand the role of SUZ12 and EZH2 sumoylation in PcG-mediated epigenetic regulation of transcription

Murine Cytomegalovirus Infection of Neural Stem Cells Alters Neurogenesis in the Developing Brain

Congenital cytomegalovirus (CMV) brain infection causes serious neuro-developmental sequelae including: mental retardation, cerebral palsy, and sensorineural hearing loss. But, the mechanisms of injury and pathogenesis to the fetal brain are not completely understood. The present study addresses potential pathogenic mechanisms by which this virus injures the CNS using a neonatal mouse model that mirrors congenital brain infection. This investigation focused on, analysis of cell types infected with mouse cytomegalovirus (MCMV) and the pattern of injury to the developing brain.We used our MCMV infection model and a multi-color flow cytometry approach to quantify the effect of viral infection on the developing brain, identifying specific target cells and the consequent effect on neurogenesis. In this study, we show that neural stem cells (NSCs) and neuronal precursor cells are the principal target cells for MCMV in the developing brain. In addition, viral infection was demonstrated to cause a loss of NSCs expressing CD133 and nestin. We also showed that infection of neonates leads to subsequent abnormal brain development as indicated by loss of CD24(hi) cells that incorporated BrdU. This neonatal brain infection was also associated with altered expression of Oct4, a multipotency marker; as well as down regulation of the neurotrophins BDNF and NT3, which are essential to regulate the birth and differentiation of neurons during normal brain development. Finally, we report decreased expression of doublecortin, a marker to identify young neurons, following viral brain infection.MCMV brain infection of newborn mice causes significant loss of NSCs, decreased proliferation of neuronal precursor cells, and marked loss of young neurons

Intracardiac acoustic radiation force impulse imaging: a novel imaging method for intraprocedural evaluation of radiofrequency ablation lesions.

BACKGROUND: Arrhythmia recurrence after cardiac radiofrequency ablation (RFA) for atrial fibrillation has been linked to conduction through discontinuous lesion lines. Intraprocedural visualization and corrective ablation of lesion line discontinuities could decrease postprocedure atrial fibrillation recurrence. Intracardiac acoustic radiation force impulse (ARFI) imaging is a new imaging technique that visualizes RFA lesions by mapping the relative elasticity contrast between compliant-unablated and stiff RFA-treated myocardium. OBJECTIVE: To determine whether intraprocedure ARFI images can identify RFA-treated myocardium in vivo. METHODS: In 8 canines, an electroanatomical mapping-guided intracardiac echo catheter was used to acquire 2-dimensional ARFI images along right atrial ablation lines before and after RFA. ARFI images were acquired during diastole with the myocardium positioned at the ARFI focus (1.5 cm) and parallel to the intracardiac echo transducer for maximal and uniform energy delivery to the tissue. Three reviewers categorized each ARFI image as depicting no lesion, noncontiguous lesion, or contiguous lesion. For comparison, 3 separate reviewers confirmed RFA lesion presence and contiguity on the basis of functional conduction block at the imaging plane location on electroanatomical activation maps. RESULTS: Ten percent of ARFI images were discarded because of motion artifacts. Reviewers of the ARFI images detected RFA-treated sites with high sensitivity (95.7%) and specificity (91.5%). Reviewer identification of contiguous lesions had 75.3% specificity and 47.1% sensitivity. CONCLUSIONS: Intracardiac ARFI imaging was successful in identifying endocardial RFA treatment when specific imaging conditions were maintained. Further advances in ARFI imaging technology would facilitate a wider range of imaging opportunities for clinical lesion evaluation

A phase II study of capecitabine, carboplatin, and bevacizumab for metastatic or unresectable gastroesophageal junction and gastric adenocarcinoma.

115 Background: Gastroesophageal junction (GEJ) and gastric adenocarcinomas constitute a major health problem worldwide. In the United States, the incidence of adenocarcinoma of the esophagus, GEJ and gastric cardia is rising rapidly. Chemotherapy for metastatic disease improves survival and quality of life when compared to best supportive care. The addition of bevacizumab to chemotherapy in a large, randomized, multinational study showed conflicting results. Methods: Patients (pts) with biopsy proven metastatic or unresectable GEJ and gastric adenocarcinomas received bevacizumab 15 mg/kg IV and carboplatin AUC 6 IV on day 1 and capecitabine 850 mg/m2twice daily by mouth on days 1-14 on a 21-day cycle. Pts with stable disease (SD) or partial response (PR) were allowed to continue therapy with bevacizumab with or without capecitabine. Primary endpoints were progression free survival (PFS) and toxicity; secondary endpoints were overall survival (OS) and response rate by RECIST. Results: Between April 2009 and April 2013, a total of 35 pts were enrolled. At present, 29 patients are off treatment and 6 are still actively receiving treatment. 29 pts are available for response assessment, 6 patients came off study prior to their first tumor assessment. Baseline characteristics are: M:F = 25:10; median age = 58 years (range 25-81); primary site = GEJ (17) and gastric (18); degree of differentiation = well (3), moderate (12), poor/signet ring (18), and unknown (2); race = White Non-Hispanic (24), White Hispanic (6), and Asian (5). The 1-year PFS is 21% and median PFS is 8.5 months. Median OS is 14.3 months. Best response by RECIST is as follows: PR in 17 pts (49%), SD in 6 pts (17%), and progressive disease (PD) in 6 pts (17%). The treatment was well-tolerated with toxicities as expected. Conclusions: The combination of capecitabine, carboplatin and bevacizumab in metastatic or unresectable unresectable GEJ and gastric adenocarcinomas is well tolerated and shows promising response rates, though did not meet the primary endpoint of PFS. Clinical trial information: NCT00780494