Methylation profiling and evaluation of demethylating therapy in renal cell carcinoma.

BACKGROUND: Despite therapeutic advances in targeted therapy, metastatic renal cell carcinoma (RCC) remains incurable for the vast majority of patients. Key molecular events in the pathogenesis of RCC include inactivation of the VHL tumour suppressor gene (TSG), inactivation of chromosome 3p TSGs implicated in chromatin modification and remodelling and de novo tumour-specific promoter methylation of renal TSGs. In the light of these observations it can be proposed that, as in some haematological malignancies, demethylating agents such as azacitidine might be beneficial for the treatment of advanced RCC. RESULTS: Here we report that the treatment of RCC cell lines with azacitidine suppressed cell proliferation in all 15 lines tested. A marked response to azacitidine therapy (>50% reduction in colony formation assay) was detected in the three cell lines with VHL promoter methylation but some RCC cell lines without VHL TSG methylation also demonstrated a similar response suggesting that multiple methylated TSGs might determine the response to demethylating therapies. To identify novel candidate methylated TSGs implicated in RCC we undertook a combined analysis of copy number and CpG methylation array data. Candidate novel epigenetically inactivated TSGs were further prioritised by expression analysis of RCC cell lines pre and post-azacitidine therapy and comparative expression analysis of tumour/normal pairs. Thus, with subsequent investigation two candidate genes were found to be methylated in more than 25% of our series and in the TCGA methylation dataset for 199 RCC samples: RGS7 (25.6% and 35.2% of tumours respectively) and NEFM in (25.6% and 30.2%). In addition three candidate genes were methylated in >10% of both datasets (TMEM74 (15.4% and 14.6%), GCM2 (41.0% and 14.6%) and AEBP1 (30.8% and 13.1%)). Methylation of GCM2 (P = 0.0324), NEFM (P = 0.0024) and RGS7 (P = 0.0067) was associated with prognosis. CONCLUSIONS: These findings provide preclinical evidence that treatment with demethylating agents such as azacitidine might be useful for the treatment of advanced RCC and further insights into the role of epigenetic changes in the pathogenesis of RCC

A comparative study of craniofacial measurements between Ryukyuan and mainland Japanese females using lateral cephalometric images

Using lateral cephalometric images, we compared the skeletal and soft tissue configurations of Ryukyuan and mainland Japanese females. We collected lateral cephalometric images of 30 females each from Okinawa Island and mainland Japan. Sixty landmarks were plotted on each image. Then, based on the coordinates of the landmarks, 68 distances and 34 angles were calculated according to orthodontic and anthropometric methods. We confirmed that the Ryukyuans have a smaller height in the upper and midfacial region than the mainland Japanese. Moreover, our findings indicate that, compared with the mainland Japanese females, the Ryukyuan females clearly have the following features: (1) a shallower mandibular notch, (2) an anterior-inclined symphysis of mandible, and (3) a smaller depth from upper lip to incisors. We also found that an anterior-inclined mandibular corpus and incisors are associated with a smaller distance between the surfaces of the upper lip and teeth and with a more protruded lip shape

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Renal cell carcinoma(RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival

RURAL-URBAN DIFFERENCES IN THE UTILIZATION AND AMELIORATIVE EFFECTS OF WELFARE PROGRAMS

At a time when welfare policy analysts are preoccupied with the problem of welfare dependency, this paper refocuses attention on the ability of welfare (AFDC and general assistance) to reduce poverty among families, by highlighting and explaining rural-urban differences in this ameliorative effect. Descriptive and multivariate methods are used to analyze data from the March 1987 Current Population Survey. Results show that despite comparatively high poverty rates in nonmetro areas, the nonmetro poor were much less likely than their urban counterparts t o receive welfare. Moreover, nonmetro welfare recipients received considerably less welfare income, on average, than metro recipients. Accordingly, the ameliorative effect of welfare was lowest in nonmetro areas and highest in central cities. Logistic regression analysis revealed that nonmetro poor families were less likely to receive welfare than those in metro areas because they were more likely to be working, older, childless, and headed by a married couple. Copyright 1988 by The Policy Studies Organization.