Showing papers by "Carolyn J. Brown published in 2010"

Acquired TNFRSF14 Mutations in Follicular Lymphoma Are Associated with Worse Prognosis

Abstract: Clinical correlative studies have linked 1p36 deletions with worse prognosis in follicular lymphoma (FL). In this study, we sought to identify the critical gene(s) in this region that is responsible for conferring inferior prognosis. BAC array technology applied to 141 FL specimens detected a minimum region of deletion (MRD) of ∼97 kb within 1p36.32 in 20% of these cases. Frequent single-nucleotide polymorphism–detected copy-neutral loss of heterozygosity was also found in this region. Analysis of promoter CpGs in the MRD did not reveal differential patterns of DNA methylation in samples that differed in 1p36 status. Exon sequencing of MRD genes identified somatic alterations in the TNFRSF14 gene in 3 of 11 selected cases with matching normal DNA. An expanded cohort consisting of 251 specimens identified 46 cases (18.3%) with nonsynonymous mutations affecting TNFRSF14. Overall survival (OS) and disease-specific survival (DSS) were associated with the presence of TNFRSF14 mutation in patients whose overall treatment included rituximab. We further showed that inferior OS and DSS were most pronounced in patients whose lymphomas contained both TNFRSF14 mutations and 1p36 deletions after adjustment for the International Prognostic Index [hazard ratios of 3.65 (95% confidence interval, 1.35–9.878, P = 0.011) and 3.19 (95% confidence interval, 1.06–9.57, P = 0.039), respectively]. Our findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes. Cancer Res; 70(22); 9166–74. ©2010 AACR.

Identification of regulatory elements flanking human XIST reveals species differences

Abstract: The transcriptional silencing of one X chromosome in eutherians requires transcription of the long non-coding RNA gene, XIST. Many regulatory elements have been identified downstream of the mouse Xist gene, including the antisense Tsix gene. However, these elements do not show sequence conservation with humans, and the human TSIX gene shows critical differences from the mouse. Thus we have undertaken an unbiased identification of regulatory elements both downstream and upstream of the human XIST gene using DNase I hypersensitivity mapping. Downstream of XIST a single DNase I hypersensitive site was identified in a mouse undifferentiated ES cell line containing an integration of the human XIC region. This site was not observed in somatic cells. Upstream of XIST, the distance to the flanking JPX gene is expanded in humans relative to mice, and we observe a hypersensitive site 65 kb upstream of XIST, in addition to hypersensitive sites near the XIST promoter. This -65 region has bi-directional promoter activity and shows sequence conservation in non-rodent eutheria. The lack of regulatory elements corresponding to human TSIX lends further support to the argument that TSIX is not a regulator of XIST in humans. The upstream hypersensitive sites we identify show sequence conservation with other eutheria, but not with mice. Therefore the regulation of XIST seems to be different between mice and man, and regulatory sequences upstream of XIST may be important regulators of XIST in non-rodent eutheria instead of Tsix which is critical for Xist regulation in rodents.

Active chromatin marks are retained on X chromosomes lacking gene or repeat silencing despite XIST/Xist expression in somatic cell hybrids.

Abstract: Background X-chromosome inactivation occurs early in mammalian development and results in the inactive X chromosome acquiring numerous hallmarks of heterochromatin. While XIST is a key player in the inactivation process, the method of action of this ncRNA is yet to be determined.