Tumor Transcriptome Sequencing Reveals Allelic Expression Imbalances Associated with Copy Number Alterations

Due to growing throughput and shrinking cost, massively parallel sequencing is rapidly becoming an attractive alternative to microarrays for the genome-wide study of gene expression and copy number alterations in primary tumors. The sequencing of transcripts (RNA-Seq) should offer several advantages over microarray-based methods, including the ability to detect somatic mutations and accurately measure allele-specific expression. To investigate these advantages we have applied a novel, strand-specific RNA-Seq method to tumors and matched normal tissue from three patients with oral squamous cell carcinomas. Additionally, to better understand the genomic determinants of the gene expression changes observed, we have sequenced the tumor and normal genomes of one of these patients. We demonstrate here that our RNA-Seq method accurately measures allelic imbalance and that measurement on the genome-wide scale yields novel insights into cancer etiology. As expected, the set of genes differentially expressed in the tumors is enriched for cell adhesion and differentiation functions, but, unexpectedly, the set of allelically imbalanced genes is also enriched for these same cancer-related functions. By comparing the transcriptomic perturbations observed in one patient to his underlying normal and tumor genomes, we find that allelic imbalance in the tumor is associated with copy number mutations and that copy number mutations are, in turn, strongly associated with changes in transcript abundance. These results support a model in which allele-specific deletions and duplications drive allele-specific changes in gene expression in the developing tumor

Birt-Hogg-Dube syndrome presenting as multiple oncocytic parotid tumors

<p>Abstract</p> <p>Mutations in <it>FLCN</it> cause Birt-Hogg-Dubé syndrome, an autosomal dominant disorder notable for development of cutaneous fibrofolliculomas or trichodiscomas, a variety of renal tumors, and spontaneous pneumothorax due to cystic lung changes. We present a woman referred for genetic evaluation due to bilateral parotid gland tumors, who was subsequently diagnosed with Birt-Hogg-Dubé syndrome.</p

Equal pay as a precondition of justice?

Equality is typically presumed to be an end of justice, however, in this chapter, we argue that it is better understood as a condition of justice. Our argument draws on the Just World Fallacy, the phenomenon of people mistakenly believing fortuitous patterns of reward or harm to be reflective of justice. This phenomenon can undermine relationships of equality even where differences in reward or harm are ostensibly deserved. If everyone received equal pay, then the propensity for people to defer to the more successful or derogate the less successful would be diminished, and thus there would be greater scope for people to enter into the sorts of relationships of equal respect and regard that just communities require