Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction

Increasing expression of fascin in renal cell carcinoma associated with clinicopathological parameters of aggressiveness

Aim: To determine whether higher expression of fascin, an actin-bundling protein associated with motility, in conventional renal cell carcinoma (RCC) is associated with more advanced stages of the disease. Methods: Immunohistochemical analysis of fascin expression was performed in tissue microarrays of 108 RCCs including 55 clear cell RCCs (CRCCs), 39 CRCCs with granular cell differentiation (GRCCs), 8 CRCCs with sarcomatoid differentiation (SRCCs) and 6 metastatic RCCs. Results: The expression of fascin was undetectable in normal renal tubules of all control cases. However, among the 108 RCC cases, fascin immunoreactivity was seen on the cell membrane and cytoplasm. The average immunostaining score for fascin was 128/400 in grade I, 170/400 in grade II, 207/400 in grade III, and 323/400 in grade IV RCC. The average immunostaining score of fascin was 187/400 for stage T1, 205/400 for stage T2, 288/400 for stage T3, and 355/400 for stage T4 cases of RCCs. Higher fascin scores in RCC were significantly correlated with higher T and N stages and nuclear grade. In addition, the fascin scores in GRCC (368±19) and SRCC (263±21) were significantly higher than in CRCC 95±18). Conclusions: Our findings demonstrate for the first time that increased expression of fascin is associated with clinicopathological parameters of aggressiveness in patients with RCC. Fascin may be a novel biomarker for diagnosis and treatment of RCC

The clonal origin and clonal evolution of epithelial tumours

While the origin of tumours, whether from one cell or many, has been a source of fascination for experimental oncologists for some time, in recent years there has been a veritable explosion of information about the clonal architecture of tumours and their antecedents, stimulated, in the main, by the ready accessibility of new molecular techniques. While most of these new results have apparently confirmed the monoclonal origin of human epithelial (and other) tumours, there are a significant number of studies in which this conclusion just cannot be made. Moreover, analysis of many articles show that the potential impact of such considerations as patch size and clonal evolution on determinations of clonality have largely been ignored, with the result that a number of these studies are confounded. However, the clonal architecture of preneoplastic lesions provide some interesting insights — many lesions which might have been hitherto regarded as hyperplasias are apparently clonal in derivation. If this is indeed true, it calls into some question our hopeful corollary that a monoclonal origin presages a neoplastic habitus. Finally, it is clear, for many reasons, that methods of analysis which involve the disaggregation of tissues, albeit microdissected, are far from ideal and we should be putting more effort into techniques where the clonal architecture of normal tissues, preneoplastic and preinvasive lesions and their derivative tumours can be directly visualized in situ