Quantifying the genetic correlation between cancers can provide important insights into themechanisms driving cancer etiology. Using genome-wide association study summary sta-tistics across six... Show moreQuantifying the genetic correlation between cancers can provide important insights into themechanisms driving cancer etiology. Using genome-wide association study summary sta-tistics across six cancer types based on a total of 296,215 cases and 301,319 controls ofEuropean ancestry, here we estimate the pair-wise genetic correlations between breast,colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 otherdiseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg = 0.57, p = 4.6 × 10−8), breast and ovarian cancer (rg = 0.24, p = 7 × 10−5 ),breast and lung cancer (rg = 0.18, p =1.5 × 10−6) and breast and colorectal cancer (rg = 0.15,p = 1.1 × 10−4 ). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functionalenrichment analysis revealed a significant excess contribution of conserved and regulatoryregions to cancer heritability. Our comprehensive analysis of cross-cancer heritability sug-gests that solid tumors arising across tissues share in part a common germline genetic basis. Show less
Tiffon, C.E.; Adams, J.E.; Fits, L. van der; Wen, S.; Townsend, P.A.; Ganesan, A.; ... ; Packham, G. 2010
Background and purpose. Vorinostat and romidepsin are histone deacetylase inhibitors (HDI), approved for the treatment of cutaneous T-cell lymphoma (CTCL). However, the mechanism(s) by which these... Show moreBackground and purpose. Vorinostat and romidepsin are histone deacetylase inhibitors (HDI), approved for the treatment of cutaneous T-cell lymphoma (CTCL). However, the mechanism(s) by which these drugs exert their anti-cancer effects are not fully understood. Since CTCL is associated with immune dysregulation, we investigated whether these HDI modulated cytokine expression in CTCL cells. Experimental approach. CTCL cell lines and primary CTCL cells were treated in vitro with vorinostat or romidepsin, or with STAT3 pathway inhibitors. Cell cycle parameters and apoptosis were analysed by propidium iodide and annexin V/propidium iodide staining, respectively. Cytokine expression was analysed using Q-RT-PCR and ELISA assays. STAT3 expression/phosphorylation and transcriptional activity were analysed using immunoblotting and transfection/reporter assays, respectively. Key results. Vorinostat and romidepsin strongly downregulated expression of the immunosuppressive cytokine, interleukin (IL)-10, frequently overexpressed in CTCL, at both the RNA and protein level in CTCL cell lines and at the RNA level in primary CTCL cells Vorinostat and romidepsin also increased expression of IFNG RNA and decreased expression of IL-2 and IL-4, although to a lesser extent compared to IL-10. Transient exposure to vorinostat was sufficient to suppress IL-10 secretion but was not sufficient to irreversibly commit cells to undergo cell death. STAT3 pathway inhibitors decreased production of IL-10 and vorinostat/romidepsin partially decreased STAT3-dependent transcription without effects on STAT3 expression or phosphorylation. Conclusions and implications. These results demonstrate that HDI modulate cytokine expression in CTCL cells, potentially via effects on STAT3. Immunomodulation may contribute to the clinical activity of HDI in this disease. Show less
