No abstract

Copy number alterations (CNAs) can promote tumor progression by altering gene expression levels. Due to transcriptional adaptive mechanisms, however, CNAs do not always translate proportionally into altered expression levels. By reanalyzing >34,000 gene expression profiles, we reveal the degree of transcriptional adaptation to CNAs in a genome-wide fashion, which strongly associate with distinct biological processes. We then develop a platformindependent method-transcriptional adaptation to CNA profiling (TACNA profiling)-that extracts the transcriptional effects of CNAs from gene expression profiles without requiring paired CNA profiles. By applying TACNA profiling to >28,000 patient-derived tumor samples we define the landscape of transcriptional effects of CNAs. The utility of this landscape is demonstrated by the identification of four genes that are predicted to be involved in tumor immune evasion when transcriptionally affected by CNAs. In conclusion, we provide a novel tool to gain insight into how CNAs drive tumor behavior via altered expression levels.

There is no consensus on the preferred type of biliary reconstruction for patients undergoing orthotopic liver transplantation (OLT) for primary sclerosing cholangitis (PSC). The aim of this study was to compare long-term outcomes after OLT for PSC using either duct-to-duct anastomosis or Roux-en-Y hepaticojejunostomy for biliary reconstruction. In a consecutive series of 98 adult patients undergoing OLT for PSC, 45 underwent duct-to-duct reconstruction, and 53 underwent Roux-en-Y biliary reconstruction. The median follow-up was 8.2 years (interquartile range 5 3.9-14.5 years). The outcomes of the 2 groups were compared. There were no significant differences in patient demographics or general surgical variables between the groups. The overall patient and graft survival rates were similar for the 2 groups. The incidence of biliary strictures and biliary leakage within the first year after transplantation did not differ between the 2 groups. However, significantly more patients in the Roux-en-Y group suffered at least 1 episode of cholangitis within the first year (9% in the duct-to-duct group versus 25% in the Roux-en-Y group, P 5 0.04). In addition, Roux-en-Y reconstruction was associated with a significantly higher rate of late-onset (>1 year after transplantation) nonanastomotic biliary strictures (NAS) in comparison with duct-toduct reconstruction (24% versus 7% at 5 years and 30% versus 7% at 10 years, P 5 0.01). In conclusion, duct-to-duct biliary reconstruction in patients with PSC is associated with lower rates of posttransplant cholangitis and late-onset NAS in comparison with Roux-en-Y hepaticojejunostomy. If technically and anatomically feasible, duct-to-duct anastomosis can be performed safely in patients undergoing OLT for PSC.