The optimal treatment of patients with cancer depends on establishing accurate diagnoses by using a complex combination of clinical and histopathological data. In some instances, this task is difficult or impossible because of atypical clinical presentation or histopathology. To determine whether the diagnosis of multiple common adult malignancies could be achieved purely by molecular classification, we subjected 218 tumor samples, spanning 14 common tumor types, and 90 normal tissue samples to oligonucleotide microarray gene expression analysis. The expression levels of 16,063 genes and expressed sequence tags were used to evaluate the accuracy of a multiclass classifier based on a support vector machine algorithm. Overall classification accuracy was 78%, far exceeding the accuracy of random classification (9%). Poorly differentiated cancers resulted in low-confidence predictions and could not be accurately classified according to their tissue of origin, indicating that they are molecularly distinct entities with dramatically different gene expression patterns compared with their well differentiated counterparts. Taken together, these results demonstrate the feasibility of accurate, multiclass molecular cancer classification and suggest a strategy for future clinical implementation of molecular cancer diagnostics.

The androgen-signaling pathway is critical to the development and progression of prostate cancer and androgen ablation is a mainstay of therapy for this disease. We performed a genome-wide expression analysis of human prostate cancer during androgen ablation therapy to identify genes regulated by androgen and genes differentially expressed after the development of resistance. Six hundred and fifty-four of 63,175 probe sets detected significant expression changes after 3 months of treatment with goserelin and flutamide. This included 149 genes that were also differentially expressed 36 hours after androgen withdrawal in LNCaP cells. These genes reflect the physiological changes that occur in treated tumors and include potential direct targets of the androgen receptor. Expression profiles of androgen ablation-resistant tumors demonstrated that many of the gene expression changes detected during therapy were no longer present suggesting a reactivation of the androgen response pathway in the absence of exogenous hormone. Therapy resistance was associated with differential expression of a unique set of genes that reflect potential mechanisms of reactivation. Specifically an up-regulation of the androgen receptor and key enzymes for steroid biosynthesis suggest that resistant tumors have increased sensitivity to and endogenous synthesis of androgenic hormones. The specific pathways of reactivation provide opportunities for classification of resistant tumors and targeted therapies.

Human polyomaviruses are ubiquitous, with primary infections that typically occur during childhood and subsequent latency that may last a lifetime. Polyomavirus-mediated disease has been described in immunocompromised patients; its relationship to oncogenesis is poorly understood. We present deep sequencing data from a high-grade BK virus-associated tumor expressing large T antigen. The carcinoma arose in a kidney allograft 6 years after transplantation. We identified a novel genotype 1a BK polyomavirus, called Chapel Hill BK polyomavirus 2 (CH-2), that was integrated into the BRE gene in chromosome 2 of tumor cells. At the chromosomal integration site, viral break points were found, disrupting late BK gene sequences encoding capsid proteins VP1 and VP2/3. Immunohistochemistry and in situ hybridization studies demonstrated that the integrated BK virus was replication incompetent. We propose that the BK virus CH-2 was integrated into the human genome as a concatemer, resulting in alterations of feedback loops and overexpression of large T antigen. Collectively, these findings support the emerging understanding that viral integration is a nearly ubiquitous feature in polyomavirus-associated malignancy and that unregulated large T antigen expression drives a proliferative state that is conducive to oncogenesis. Based on the current observations, we present an updated model of polyomavirus-mediated oncogenesis.

Significant changes in the criteria for chronic active antibody-mediated rejection (CAABMR) were made in the Banff 2013 classification. These modifications expanded the number of patients diagnosed with CAABMR, with undetermined clinical significance. We compared the 2007 and 2013 criteria for the composite end point of death-censored graft failure or doubling of serum creatinine in 123 patients meeting the criterion related to the morphologic evidence of chronic tissue injury. In all, 18% and 36% of the patients met the 2007 and 2013 criteria, respectively. For the criterion related to antibody interaction with endothelium, only 25% were positive based on the 2007 definition compared with 82% using the 2013 definition. Cox modeling revealed that a 2013 but not a 2007 diagnosis was associated with the composite end point (adjusted hazard ratio 2.5 [95% confidence interval (CI) 1.2-5.2] vs. 1.6 [95% CI 0.7-3.8], respectively). The 2013 criterion based on both the C4d score and the glomerulitis plus peritubular capillaritis score (g+ptc) was more strongly associated with the end point than the 2007 criterion based only on C4d; however, when dissected by component, only the C4d component was significant. The association with clinical outcomes improved with the 2013 criteria. This is related to the new C4d threshold but not to the g+ptc ≥2 component.