S-phase kinase protein 2 is an attractive therapeutic target in a subset of diffuse large B-cell lymphoma

S-phase kinase protein 2 (SKP2), an F-box protein, targets cell-cycle regulators including cycle-dependent kinase inhibitor p27KiP1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancer cells and has been implicated in oncogenesis; however, its role in diffuse large B-cell lymphoma (DLBCL) has not been elucidated. Therefore, we investigated the role of SKP2 and its ubiquitin-proteasome pathway in a large series (301) of DLBCL patient samples and a panel of DLBCL cell lines. Using immunohistochemistry, SKP2 was detected in 41.6% of DLBCL tumours and was inversely associated with p27Kip1 protein level. The DLBCL subset with high SKP2 and low p27Kip1 showed a strong correlation with the proliferating index marker Ki-67 (p \u3c 0.0001) and also with the germinal centre phenotype (p = 0.0147). Treatment of DLBCL cell lines with bortezomib or expression of SKP2-specific siRNA causes down-regulation of SKP2 and accumulation of p27Kip1, leading to suppression of growth by inducing apoptosis. Furthermore, treatment of DLBCL cells with bortezomib causes apoptosis via involving the mitochondrial pathway and activation of caspases. Finally, treatment of DLBCL cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Altogether, these results suggest that SKP2 and the ubiquitin-proteasome pathway may be a potential target for therapeutic intervention in DLBCL

ICGC-ARGO precision medicine: familial matters in pancreatic cancer

The International Cancer Genome Consortium–Accelerating Research in Genomic Oncology (ICGC-ARGO)1 will analyse the tumours of more than 100 000 patients with cancer during the next 10 years in a standardised way, using high-quality multiomic and clinical data (in particular outcome and treatment information) to address outstanding questions that are vital to our quest to defeat cancer (ie, the delineation of markers of prognosis, therapeutic response, and resistance). ICGC-ARGO aims to deliver a million patient-years of precision oncology knowledge, by making data available to the research community in a rapid and responsible way, to accelerate research into the causes, and control, of cancer. Here, we present the first report of a series of precision medicine-informed cases discussed by tumour boards within ICGC-ARGO programmes: two sisters, diagnosed with pancreatic ductal adenocarcinoma 7 years apart, whose disease was characterised by an uncommon clinical course; the somatic and germline profiling of these two sisters informed treatment decisions and risk management for a third sister who was not diagnosed with pancreatic ductal adenocarcinoma, but with thyroid cancer and meningioma

Tissue Microarray: A rapidly evolving diagnostic and research tool

Tissue microarray is a recent innovation in the field of pathology. A microarray contains many small representative tissue samples from hundreds of different cases assembled on a single histologic slide, and therefore allows high throughput analysis of multiple specimens at the same time. Tissue microarrays are paraffin blocks produced by extracting cylindrical tissue cores from different paraffin donor blocks and re-embedding these into a single recipient (microarray) block at defined array coordinates. Using this technique, up to 1000 or more tissue samples can be arrayed into a single paraffin block. It can permit simultaneous analysis of molecular targets at the DNA, mRNA, and protein levels under identical, standardized conditions on a single glass slide, and also provide maximal preservation and use of limited and irreplaceable archival tissue samples. This versatile technique, in which data analysis is automated facilitates retrospective and prospective human tissue studies. It is a practical and effective tool for high-throughput molecular analysis of tissues that is helping to identify new diagnostic and prognostic markers and targets in human cancers, and has a range of potential applications in basic research, prognostic oncology and drug discovery. This article summarizes the technical aspects of tissue microarray construction and sectioning, advantages, application, and limitations

Multiple gene aberrations and breast cancer: lessons from super-responders

BACKGROUND: The presence of multiple molecular aberrations in patients with breast cancer may correlate with worse outcomes. CASE PRESENTATIONS: We performed in-depth molecular analysis of patients with estrogen receptor-positive, HER2-negative, hormone therapy-refractory breast cancer, who achieved partial or complete responses when treated with anastrozole and everolimus. Tumors were analyzed using a targeted next generation sequencing (NGS) assay in a Clinical Laboratory Improvement Amendments laboratory. Genomic libraries were captured for 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to high coverage. Patients received anastrozole (1 mg PO daily) and everolimus (5 or 10 mg PO daily). Thirty-two patients with breast cancer were treated on study and 5 (16 %) achieved a partial or complete response. Primary breast tissue was available for NGS testing in three of the responders (partial response with progression free survival of 11 and 14 months, respectively; complete response with progression free survival of 9+ months). The following molecular aberrations were observed: PTEN loss by immunohistochemistry, CCDN1 and FGFR1 amplifications, and PRKDC re-arrangement (NGS) (patient #1); PIK3CA and PIK3R1 mutations, and CCDN1, FGFR1, MYC amplifications (patient #2); TP53 mutation, CCNE1, IRS2 and MCL1 amplifications (patient #3). Some (but not all) of these aberrations converge on the PI3K/AKT/mTOR pathway, perhaps accounting for response. CONCLUSIONS: Patients with estrogen receptor-positive breast cancer can achieve significant responses on a combination of anastrozole and everolimus, even in the presence of multiple molecular aberrations. Further study of next generation sequencing-profiled tumors for convergence and resistance pathways is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1439-y) contains supplementary material, which is available to authorized users