The proteomic landscape of soft tissue sarcomas.

Soft tissue sarcomas (STS) are rare and diverse mesenchymal cancers with limited treatment options. Here we undertake comprehensive proteomic profiling of tumour specimens from 321 STS patients representing 11 histological subtypes. Within leiomyosarcomas, we identify three proteomic subtypes with distinct myogenesis and immune features, anatomical site distribution and survival outcomes. Characterisation of undifferentiated pleomorphic sarcomas and dedifferentiated liposarcomas with low infiltrating CD3 + T-lymphocyte levels nominates the complement cascade as a candidate immunotherapeutic target. Comparative analysis of proteomic and transcriptomic profiles highlights the proteomic-specific features for optimal risk stratification in angiosarcomas. Finally, we define functional signatures termed Sarcoma Proteomic Modules which transcend histological subtype classification and show that a vesicle transport protein signature is an independent prognostic factor for distant metastasis. Our study highlights the utility of proteomics for identifying molecular subgroups with implications for risk stratification and therapy selection and provides a rich resource for future sarcoma research.

Errors in prostate core biopsy diagnosis in an era of specialisation and double reporting.

AIM: To examine the effects of specialist reporting on error rates in prostate core biopsy diagnosis. METHOD: Biopsies were reported by eight specialist uropathologists over 3 years. New cancer diagnoses were double-reported and all biopsies were reviewed for the multidisciplinary team (MDT) meeting. Diagnostic alterations were recorded in supplementary reports and error rates were compared with a decade previously. RESULTS: 2600 biopsies were reported. 64.1% contained adenocarcinoma, a 19.7% increase. The false-positive error rate had reduced from 0.4% to 0.06%. The false-negative error rate had increased from 1.5% to 1.8%, but represented fewer absolute errors due to increased cancer incidence. CONCLUSIONS: Specialisation and double-reporting have reduced false-positive errors. MDT review of negative cores continues to identify a very low number of false-negative errors. Our data represents a 'gold standard' for prostate biopsy diagnostic error rates. Increased use of MRI-targeted biopsies may alter error rates and their future clinical significance.

Proteomic profiling of soft tissue sarcomas with SWATH mass spectrometry.

Soft tissue sarcomas (STS) are a group of rare and heterogeneous cancers. While large-scale genomic and epigenomic profiling of STS have been undertaken, proteomic analysis has thus far been limited. Here we utilise sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) for proteomic profiling of formalin fixed paraffin embedded (FFPE) specimens from a cohort of STS patients (n = 36) across four histological subtypes (leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma). We quantified 2951 proteins across all cases and show that there is a significant enrichment of gene sets associated with smooth muscle contraction in leiomyosarcoma, RNA splicing regulation in synovial sarcoma and leukocyte activation in undifferentiated pleomorphic sarcoma. We further identified a subgroup of STS cases that have a distinct expression profile in a panel of proteins, with worse survival outcomes when compared to the rest of the cohort. Our study highlights the value of comprehensive proteomic characterisation as a means to identify histotype-specific STS profiles that describe key biological pathways of clinical and therapeutic relevance; as well as for discovering new prognostic biomarkers in this group of rare and difficult-to-treat diseases.