SUMMARY Sarcomas are a broad family of mesenchymal malignancies exhibiting remarkable histologic diversity. We describe the multi-platform molecular landscape of 206 adult soft tissue sarcomas representing 6 major types. Along with novel insights into the biology of individual sarcoma types, we report three overarching findings: 1) unlike most epithelial malignancies, these sarcomas (excepting synovial sarcoma) are characterized predominantly by copy number changes, with low mutational loads and only a few genes (TP53, ATRX, RB1) highly recurrently mutated across sarcoma types, 2) within sarcoma types, genomic and regulomic diversity of driver pathways defines molecular subtypes associated with patient outcome, and 3) the immune microenvironment, inferred from DNA methylation and mRNA profiles, associates with outcome and may inform clinical trials of immune checkpoint inhibitors. Overall, this large-scale analysis reveals previously unappreciated sarcoma type-specific changes in copy number, methylation, RNA, and protein, providing insights into refining sarcoma therapy and relationships to other cancer types.

Conflicting reports regarding whether high tumor-associated neutrophils (TAN) are associated with outcomes in colorectal cancer (CRC) exist. Previous investigators have counted TAN using non-neutrophil-specific immunohistochemistry (IHC) stains. We examined whether TAN levels as determined by multi-field manual counting would predict prognosis. IRB approval was obtained and two pathologists, blinded to stage/outcome, counted TAN in 20 high power fields (HPF) per specimen. TAN score was defined as the mean of these counts. High TAN was defined as at or greater than the median score for that stage. Demographics, tumor characteristics, and overall survival (OS) were obtained from the records and examined for association with TAN score. IHC for arginase expression was performed in a subset of samples. 221 patients were included. Stage II patients with high TAN scores had an OS of 232 months as compared to those with low TAN (OS = 85 months, p = 0.03). The survival benefit persisted in multivariable analysis (HR 0.48, CI 0.25–0.91, p = 0.026) controlling for age and sex. Women had increased survival as compared to men, and there were no significant prognostic associations with TAN count in stage III/IV patients, although there were only 12 stage IV patients. Arginase staining did not provide additional information. Stage II colorectal cancer patients with high TAN live nearly 3 times longer than those with low TAN. Women with stage II disease and high TAN counts appear to be driving the survival benefit seen in the stage II patients and have increased overall survival in all stages.

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Pancreatic ductal adenocarcinoma (PDAC) is a poor prognosis cancer with an aggressive growth profile that is often diagnosed at late stage and that has few curative or therapeutic options. PDAC growth has been linked to alterations in the pancreas microbiome, which could include the presence of the fungus Malassezia. We used RNA-sequencing to compare 14 paired tumor and normal (tumor adjacent) pancreatic cancer samples and found Malassezia RNA in both the PDAC and normal tissues. Although the presence of Malassezia was not correlated with tumor growth, a set of immune- and inflammatory-related genes were up-regulated in the PDAC compared to the normal samples, suggesting that they are involved in tumor progression. Gene set enrichment analysis suggests that activation of the complement cascade pathway and inflammation could be involved in pro PDAC growth.

Background: GPR30 expression, a new estrogen receptor, has been previously associated with HER-2, tumor size and metastasis in invasive breast cancer (BC) but its role in paired normal (N), invasive (I), and metastatic (M), samples is unknown. We described GPR30 and HER-2 expression in a collection of paired N/I/M samples, derived from the same individual.Materials and Methods: GPR30 and HER-2 expression was assessed by immunohistochemistry (IHC) in tissue microarrays, containing paraffin-embedded cores from 100 patients diagnosed with invasive BC. N and M samples were also available from the same patient. GPR30 expression was evaluated by an H-score (Intensity (0, negative; 1+, weak; 2+, moderate; 3+, strong) x Percentage of stained epithelial cells). HER-2 expression was evaluated per standard criteria. Log rank tests and Wald tests were employed to assess the clinical impact of these molecular targets on patient outcome based on Kaplan-Meier Product estimator and Cox Proportional Hazard Regression.Results: GPR30 was expressed in 50%, 76%, and 72% of N, I and M, respectively, samples. HER-2 (3+) was found in 14% and 18% of I and M samples, respectively. GPR30 expression in I cases correlated with expression in M cases, and HER-2 expression in I but not M cases. GPR30 expression in M cases correlated with expression in HER-2 expression in M cases. HER-2 expression in I cases correlated with expression in M samples (P<0.05 for all comparisons). GPR30 and HER-2 expression were not associated with grade or stage (P>0.05). GPR30 expression in I or M samples was not associated with either overall survival (OS) or BC-specific survival (BCSS)(P>0.5). HER-2 expression was marginally associated with OS in I (P=0.06; Hazard Ratios (HR): 1.91; 95%CI: 0.956, 3.83) but not in M (P=0.23) cases. HER-2 was significantly associated with BCSS in I cases (P=0.03; HR: 2.39; 95%CI: 1.07, 5.32) and marginally in M (P=0.08) cases.Discussion: A previous study suggested that GPR30 expression predicted the development of metastasis. We found high GPR30 expression in both the primary and metastatic sample but the difference was not significant. While GPR30 expression was not associated with OS or BCSS, HER-2 expression was marginally associated with OS and significantly associated with BCSS in invasive cases. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4158.