Summary The Cancer Genome Atlas (TCGA) project has analyzed mRNA expression, miRNA expression, promoter methylation, and DNA copy number in 489 high-grade serous ovarian adenocarcinomas (HGS-OvCa) and the DNA sequences of exons from coding genes in 316 of these tumors. These results show that HGS-OvCa is characterized by TP53 mutations in almost all tumors (96%); low prevalence but statistically recurrent somatic mutations in 9 additional genes including NF1, BRCA1, BRCA2, RB1, and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three miRNA subtypes, four promoter methylation subtypes, a transcriptional signature associated with survival duration and shed new light on the impact on survival of tumors with BRCA1/2 and CCNE1 aberrations. Pathway analyses suggested that homologous recombination is defective in about half of tumors, and that Notch and FOXM1 signaling are involved in serous ovarian cancer pathophysiology.

Human epidermal growth factor receptor 2 (HER2) amplification/overexpression is an effective therapeutic target in breast and gastric cancer. Although HER2 positivity has been reported in other malignancies, previous studies generally focused on one cancer type, making it challenging to compare HER2 positivity across studies/malignancies. Herein, we examined 37,992 patient samples for HER2 expression (+/− amplification) in a single laboratory. All 37,992 patients were tested by immunohistochemistry (IHC); 21,642 of them were also examined for HER2 amplification with either fluorescent in situ hybridization (FISH) (11,670 patients) or chromogenic in situ hybridization (CISH) (9,972 patients); 18,262 patients had tumors other than breast or gastric cancer. All tissues were analyzed in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Caris Life Sciences) at the request of referring physicians. HER2 protein overexpression was found in 2.7 % of samples. Over-expressed HER2 was detected predominantly in malignancies of epithelial origin; for cancers derived from mesenchyme, neuroendocrine tissue, central nervous system, and kidney, HER2 expression and amplification were remarkably rare or non-existent. Bladder carcinomas, gallbladder, extrahepatic cholangiocarcinomas, cervical, uterine, and testicular cancers showed HER2 positivity rates of 12.4, 9.8, 6.3, 3.9, 3.0, and 2.4 %, respectively. HER2 overexpression and/or amplification is frequently found across tumor types. These observations may have significant therapeutic implications in cancers not traditionally thought to benefit from anti-HER2 therapies.Electronic supplementary materialThe online version of this article (doi:10.1007/s10555-015-9552-6) contains supplementary material, which is available to authorized users.

PI3K pathway aberrations are among the most common in cancer. They do not segregate by classic cancer histologic characteristics. Patterns of biomarker coalterations involving HER2 and hormone receptors may be important for optimizing combination treatments across cancer types.

Background: Drug development in sarcoma has been hampered by the rarity and heterogeneity of the disease and lack of predictive biomarkers to therapies. We assessed protein expression and gene alterations in a large number of bone and soft tissue sarcomas in order to categorize the molecular alterations, identify predictive biomarkers and discover new therapeutic targets. Methods: Data from sarcoma specimens profiled for protein expression, gene amplification/translocation and DNA sequencing was reviewed. Results: 2539 sarcoma specimens of 22 subtypes were included. TOPO2A was the most overexpressed protein at 52.8%. There was overexpression or loss of other sarcoma relevant proteins such as SPARC, PTEN and MGMT. Approximately 50% of the sarcomas expressed PD-L1 by IHC and presented with PD-1+ TILs, notably the LMS, chondrosarcomas, liposarcomas and UPS. Gene amplification/rearrangement of ALK, cMYC, HER2, PIK3CA, TOPO2A and cMET was relatively uncommon. EGFR gene amplification occurred at a rate of 16.9%. DNA sequencing of 47 genes identified mutations in 47% of the samples. The most commonly mutated genes were TP53 (26.3%) and BRCA2 (17.6%). Overexpression of TOPO2A was associated with TP53 mutation (P = 0.0001). Conclusion: This data provides the landscape of alterations in sarcoma. Future clinical trials are needed to validate these targets.

Monoclonal antibodies that target the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) axis have antitumor activity against multiple cancers. The presence of sarcomatoid differentiation in renal cell carcinoma (RCC) is associated with resistance to targeted therapy and poor responses to interleukin-2 immunotherapy. Given the aggressive nature of RCC with sarcomatoid differentiation and the exclusion of sarcomatoid histology from metastatic RCC clinical trials, less is understood regarding selection of therapies. Here, we characterized the PD-1/PD-L1 axis in RCC with sarcomatoid differentiation. We directly compared two PD-L1 antibodies and found concordance of PD-L1 positivity in 89% of tested RCCs with sarcomatoid differentiation. Coexpression of PD-L1 on neoplastic cells and the presence of PD-1–positive tumor-infiltrating lymphocytes was identified in 50% (13/26) of RCCs with sarcomatoid differentiation. In contrast, only 1 of 29 clear cell RCCs (3%) had concurrent expression of PD-L1 and PD-1 (P=.002). Our study suggests that RCC with sarcomatoid differentiation may express PD-1/PD-L1 at a higher percentage than RCC without sarcomatoid differentiation and patients with these tumors may be good candidates for treatment with anti-PD-1/PD-L1 therapies.