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Tumor protein p53 (TP53) is the most frequently mutated gene in cancer 1,2 . In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease 3,4 , rapid transformation to acute myeloid leukemia (AML) 5 , resistance to conventional therapies 6-8 and dismal outcomes 9 . Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations 10 . However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R) 11 . Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.

Plasmacytoid bladder cancer is an aggressive histologic variant with a high risk of disease-specific mortality. Using whole-exome and targeted sequencing, we find that truncating somatic alterations in the CDH1 gene occur in 84% of plasmacytoid carcinomas and are specific to this histologic variant. Consistent with the aggressive clinical behavior of plasmacytoid carcinomas, which frequently recur locally, CRISPR/Cas9-mediated knockout of CDH1 in bladder cancer cells enhanced cell migration.

Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyenet al, 2014; Uebelhoeret al, 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limayeet al, 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease., (Copyright © 2016, American Association for the Advancement of Science.)

Purpose: Vascular endothelial growth factor receptor (VEGFR2) directed therapies result in a modest survival benefit for patients with advanced esophageal and gastroesophageal (GE) junction cancer. Platelet-derived growth factor receptor (PDGFR) may contribute to escape from VEGFR2 inhibition. We evaluated the efficacy of sorafenib, a broad spectrum tyrosine kinase inhibitor targeting VEGFR2 and PDGFR as well as RET and RAF1, in patients with metastatic chemotherapy refractory esophageal and GE junction cancer., Patients and Methods: This phase II trial of sorafenib 400 mg twice daily enrolled chemotherapy refractory patients with metastatic esophageal and GE junction cancer with primary endpoint of progression-free survival (PFS) rate at two months. Secondary endpoints included overall survival, objective response rate and toxicity., Results: Among 34 patients, 8 week Kaplan-Meier estimated PFS was 61% (90%CI 45 to 73%). Median PFS is 3.6 months (95% CI 1.8 to 3.9 months), with median overall survival OS 9.7 months (95% CI 5.9 to 11.6 months). Grade 3 toxicities were uncommon and included hand foot skin reaction, rash, dehydration and fatigue. One patient (3%) with ongoing complete response and remains on trial for over 5 years. Whole exome sequencing of this tumor revealed mutations in many cancer-associated genes including ARID1A, PIK3CA, and TP53, and focal amplifications of HMGA2 and MET., Conclusion: Sorafenib therapy results in disease stabilization and encouraging PFS in patients with refractory esophageal and GE junction cancer., Trial Registration: ClinicalTrials.gov NCT00917462.

Background: Malignant transformation requires the interaction of cancer cells with their microenvironment, including infiltrating leukocytes. However, somatic mutational studies have focused on alterations in cancer cells, assuming that the microenvironment is genetically normal. Because we hypothesized that this might not be a valid assumption, we performed exome sequencing and targeted sequencing to investigate for the presence of pathogenic mutations in tumor-associated leukocytes in breast cancers., Methods: We used targeted sequencing and exome sequencing to evaluate the presence of mutations in sorted tumor-infiltrating CD45-positive cells from primary untreated breast cancers. We used high-depth sequencing to determine the presence/absence of the mutations we identified in breast cancer-infiltrating leukocytes in purified tumor cells and in circulating blood cells., Results: Capture-based sequencing of 15 paired tumor-infiltrating leukocytes and matched germline DNA identified variants in known cancer genes in all 15 primary breast cancer patients in our cohort. We validated the presence of mutations identified by targeted sequencing in infiltrating leukocytes through orthogonal exome sequencing. Ten patients harbored alterations previously reported as somatically acquired variants, including in known leukemia genes ( DNTM3A , TET2 , and BCOR) . One of the mutations observed in the tumor-infiltrating leukocytes was also detected in the circulating leukocytes of the same patients at a lower allele frequency than observed in the tumor-infiltrating cells., Conclusions: Here we show that somatic mutations, including mutations in known cancer genes, are present in the leukocytes infiltrating a subset of primary breast cancers. This observation allows for the possibility that the cancer cells interact with mutant infiltrating leukocytes, which has many potential clinical implications., Competing Interests: The authors declare no conflict of interest.

Background: The high mortality rate associated with epithelial ovarian carcinoma (EOC) reflects diagnosis commonly at an advanced stage, but improved early detection is hindered by uncertainty as to the histologic origin and early natural history of this malignancy., Methodology/principal Findings: Here we report combined molecular genetic and morphologic analyses of normal human ovarian tissues and early stage cancers, from both BRCA mutation carriers and the general population, indicating that EOCs frequently arise from dysplastic precursor lesions within epithelial inclusion cysts. In pathologically normal ovaries, molecular evidence of oncogenic stress was observed specifically within epithelial inclusion cysts. To further explore potential very early events in ovarian tumorigenesis, ovarian tissues from women not known to be at high risk for ovarian cancer were subjected to laser catapult microdissection and gene expression profiling. These studies revealed a quasi-neoplastic expression signature in benign ovarian cystic inclusion epithelium compared to surface epithelium, specifically with respect to genes affecting signal transduction, cell cycle control, and mitotic spindle formation. Consistent with this gene expression profile, a significantly higher cell proliferation index (increased cell proliferation and decreased apoptosis) was observed in histopathologically normal ovarian cystic compared to surface epithelium. Furthermore, aneuploidy was frequently identified in normal ovarian cystic epithelium but not in surface epithelium., Conclusions/significance: Together, these data indicate that EOC frequently arises in ovarian cystic inclusions, is preceded by an identifiable dysplastic precursor lesion, and that increased cell proliferation, decreased apoptosis, and aneuploidy are likely to represent very early aberrations in ovarian tumorigenesis.

Objective: It is widely recognized that racial disparity in survival exists between African-American and Caucasian women with endometrial cancer (EC). Differential mutation frequencies in select genes have been postulated to explain these survival differences. The purpose of this study was to test the hypothesis that African-American women with EC have a distinct gene expression profile compared to Caucasian women with EC., Methods: Microarray-based expression profiling using the Affymetrix U133A oligonucleotide array was performed on a series of ECs from African-American (n = 14) and Caucasian (n = 25). The two groups were matched for possible confounding variables including stage, histologic grade, and subtype. A model-based class comparison analysis was performed to generate a list of differentially expressed genes using a P value of <0.001., Results: The class comparison analysis of genes differentially expressed by tumors from the two groups revealed 16 genes differentially expressed at P < 0.001, which was not statistically significant (P = 0.68). In addition, hierarchical clustering analysis did not segregate these tumors into two distinct groups based on race., Conclusion: These data indicate that there is no discernible difference in global gene expression profiles of ECs from African-American and Caucasian women. Thus, racial disparities in clinical outcomes are unlikely to reflect differences in gene expression and may instead be attributable to other epidemiologic, clinical, or pathologic factors.

Purpose: Endometrial cancers classified as "intermediate risk" based on clinical and/or pathologic features are associated with a 15% to 20% risk of recurrence. Here, we test whether global gene expression profiling can distinguish intermediate-risk tumors into high-risk and low-risk subgroups., Experimental Design: Tumor specimens were obtained from 75 intermediate-risk endometrial cancer patients, 13 who had recurred and 62 who had not recurred with a median follow-up of 24 months. Gene expression profiles were obtained using the Affymetrix U133A GeneChip oligonucleotide microarray. The genes most associated with risk of recurrence were used to create a risk score using a leave-one-out cross-validation method and the univariate Cox proportional hazards regression model. Time to recurrence curves for the high-risk and low-risk subgroups were estimated using the Kaplan-Meier method, and the difference in time to recurrence between these two subgroups was tested using the log-rank test., Results: There was a significant difference in time to recurrence between high-risk and low-risk patients using risk scores as defined above (P = 0.04). The estimated hazard ratio (95% confidence interval) was 3.07 (1.00-9.43)., Conclusions: Patients with intermediate-risk endometrial cancers identified as high-risk for recurrence according to a gene expression-based risk score have a significantly increased risk for recurrence compared with those classified as low risk. These findings suggest that gene expression profiling can potentially contribute to the clinical classification and management of intermediate-risk endometrial cancers.

Objective: Endometrial cancers associated with tamoxifen exposure potentially represent a unique resource for investigating the molecular mechanisms of estrogen-induced tumorigenesis. The purpose of this study was to test the hypothesis that tamoxifen-associated endometrial carcinomas have a distinct gene expression profile compared to matched cases not associated with this exposure., Methods: Microarray-based expression profiling was performed on a series of tamoxifen-associated (N = 10) and matched sporadic cases (N = 29) of endometrial carcinoma., Results: Supervised class comparison revealed no statistically significant difference between the two groups (P = 0.48). However, unsupervised hierarchical clustering of the entire sample of tumors revealed two groups with extremely diverse molecular profiles that were independent of tamoxifen exposure. Of recognized clinicopathological factors, histologic grade correlated best with these two molecular classes., Conclusions: These data suggest that the molecular profile of tamoxifen-associated endometrial cancers is not different from that of endometrial carcinomas generally, and further, that there exist two highly distinct molecular subtypes of endometrial carcinoma.