Summary Adenosine-to-inosine (A-to-I) RNA editing is a widespread post-transcriptional mechanism, but its genomic landscape and clinical relevance in cancer have not been investigated systematically. We characterized the global A-to-I RNA editing profiles of 6236 patient samples of 17 cancer types from The Cancer Genome Atlas and revealed a striking diversity of altered RNA-editing patterns in tumors relative to normal tissues. We identified an appreciable number of clinically relevant editing events, many of which are in noncoding regions. We experimentally demonstrated the effects of several cross-tumor nonsynonymous RNA editing events on cell viability and provide the evidence that RNA editing could selectively affect drug sensitivity. These results highlight RNA editing as an exciting theme for investigating cancer mechanisms, biomarkers and treatments.

SUMMARY Hippo signaling has been recognized as a key tumor suppressor pathway. Here, we perform a comprehensive molecular characterization of 19 Hippo core genes in 9,125 tumor samples across 33 cancer types using multidimensional “omic” data from The Cancer Genome Atlas. We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ. Hippo pathway activity is best characterized by a YAP/TAZ transcriptional target signature of 22 genes, which shows robust prognostic power across cancer types. Our elastic-net integrated modeling further reveals cancer-type-specific pathway regulators and associated cancer drivers. Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns. This study represents a systems-biology approach to characterizing key cancer signaling pathways in the post-genomic era.

SINE appears not to be rare after TEVAR for type B dissection and is associated with substantial mortality. The stress yielded by the endograft seems to play a predominant role in its occurrence. It is important to take this stress-induced injury into account during both design and placement of the endograft.

Background-Retrograde type A aortic dissection has been deemed a rare complication after endovascular stent graft placement for type B dissection. However, this life-threatening event appears to be underrecognized and is worth being investigated further. Methods and Results-Eleven of 443 patients developed retrograde type A aortic dissection during or after stent grafting for type B dissection from August 2000 to June 2007. Of these 11 patients, 3 had Marfan syndrome. The Kaplan-Meier estimate of the rate of freedom from this event at 36 months is 97.4% (95% confidence interval, 0.95 to 0.99). The new entry was located at the tip of the proximal bare spring of the stent graft in 9 patients, was within the anchoring area of the proximal bare spring in 1, and remained unknown in 1 patient. Eight patients were converted to open surgery, and 2 received medical treatment. One patient suddenly died 2 hours after the primary stent grafting, and 2 died within 1 week after the surgical conversion, so mortality reached 27.3%. During the follow-up from 3 to 50 months, type I endoleak was identified in 1 patient 3 months after the surgical exploration and disappeared at 6 months. Conclusions-Retrograde type A aortic dissection after stent grafting for type B dissection appears not to be rare and results from mixed causes. Fragility of the aortic wall and disease progression may predispose to it, whereas stent grafting-related factors make important and provocative contributions. Avoiding aortic arch stent grafting in Marfan patients, preferably selecting the endograft without the proximal bare spring for patients with a kinked aortic arch or with Marfan syndrome (if endografting is used), improving the device design, and standardizing endovascular manipulation might lessen its occurrence.

Adenosine (A) to inosine (I) RNA editing introduces many nucleotide changes in cancer transcriptomes. However, due to the complexity of post-transcriptional regulation, the contribution of RNA editing to proteomic diversity in human cancers remains unclear. Here, we performed an integrated analysis of TCGA genomic data and CPTAC proteomic data. Despite limited site diversity, we demonstrate that A-to-I RNA editing contributes to proteomic diversity in breast cancer through changes in amino acid sequences. We validate the presence of editing events at both RNA and protein levels. The edited COPA protein increases proliferation, migration, and invasion of cancer cells in vitro. Our study suggests an important contribution of A-to-I RNA editing to protein diversity in cancer and highlights its translational potential.

RNA editing, a widespread post-transcriptional mechanism, has emerged as a new player in cancer biology. Recent studies have reported key roles for individual miRNA editing events, but a comprehensive picture of miRNA editing in human cancers remains largely unexplored. Here, we systematically characterized the miRNA editing profiles of 8595 samples across 20 cancer types from miRNA sequencing data of The Cancer Genome Atlas and identified 19 adenosine-to-inosine (A-to-I) RNA editing hotspots. We independently validated 15 of them by perturbation experiments in several cancer cell lines. These miRNA editing events show extensive correlations with key clinical variables (e.g., tumor subtype, disease stage, and patient survival time) and other molecular drivers. Focusing on the RNA editing hotspot in miR-200b, a key tumor metastasis suppressor, we found that the miR-200b editing level correlates with patient prognosis opposite to the pattern observed for the wild-type miR-200b expression. We further experimentally showed that, in contrast to wild-type miRNA, the edited miR-200b can promote cell invasion and migration through its impaired ability to inhibit ZEB1/ZEB2 and acquired concomitant ability to repress new targets, including LIFR, a well-characterized metastasis suppressor. Our study highlights the importance of miRNA editing in gene regulation and suggests its potential as a biomarker for cancer prognosis and therapy.

BackgroundIntrahepatic cholangiocarcinoma (ICC) is a highly mortal malignancy with limited therapeutic options. Immunotherapies targeting PD-1/PD-L1 pathway represent a promising treatment for ICC. However, PD-L1 expression and microsatellite instability are not common in ICC. This study aimed to investigate whether HHLA2, a newly identified B7 family immune checkpoint for T cells, could be a therapeutic target next to PD-L1 in ICC.MethodsExpression levels of PD-L1 and HHLA2 as well as infiltrations of CD3+, CD8+, CD4 + Foxp3+, CD68+, CD163+ and CD20+ cells were evaluated by immunohistochemistry in 153 resected ICC samples. Comprehensive comparisons were made between PD-L1 and HHLA2 in terms of the expression rates, clinicopathological features and infiltrations of different immune cells. The expression level and prognostic significance of HHLA2 were further validated in an independent cohort.ResultsExpression of HHLA2 is more frequent than PD-L1 in ICC (49.0% vs 28.1%). Co-expression of both immune checkpoints was infrequent (13.1%) and 50% PD-L1 negative cases were with elevated HHLA2. HHLA2 overexpression was associated with sparser CD3+ tumor infiltrating lymphocytes (TILs), CD8+ TILs and a higher CD4 + Foxp3+/CD8+ TIL ratio, whereas PD-L1 expression was associated with prominent T cells and CD163+ tumor associated macrophages infiltrations. PD-L1 failed to stratify overall survival (OS) but HHLA2 was identified as an independent prognostic indicator for OS in two independent cohorts.ConclusionsCompared with PD-L1, HHLA2 is more prevalent and possesses more explicit prognostic significance, which confer the rationale for HHLA2 as a potential immunotherapeutic target next to PD-L1 for ICC patients.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0554-8) contains supplementary material, which is available to authorized users.

Long noncoding RNAs (lncRNAs) are involved in the pathology of colorectal cancer (CRC). Current efforts to eradicate CRC predominantly focused on targeting the proliferation of rapidly growing cancer epithelial cells. This is largely ineffective with resistance arising in most tumors after exposure to chemotherapy. Despite the long‐standing recognition of the crosstalk between carcinoma‐associated fibroblasts (CAFs) and cancer cells in the tumor microenvironment, how CAFs may contribute to drug resistance in neighboring cancer cells is not well characterized. Here, we show that lncRNA CCAL (colorectal cancer‐associated lncRNA) promotes oxaliplatin (Oxa) resistance of CRC cells. RNA‐ISH shows higher CCAL expressed in the tumor stroma compared to cancer nests of CRC tissues. Functional studies reveal that CCAL is transferred from CAFs to the cancer cells via exosomes, where it suppresses CRC cell apoptosis, confers chemoresistance and activates β‐catenin pathway in vitro and in vivo. Mechanistically, CCAL interacts directly with mRNA stabilizing protein HuR (human antigen R) to increase β‐catenin mRNA and protein levels. Our findings indicate that CCAL expressed by CAFs of the colorectal tumor stroma contributes to tumor chemoresistance and CCAL may serve as a potential therapeutic target for Oxa resistance.