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SUMMARY Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis.

SUMMARYFor the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases.

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Introduction: A new treatment method involving neoadjuvant chemoembolization of tumor vessels 5 days prior to surgery combined with intraoperative radiotherapy (IORT) followed by adjuvant chemotherapy was established for patients with resectable pancreatic cancer. The aim of the present study was to assess the safety and efficacy of this treatment scheme. Method: Records of 161 patients with resectable PDAC treated in Botkin Hospital between 2013e2017 were reviewed. In 49 cases was used perioperative chemoradiotherapy (PeriCRT). IORT was performed using Carl Zeiss Intrabeam PRS 500 system. After resection stage, a single dose of 20 Gy IORT boost was delivered using 50-kV x-rays to a depth of 1 mm from the applicator surface. Afterward a histological examination and electron microscopy of irradiated resection margin were performed. Results: All 161 patients with PDAC underwent gross total resection (R0) with lymphadenectomy D2. The estimated median survival was 338, 358, 372 and 337 days. Long-term survival was 70,2% (NACE), 75,1% (IORT), 80,7% (PeriCRT), 61,3% (control) for 3-year