No abstract

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.

No abstract

2553 Background: Spartalizumab and LAG525 are monoclonal antibodies targeting PD-1 and LAG-3, respectively. Dual blockade of PD-1 and LAG-3 has shown synergistic antitumor activity in preclinical models. Here we describe preliminary efficacy of spartalizumab + LAG525 across seven tumor types. Methods: Phase II, open-label, parallel-cohort study was conducted in pts with solid or hematologic malignances relapsed and/or refractory to standard-of-care therapies. Prior immunotherapy was prohibited. LAG525 (400 mg) and spartalizumab (300 mg) were dosed intravenously every 3 weeks. Primary endpoint was clinical benefit rate at 24 weeks (CBR24), assessed using a Bayesian hierarchical model-based futility analysis. Posterior probability that clinical benefit exceeds historical control (Pr) was estimated to determine futility at interim against prespecified thresholds. Results: As of January 7 2019, 76 pts received spartalizumab + LAG525; 72 pts were eligible for analysis (Table). The Pr cut-off for all arms was > 0.70. Hence, neuroendocrine tumors (NET), small cell lung cancer (SCLC) and diffuse large B-cell lymphoma (DLBCL) cohorts all met the expansion criteria with Pr of 0.971, 0.975 and 0.804 respectively. CBR24 were as follows; NET: 0.86, SCLC: 0.27, DLBCL: 0.43. Prostate, sarcoma and ovarian cohorts did not meet the expansion criterion (Pr > 0.70) but were not declared futile; enrollment was paused pending results of next analysis. Gastroesophageal (GE) cancer cohort was stopped for futility due to Pr (0.071) below the futility threshold. Conclusions: Spartalizumab and LAG525 showed promising activity in NET, SCLC and DLBCL that met expansion criteria. The GE cohort was declared futile. Remaining cohorts are paused pending further analysis. Clinical trial information: NCT03365791. [Table: see text]