The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

he Cancer Genome Atlas project identified 2 groups of endometrioid endometrial cancers (ECs) with high mutation frequency: an ultramutated group (7% of all tumors) that harbored mutations in the exonuclease domain of polymerase e (POLE), and a hypermutated group (28% of tumors) with microsatellite instability (MSI), the majority of which harbored MLH1 promoter methylation. 1 The ultramutated POLE group exhibited an extremely high mutation rate (232 × 10 −6 mutations/Mb) with a unique nucleotide change spectrum of increased C→A transversion frequency, whereas the hypermutated MSI group exhibited mutation rates of 18 × 10 −6 mutations/Mb with variable length of DNA microsatellites due to an underlying deficiency in mismatch DNA repair. [1][2][3] Mismatch DNA repair deficiency induces singlebase mismatches that lead to point mutations in coding regions of genes, as well as insertions or deletions that lead to frame-shift mutations.It has been suggested that hypermutated tumors may harbor more tumor-specific neoantigens and increased amounts of tumor-infiltrating lymphocytes (TILs). 3-7 Therefore, we assessed whether POLE and MSI ECs harbor more neoantigens and TILs than the comparatively hypomutated microsatellitestable (MSS) ECs. Methods Prediction of HLA Type and Neoantigen LoadInference of HLA type was performed using the POLY-SOLVER (polymorphic loci resolver) tool. 5 For prediction of neoantigen load, the Sage Bionetworks' Synapse resource (https://www.synapse.org and Lawrence et al 8 ) and the Net-MHCpan tool (version 2.4) 9 were used (eMethods in the Supplement).IMPORTANCE Immune checkpoint inhibitor therapy has shown benefit in various cancers, but their potential in endometrial cancer (EC) is unknown.OBSERVATIONS Prediction of neoantigen load was performed using sequencing data from the Cancer Genome Atlas data set. Evaluation of tumor-infiltrating lymphocytes (TILs) and PD-1 and PD-L1 expression was performed in 63 patients with EC referred to our institution. The predicted median (range) neoantigen load (predicted neoepitopes per sample

SUMMARY PARP inhibitors have shown promising clinical activities for patients with BRCA mutations and are changing the landscape of ovarian cancer treatment. However, the therapeutic mechanisms of action for PARP inhibition in the interaction of tumors with the tumor microenvironment and the host immune system remain unclear. We find that PARP inhibition by olaparib triggers robust local and systemic antitumor immunity involving both adaptive and innate immune responses through a STING-dependent antitumor immune response in mice bearing Brca1-deficient ovarian tumors. This effect is further augmented when olaparib is combined with PD-1 blockade. Our findings thus provide a molecular mechanism underlying antitumor activity by PARP inhibition and lay a foundation to improve therapeutic outcome for cancer patients.