Abstract
We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with KRAS wild-type (KRASWT) tumors (4 of 17). These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor-mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with NRG1-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of KRASWT tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC.Significance: Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as NRG1 fusions as disease-driving events in KRASwt tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. Cancer Discov; 8(9); 1087-95. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality and is projected to become the second leading cause of cancer-related death in 2030 [1]
Seventeen patients ages 24 to 49 years who had been diagnosed with PDAC (Table 1) were included in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) precision oncology program [6]
In 5 additional patients, we found germline variants of uncertain significance in genes involved in DNA repair, including an in-frame deletion in NBN as well as missense variants in MSH2, PALLD, RAD50, FANCI, and WRN
Summary
Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related mortality and is projected to become the second leading cause of cancer-related death in 2030 [1]. Despite extensive efforts to molecularly characterize PDAC [4], a definition of therapeutically relevant subgroups based on somatic genetic alterations is missing, and stratified therapy is not established. More than 90% of PDAC cases harbor activating KRAS mutations that cannot be addressed therapeutically. Analysis of KRAS wild-type (KRASWT) tumors has revealed considerable genetic heterogeneity, including alterations of GNAS, BRAF, CTNNB1, and additional RAS pathway genes as potential oncogenic drivers [5]; the clinical relevance of these alterations remains unclear, and none of them represent an established therapeutic target in this entity. To address the unmet therapeutic need and understand the genetic landscape of PDAC in younger patients, we performed whole-exome/genome and transcriptome sequencing in a cohort of young patients enrolled in a genomics-guided precision oncology program
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