Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

Abstract

SUMMARY We performed integrated genomic, transcriptomic and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1 and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1 and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

“…The recent characterization of the genomic landscape of PDAC [13,14,15,16,17,18] has spurred an increased interest in the development of targeted therapeutic approaches to tackle this disease. Given this dominance of KRAS mutations among the known driver lesions in PDAC, we provide a brief overview on the various approaches to therapeutically target oncogenic KRAS.…”

“…These large-scale sequencing efforts revealed that approximately 90% of PDAC cases harbor oncogenic KRAS mutations, which in the majority of the cases co-cluster with pathogenic TP53 mutations [18]. The importance of the KRAS-MAPK pathway in PDAC is further underlined by the observation that KRAS wild-type tumors frequently harbor mutations in additional RAS pathway members, as well as aberrations in GNAS , BRAF and CTNNB1 [18]. …”

“…While direct targeting of oncogenically mutated KRAS is still in its infancy [54,55], several approaches to indirectly target oncogenic KRAS, including combined CHK1/MAPKAP-K2 inhibition, CHK1 inhibition in combination with genotoxic chemotherapy, combined MEK/PI3K or combined MEK/SHP2 inhibition, have recently emerged and await clinical validation [60,61,62,64,65,66,68,71]. Second, a sizable fraction of PDAC cases harbor germline mutations in a number of DNA repair genes, particularly those involved in DSB repair [13,14,15,16,17,18,19,20,21,22,23]. Recent data derived from different in vitro systems and numerous in vivo models, including PDAC models, led to the characterization of various molecular vulnerabilities that are associated with defective HR-mediated DSB repair.…”

“…At present, this field is still in flux and it remains to be seen which tools and technologies will eventually prevail in the molecular diagnostic workup of PDAC patients. Since a number of HR genes are frequently mutated in sporadic and familial PDAC [13,14,15,16,17,18,19,20,21,22,23], PARP inhibitors including olaparib, talazoparib and rucaparib have been evaluated in the context of clinical trials (comprehensively reviewed in [83]). Particularly olaparib was evaluated in the context of a prospective, open-label, non-comparative multicenter phase II trial that enrolled individuals harboring germline BRCA1/2 mutations suffering from recurrent cancer [76].…”

“…Through the advent of next generation sequencing technology, we have gained an unprecedentedly fine-grained glimpse at the genomic underpinnings of PDAC [13,14,15,16,17,18]. These large-scale sequencing efforts revealed that approximately 90% of PDAC cases harbor oncogenic KRAS mutations, which in the majority of the cases co-cluster with pathogenic TP53 mutations [18].…”