Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer. Issue 3 (4th March 2017)

• Record Type: Journal Article
• Authors: Yang, Sujuan; Che, Sara P. Y.; Kurywchak, Paul; Tavormina, Jena L.; Gansmo, Liv B.; Correa de Sampaio, Pedro; Tachezy, Michael; Bockhorn, Maximilian; Gebauer, Florian; Haltom, Amanda R.; Melo, Sonia A.; LeBleu, Valerie S.; Kalluri, Raghu
• Is Part Of: Cancer biology & therapy. Volume 18:Issue 3(2017)
• Page Start: 158
• Page End: 165
• Publication Date: 2017-03-04
• Subjects: Circulating exosomal DNA -- digital PCR -- exosome -- KRAS -- liquid biopsy -- TP53 -- pancreatic cancer; 616.99406
• DOI: 10.1080/15384047.2017.1281499
• Languages: English
• ISSNs: 1538-4047

Abstract

ABSTRACT: Pancreatic cancer presents with a dismal mortality rate and is in urgent need of methods for early detection with potential for timely intervention. All living cells, including cancer cells, generate exosomes. We previously discovered double stranded genomic DNA in exosomes derived from the circulation of pancreatic cancer patients, which enabled the detection of prevalent mutations associated with the disease. Here, we report a proof-of-concept study that demonstrates the potential clinical utility of circulating exosomal DNA for identification of KRAS G 12 D and TP53 R 273 H mutations in patients with pancreas-associated pathologies, including pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP) and intraductal papillary mucinous neoplasm (IPMN), and in healthy human subjects. In 48 clinically annotated serum samples from PDAC patients, digital PCR analyses of exosomal DNA identified KRAS G 12 D mutation in 39.6% of cases, and TP53 R 273 H mutation in 4.2% of cases. KRAS G 12 D and TP53 R 273 H mutations were also detected in exosomal DNA from IPMN patients (2 out of 7 with KRAS G 12 D, one of which also co-presented with TP53 R 273 H mutation). Circulating exosomal DNA in 5 out of 9 CP patients enabled the detection of KRAS G 12 D mutation. In 114 healthy subject-derived circulating exosomal DNA, 2.6% presented with KRAS G 12 D mutation and none with TP53 R 273 H mutation. This study highlights the value of circulating exosomal DNA for a rapid, low-cost identification of cancer driving mutations. The identification of mutations in IPMN patients and healthy subjects suggests that liquid biopsies may allow potential assessment of cancer risk but with a cautionary note that detection of clinical cancer cannot be assumed.